Podcasts about r chop

Featuring slide presentations and related discussion from Prof Martin Hutchings, Dr Manali Kamdar, Dr Matthew Lunning and Prof Gilles Salles, including the following topics: Evolving Role of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Diffuse Large B-Cell Lymphoma (DLBCL) — Dr Kamdar (0:00) Case: A 61-year-old man with Stage IV non-GCB DLBCL receives R-CHOP but experiences disease progression 8 months later (30:39) Case: A 68-year-old man with double-hit DLBCL who experiences disease progression on chemotherapy and second-line CAR T-cell therapy receives glofitamab (39:22) Incorporation of Bispecific Antibody Therapy into DLBCL Management — Prof Hutchings (45:25) Case: A 42-year-old man with progressive DLBCL refractory to 2 lines of therapy receives glofitamab with a durable response (1:07:30) Case: An 81-year-old woman with multiregimen-refractory DLBCL experiences a prolonged response to epcoritamab (1:14:25) Case: A 69-year-old man with follicular lymphoma transformed to DLBCL and refractory to 3 lines of treatment receives glofitamab (1:21:48) Selection and Sequencing of Other Available Therapies for Relapsed/Refractory (R/R) DLBCL — Prof Salles (1:24:37) Case: An 82-year-old woman with follicular lymphoma transformed to DLBCL receives tafasitamab/lenalidomide (1:42:05) Case: A 69-year-old man with urinary bladder carcinoma and recurrent GCB DLBCL receives loncastuximab tesirine (1:46:26) Promising Investigational Approaches for Patients with R/R DLBCL — Dr Lunning (2:00:37) Case: An 80-year-old woman with multiregimen-refractory GCB DLBCL seeks treatment requiring minimal clinic visits and receives loncastuximab tesirine (2:15:59) Case: A 54-year-old man with primary refractory non-GCB DLBCL receives CAR T-cell therapy, and follow-up imaging on day 29 demonstrates a Deauville score of 4 (2:25:22) CME information and select publications

Leading into the ASH Annual Meeting, Dr. Kami Maddocks, professor in the Division of Hematology at The Ohio State University and medical director of infusion services at The James Comprehensive Cancer Center, provides an in-depth analysis of advancements in non-Hodgkin lymphoma care, with a focus on aggressive B-cell lymphoma. She explores the evolving roles of immunotherapies like CAR-T cells and bispecific antibodies in high-risk patient populations, discusses the impact of cell-of-origin testing on frontline treatment decisions, and evaluates the latest data guiding choices between R-CHOP, transplant, and CAR-T therapy after first relapse. Dr. Maddocks also highlights the promise of BTK inhibitors and maintenance approaches in transforming patient outcomes, offering insights into the future of lymphoma treatment. Check out Chadi's website for all Healthcare Unfiltered episodes and other content. www.chadinabhan.com/ Watch all Healthcare Unfiltered episodes on YouTube. www.youtube.com/channel/UCjiJPTpIJdIiukcq0UaMFsA

Featuring perspectives from Dr Christopher Flowers, Prof Grzegorz S Nowakowski and Dr Laurie H Sehn, moderated by Dr Flowers, including the following topics: Introduction (0:00) Front-Line Management of Diffuse Large B-Cell Lymphoma (DLBCL) — Dr Sehn (1:56) Case: A woman in her late 40s with epidural DLBCL and a compression fracture (Dr Flowers) (12:45) Case: A woman in her late teens with primary intestinal large B-cell lymphoma (Dr Nowakowski)(16:51) Integration of Novel Agents into the Care of Patients with Relapsed/Refractory DLBCL — Dr Flowers (21:14) Case: A man in his late 70s diagnosed with DLBCL with recurrent disease (Dr Nowakowski) (29:38) Case: A woman in her mid 70s with multiple comorbidities diagnosed with DLBCL (Dr Sehn) (36:17) Bispecific Antibody Therapy for DLBCL — Dr Nowakowski (39:39) Case: A man in his late 50s with no comorbidities with recurrent DLBCL (Dr Sehn) (50:50) Case: A patient in their mid 50s with DLBCL who experiences disease relapse after R-CHOP and CAR-T therapies (Dr Flowers) (54:34) CME information and select publications

CME credits: 0.50 Valid until: 30-05-2025 Claim your CME credit at https://reachmd.com/programs/cme/cd20-x-cd3-bispecificsredefining-treatment-for-patients-with-rr-dlbcllbcl-in-the-community-setting/17877/ In the rapidly evolving landscape of treating patients with relapsed or refractory large/diffuse large B-cell lymphoma (R/R LBCL/DLBCL), recent advancements are providing newfound hope. Immunochemotherapy with R-CHOP has long been the standard first-line treatment, but a significant portion of patients experience relapses and refractory disease. Until recently, salvage chemotherapy followed by autologous stem cell transplant (ASCT) was the only curative option. However, the introduction of novel therapies including T-cell engaging therapies has sparked a paradigm shift in R/R LBCL/DLBCL management. In this transforming landscape, bispecific antibodies (BsAbs) stand out as a remarkable addition. They offer readily available, "off-the-shelf" options that do not require a manufacturing process tailored to each patient, with the advantage of lower rates of severe side effects compared to CAR T-cell therapy, making them a promising choice, particularly for older patients and those with late-stage disease. This web-based, on-demand activity highlights key clinical trial evidence for bispecific antibodies targeting CD20 and CD3, and how to contextualize the rationale for and clinical utility of integrating CD20 X CD3 bispecific antibodies into community-based clinical practice. Expert faculty offer insights and advice based on their own real-world clinical practice experiences regarding the management and treatment of R/R DLBCL/LBCL and appropriate …=

In discussion with Dr. Mazyar Shadman from the Fred Hutch Cancer Center, covering the Chronic Lymphocytic Leukemia and Lymphoma key practice changing/informing abstracts from American Society of Hematology (ASH) 2023 conference from Community Oncology perspective. We covered 4 important practice informing studies with Dr. Shadman: - ALPINE: Ph 3, Extended Follow-up Confirms Sustained Superior PFS of Zanubrutinib vs Ibrutinib for Treatment of R/R Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma - SEQUOIA: Ph 3, Broad Superiority of Zanubrutinib Over BR Across Multiple High-Risk Factors: Biomarker Subgroup Analysis in the Treatment-Naive Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) without del(17p) - SWOG S1826: Nivolumab-AVD Is Better Tolerated and Improves PFS Compared to Bv-AVD in Older Patients (Aged ≥60 Years) with Advanced Stage Hodgkin Lymphoma - POLARIX Update: Deciphering the Clinical Benefit of Pola-R-CHP versus R-CHOP in Different Genetic Subtypes Beyond Cell of Origin in the POLARIX Study

On this episode of The HemOnc Pulse, guest Jonathan Friedberg, MD, MMSc, a hematologic oncologist at the University of Rochester Medicine – Wilmot Cancer Institute, chats with host Dr. Chadi Nabhan on the subtle but important shift in the treatment landscape of diffuse large B-cell lymphoma (DLBCL)in the post-POLARIX trial era. The POLARIX trial, which was designed to improve upon the standard R-CHOP regimen for DLBCL treatment, investigated the potential of polatuzumab vedotin. The phase III trial ultimately resulted in the US Food and Drug Administration approving the treatment in previously untreated DLBCL, not otherwise specified, or high-grade B-cell lymphoma. The approval is for patients with an International Prognostic Index (IPI) score of two or greater. "I think that this was a robustly done randomized placebo-controlled trial that showed a small but clinically significant benefit as far as progression-free survival in patients with IPI score of two and above [in] large B cell lymphoma," he said.

In this episode, CardioNerds co-founder Amit Goyal joins Dr. Iva Minga, Dr. Kevin Lee, and Dr. Juan Pablo Salazar Adum from the University of Chicago - Northshore in Evanston, IL to discuss a case of primary cardiac diffuse large B-cell lymphoma. The ECPR for this episode is provided by Dr. Amit Pursnani (Advanced Cardiac Imaging, Fellowship program director, NorthShore University HealthSystem). Audio editing by CardioNerds Academy Intern, Dr. Akiva Rosenzveig. Case synopsis: A 77-year-old man with no significant medical history presents to the emergency department with progressive shortness of breath for 1 week. He reports an unintentional 15-pound weight loss in the prior month as well as constipation and abdominal/flank pain. On examination he was found to be tachycardic with a regular rhythm and further evaluation with a chest X-ray and chest CT scan demonstrated a large pericardial effusion. This was further investigated with an urgent echocardiogram that revealed a large pericardial effusion with a large mass attached to the pericardial side of the RV free wall, as well as signs of early cardiac tamponade. A pericardiocentesis was performed and 550mL of bloody fluid was withdrawn. The fluid was sent for laboratory analysis and cytology. A cardiac MRI demonstrated a large invasive mass in the pericardium and RV wall consistent with cardiac lymphoma. Cytology confirmed diffuse large B-cell lymphoma. Subsequent CT and PET scans did not find any other site of malignancy, giving the patient a diagnosis of primary cardiac diffuse large B-cell lymphoma. The patient underwent R-CHOP chemotherapy and was followed closely with repeat cardiac MRI and PET scans which demonstrated resolution of the cardiac mass at his one-year surveillance follow-up. This case was published in US Cardiology Review, the official journal of CardioNerds. To learn more, access the case report article here. CardioNerds is collaborating with Radcliffe Cardiology and US Cardiology Review journal (USC) for a ‘call for cases', with the intention to co-publish high impact cardiovascular case reports, subject to double-blind peer review. Case Reports that are accepted in USC journal and published as the version of record (VOR), will also be indexed in Scopus and the Directory of Open Access Journals (DOAJ). CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls - A Mystery Mass in the Heart - Cardiac Lymphoma The most common cause of malignant cardiac masses is metastasis. Primary cardiac tumors are rare. Cardiac tumors are separated into 2 categories: benign and malignant. They are often differentiated based on their location and their degree of tissue invasion. Multimodality imaging is essential in the diagnosis, management, and surveillance of cardiac masses. A multidisciplinary team approach is invaluable for management of patients with cardiac tumors. Show Notes - A Mystery Mass in the Heart - Cardiac Lymphoma 1. What is the clinical presentation of cardiac masses? Cardiac masses can have a variable presentation. They can present with arrhythmias, angina, heart failure symptoms, or pericardial effusion. Patients can also be asymptomatic; the masses can be found incidentally on cardiac or chest imagining. 2. What is the differential diagnosis for cardiac masses? Cardiac masses are separated into benign and malignant. The most common malignant cardiac masses are metastases from a distant source. The location of the mass is important in narrowing the differential. 3. What imaging modalities are used to diagnose cardiac masses? Multimodality imaging is needed to describe the mass in detail and guide diagnosis. An echocardiogram is usually the first imaging modality. Cardiac MRI is a great modality that allows for the...

Featuring perspectives from Dr Ian W Flinn, including the following topics: Hodgkin Lymphoma Introduction (0:00) Case: A man in his late 30s with well-controlled HIV and newly diagnosed Stage IV classic Hodgkin lymphoma receives brentuximab vedotin with doxorubicin/vinblastine/dacarbazine (AVD) — Neil Morganstein, MD (2:30) Case: A man in his early 60s with classic Hodgkin lymphoma with a left lower lung mass and extensive regional lymphadenopathy receives brentuximab vedotin with AVD on the Phase III SWOG-S1826 trial — Ranju Gupta, MD (6:45) Mantle Cell Lymphoma (MCL) Case: A man in his late 50s with newly diagnosed MCL blastoid variant — Zanetta S Lamar, MD (16:27) Case: A man in his mid 50s with newly diagnosed Stage IV MCL — Shams Bufalino, MD (21:23) Follicular Lymphoma Case: A man in his mid 60s with incidental diagnosis of Grade IIIA follicular lymphoma after admission to the hospital for a stroke — Bhavana (Tina) Bhatnagar, DO (36:28) Case: A woman in her late 30s with extensive lymphadenopathy is diagnosed with Grade I/II follicular lymphoma and receives bendamustine/rituximab — Dr Morganstein (39:04) Diffuse Large B-Cell Lymphoma (DLBCL) Case: A physically independent man in his early 80s with DLBCL and multiple comorbidities, including cardiac issues and peripheral neuropathy, experiences disease progression after R-GCVP — Syed F Zafar MD (49:53) Case: A man in his mid 70s who presented with rapidly progressive proptosis of the left eye is diagnosed with DLBCL and receives R-CHOP and methotrexate CNS prophylaxis — Dr Lamar (55:21) CME information and select publications

Dr. John Sweetenham and Dr. Marc Braunstein discuss the role of maintenance therapy in high-risk multiple myeloma, advances in myelodysplastic syndromes in the COMMANDS study, the promise of bispecific antibodies in the pivotal EPCORE NHL-1 in relapsed/refractory large B-cell lymphoma, and improving outcomes for patients with chronic lymphocytic leukemia in the CAPTIVATE trial.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. My guest today is Dr. Marc Braunstein, a hematologist and oncologist at the NYU Perlmutter Cancer Center. Today, we'll be discussing key posters and oral abstracts highlighting advances in hematologic malignancies that will be featured at the 2023 ASCO Annual Meeting.   You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the ASCO Daily News Podcast are available on our transcripts at asco.org/DNpod.  Dr. John Sweetenham: So, Marc, thanks for returning to us and coming to join us on the podcast today. Dr. Marc Braunstein: Thanks for inviting me back. Dr. John Sweetenham: I'd like to start out with Abstract 8001. This is a study which is addressing the role of maintenance therapy in patients with high-risk multiple myeloma. Could you take us through this study and the key take-home points that you think are the most important ones? Dr. Marc Braunstein: Sure, absolutely. So, the first abstract that we're going to discuss is an oral abstract being presented by Dr. Nooka regarding maintenance therapy in high-risk multiple myeloma patients. Outcomes of patients with multiple myeloma are clearly improving, yet those with high-risk cytogenetic abnormalities, which represent about 10-20% of all multiple myeloma, tend to have poorer survival, and worst among these are those with what's called ultra-high-risk or double-hit multiple myeloma who have more than 1 high-risk cytogenetic abnormality. So, this study looked at maintenance therapy following stem cell transplantation in 26 high-risk patients, about 59% of whom had double hit disease, representing very high-risk disease. This was a phase II study looking at using carfilzomib, pomalidomide, and dexamethasone in high-risk multiple myeloma patients who achieved at least a partial remission following stem cell transplant. There were 26 patients enrolled. The median age was 60. Of note, about 59% of patients were Black, which is important because these patients tend to be historically underrepresented in studies. And what they found was that at study entry, about 24% of patients were in a complete remission or better, and that deepened to 79% while on the study. And the median time to best response was 2 months, which is fairly brisk. With a median follow-up of about 26 months, the 36-month progression-free survival was 63%, and the overall survival was 72%, which is impressive, again in the context of patients who have very high-risk disease. So, although it remains to be determined what the optimal regimen or duration of maintenance should be in multiple myeloma, clearly, combination therapy is effective and should be used in patients who have high-risk or ultra-high-risk multiple myeloma. Dr. John Sweetenham: Great. Thanks, Marc. So, as you say, I mean, clearly the take-home message is around the effectiveness of this type of maintenance therapy. I just have a couple of quick follow-up questions for you. The first of those is, where do you see this going next? I mean, in your opinion, what would be the next logical study with this combination or similar combinations? And then secondly, what do you see on the horizon for those patients with very high-risk myeloma, particularly the double-hit population that you just mentioned? Dr. Marc Braunstein: It's a paradigm in multiple myeloma that combination therapy tends to be more effective as long as we're able to manage the adverse events that come with additional combinations. And we've been able to succeed in that regard with quadruplet regimens, even now that we have monoclonal antibodies that tend to be better tolerated and more targeted in nature. In terms of maintenance therapy, single-agent lenalidomide has been the long-standing agent of use for the majority of patients. But we now understand that the combination of an immunomodulator like lenalidomide and a proteasome inhibitor like bortezomib or carfilzomib is more effective for patients with higher risk disease.   We also have data from various upfront studies of quadruplet regimens, such as the FORTE study, which looked at carfilzomib and lenalidomide maintenance after transplant that shows that we can improve progression-free survival in all comers with multiple myeloma following transplants. So, I think down the road we're going to be looking at more use of combination therapies and maintenance. And as far as for high-risk patients, whether that's going to be using monoclonal antibodies in maintenance or combination proteasome inhibitors and immunomodulators or even other immunotherapies like bispecific antibodies as maintenance in the future remains to be determined, but clearly, for high-risk patients, we should be using combination therapies. Dr. John Sweetenham: Thanks, Marc. Let's change gears a little now and take a look at Abstract 7003, which addresses patients with myelodysplastic syndrome. This study addresses the efficacy and safety results from a study of luspatercept versus epoetin alfa in low-risk myelodysplastic syndrome. I wonder if you could describe this study and the results to us and maybe also for the benefit of our listeners, just mention quickly the mechanism of action of the experimental agent here.  Dr. Marc Braunstein: This is an oral abstract being presented by Dr. Garcia-Manero looking at a phase 3 study, as you mentioned, called the COMMANDS study, and this is looking at an agent called luspatercept in patients with low-risk myelodysplastic syndrome (MDS). So, patients with MDS can have inferior quality of life and survival when they become transfusion dependent. An earlier study called the MEDALIST study, which was published in the New England Journal of Medicine in 2020, randomized low-risk or intermediate-risk patients with MDS who were refractory or unlikely to respond to erythropoietin stimulating agents to either luspatercept, which is an agent that binds to TGF-beta family members and helps stimulate erythropoiesis. Patients were randomized in the MEDALIST study to luspatercept or placebo. And that study showed that luspatercept could improve a degree of anemia and lead to transfusion independence in certain patients. So, the COMMANDS study is a randomized controlled study that randomized 354 patients with low-risk MDS who were transfusion dependent and naive to an erythropoietin stimulating agent to receive either luspatercept or the erythropoietin stimulating agent erythropoietin alfa with the primary endpoint of transfusion independence at some time between 12 to 24 weeks. So, patients were randomized 1:1 to receive either luspatercept or epoetin alfa, and the primary endpoint again was transfusion independence. So, 354 patients were randomized in the study and the median treatment durations were 42 weeks of luspatercept and 27 weeks of epoetin alfa. And transfusion independence occurred in greater quantity in the patients who got luspatercept. For example, in the patients who received luspatercept at 8 weeks, transfusion independence was achieved in 74 versus 51% in the epoetin alfa group. So, in terms of treatment-related adverse events, they were fairly similar between the groups and consistent with the classes -  they were reported in 30% in the luspatercept group and 17% in the erythropoietin group, with no difference in patients who progressed to acute myeloid leukemia.  So, I think when it comes to MDS in low-risk patients, it's really important to preserve their quality of life by limiting their transfusion burden. And I think this study demonstrates that luspatercept continues to be an important part of the management in these low-risk patients. And whether or not you would start a patient with low-risk transfusion-dependent MDS on an erythropoietin stimulating agent or luspatercept is really addressed by this study showing that you can achieve greater rates of improvement in anemia and transfusion independence with luspatercept.  Dr. John Sweetenham: Great. Thanks, Marc. A really interesting study. And I do have one question for you about this study, which I think will make it clear to you that I am an expert neither in myelodysplastic syndrome nor in erythropoiesis. But my question is based on the mechanism of action. Is there any rationale for combining these 2 agents in future studies?  Dr. Marc Braunstein: Yes, it would potentially make sense to use 2 synergistic mechanisms to improve erythropoiesis. We would have to see what the potential for adverse events are. I think epoetin alfa tends to be a fairly low burden in terms of its side effect profile. Luspatercept can have some potentially dose-limiting side effects, such as GI side effects, but you can make dose adjustments to both of these medications. So we may need to find the correct doses of either of them in combination. But from a theoretical standpoint, it makes sense that these could potentially be synergistic, especially in patients who are likely to respond to erythropoietin by having a baseline lower erythropoietin level. Dr. John Sweetenham: Okay, let's move on in another change of gear now. And for the rest of the podcast, we're going to be talking about some studies in lymphoid malignancy, beginning with Abstract 7535, which is a follow-up of the phase 2 CAPTIVATE study which now has significantly extended follow-up from the original report. So Marc, can you walk us through this study and the outcomes to date? Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Barr and it is looking at CLL, which is a field that is really moving away from chemotherapy for newly diagnosed patients, thanks to the development of novel targeted agents. The CLL14 trial, which was published in the New England Journal of Medicine in 2019, showed that fixed-duration venetoclax plus obinutuzumab improved progression-free survival and rates of negativity of minimal residual disease, or MRD, when compared to chlorambucil and obinutuzumab. So building on the success of that study, combining a monoclonal antibody and a BCL2 inhibitor, the CAPTIVATE study is a phase II study, which examines venetoclax with ibrutinib, the BTK inhibitor, and previously untreated CLL. So it's kind of combining 2of the novel targeted therapies in a fixed duration, similar to what was done in the CLL14 study where patients received 1 year of therapy and then stopped treatment.   So in the CAPTIVATE study, 154 patients were enrolled. This was a phase 2 study that included about 56% of higher-risk patients who had unmutated IGHV, and the median time on the study was 50 months, with a CR rate of 58% at a 4-year follow-up and an overall response rate of 96%, which is quite high, especially considering that more than half of patients had high-risk disease. The progression-free survival was 79% and the overall survival rate was 98% at 4 years. And when they looked at patients who had undetectable minimal residual disease, the 4-year overall survival rate was 100%, which also suggests that MRD can help serve as a predictive marker of longer-term survival. So I think we have to also consider what the side effects are of combining these 2 agents and the most common adverse events were hematologic, which is expected based on what we know about the 2 classes. So I think the implication of the study is that giving 2 oral agents for a fixed period of treatment for 12 cycles is a rational approach that may spare patients indefinite therapy and can lead to positive outcomes, including in patients who have high-risk features with CLL.  Dr. John Sweetenham: Yeah, the other interesting observation that was made in the abstract, which I found to be really encouraging, was the fact that a number of these patients apparently have been re-treated successfully upon progression with ibrutinib again, which seems to be somewhat reassuring as well.  Dr. Marc Braunstein: That's right. There were 4 patients who started re-treatment in the study and perhaps we'll see the outcomes of that small subgroup are at the poster presentation. But I think when we discuss fixed-duration treatment, it also opens the door to potentially re-challenging patients when they relapse. We know that when we stop single-agent BTK inhibitors, which are historically given indefinitely in patients with CLL, those patients who stop, many will relapse, but you can potentially re-challenge them with the BTK inhibitor. So this study with the CAPTIVATE trial gives us some liberty to discontinue therapy, but also considering re-challenging upon relapse.   Dr. John Sweetenham: Yeah, absolutely. Moving on to aggressive B-cell lymphoma, now, the next abstract I'd like to discuss with you is Abstract 7525. I find this one particularly interesting as the continued excitement around CAR T cell therapy for relapsed aggressive lymphoma remains high at the moment. It's intriguing that t cell-engaging antibodies also have been reported, at least, to have remarkable activity in this set of diseases. So can you take us through Abstract 7525 and what they're reporting?  Dr. Marc Braunstein: Absolutely. Bispecific antibodies represent an emerging field in multiple hematologic malignancies, and this is a class of antibodies that bind to both the tumor cell as well as T-cells, and activate T-cell immunity against the tumor cell. So epcoritamab is a bispecific antibody that binds to CD3, which is expressed on T cells, and CD20, which is expressed on B cells. And Thieblemont et al published results in the Journal of Clinical Oncology last year in a phase I/2 study that looked at epcoritamab in patients with diffuse large B cell lymphoma following 2 prior lines of therapy, and this was given subcutaneously until progression of disease. In that study, at a median follow-up of about 11 months, the overall response rate was 63% with 39% complete remissions.   So the EPCORE NHL-1 study, which is being presented at this year's ASCO meeting, is presenting the updated results of that study looking at patients with diffuse large B cell lymphoma that includes a small population as well of patients with high-grade B cell lymphomas and primary mediastinal B cell lymphomas who had at least 2 prior lines of therapy. In this presentation, 157 patients were included in this study, and 61% had primary refractory disease, and actually, 39% had prior CAR T-cell therapy, of whom 75% progressed within 6 months. So these were patients who were not only refractory to treatment but also had prior T-cell therapy.   So at a median follow-up of 20 months, the overall response rate was 63% and the complete response rate was again about 39%, and the median duration of complete remission was 21 months. In terms of overall survival, the median was about 19 months, which is substantial for this group of patients who really wouldn't be expected to respond very well to conventional therapies.   As we know, T-cell-engaging therapies, such as these bispecific antibodies or CAR T-cells have the potential risk for certain immune-related adverse events, including cytokine release syndrome or icons, and a neurologic syndrome related to the therapy. And it's worth noting that the CRS in this study was predominantly low-grade. There were only 3% of patients who had grade III CRS, and 9 patients, or 6% had grade I to II icons. I think that also reflects how we're better managing those side effects and intervening earlier. So I think the results are impressive from the standpoint of the population studied, who were quite refractory to treatment and show relatively high rates of response. In fact, the median overall survival was not reached in the overall population.   So I think what we take away from this abstract is that bispecific antibodies are going to play a vital role in the relapse-refractory setting for large cell lymphoma and may also offer an alternative to patients who aren't necessarily fit for CAR T-cell therapy, which plays a vital role in patients who are both refractory to first-line therapy or relapse-refractory to subsequent disease. So these are very encouraging results, and I'm sure we'll see randomized data as well in the future, further supporting the use of bispecific antibodies like epcoritamab.  Dr. John Sweetenham: Yeah, I agree. Thanks, Marc. I think that's a great summary. And it's particularly exciting to me that the investigators were able to achieve this kind of level of response and progression-free survival with a subcutaneous treatment. It's really quite remarkable and really exciting to see that.  We're going to wind up with our final abstract today, which is looking at the utilization of circulating tumor DNA in, again, in patients with aggressive B cell lymphoma. This is Abstract 7523, so maybe you could walk us through this one, Marc.  Dr. Marc Braunstein: Absolutely. So this is a poster being presented by Dr. Herrera looking at a, I guess you could call it a biomarker in the blood using circulating tumor DNA in patients with newly diagnosed diffuse large B cell lymphoma in the POLARIX study. So the results of the phase 3 POLARIX study were published last year in the New England Journal of Medicine and showed improvement in progression-free survival with the addition of these anti-CD79b antibody polatuzumab to standard R-CHOP chemotherapy compared to R-CHOP alone. And this study actually led to the approval of first-line treatment that includes polatuzumab.   In the abstract being presented by Dr. Herrera, the investigators looked at the value of circulating tumor DNA as a potential marker to serve as a guide for prognosis and predicting longer-term responses, particularly when the blood is cleared of circulating tumor DNA. So the study involved 654 patients who had ctDNA results both at baseline and then with longitudinal assessment, and they used an assay called the CAPP-Seq assay to assess circulating tumor DNA and assess for its clearance. In the study, undetectable circulating tumor DNA was achieved in 57% of patients who got the polatuzumab R-CHP combination and 59% of the patients who got R-CHOP by cycle 5 and then 6% in the polatuzumab group at 67% in the R-CHOP group.  So the rates of circulating tumor DNA clearance were similar between the 2 arms. But what's notable is that patients in the polatuzumab arm who achieved a complete response at the end of treatment plus cleared their circulating tumor DNA had superior progression-free and overall survival compared to patients who achieved a CR but retained circulating tumor DNA in their blood.   And this has implications because it might help gauge, for example, if patients may need additional cycles to clear the circulating tumor DNA, although we still need more data to answer whether that's necessary or not. And it may help serve as a predictive marker for longer-term remission, particularly in patients who perhaps have higher risk factors at baseline. So I don't think this is necessarily ready for primetime to use in clinical practice, but it is intriguing to know that we could finally have a tumor-specific biomarker in the blood to help monitor patients and potentially predict their longer-term remissions.  Dr. John Sweetenham: Thanks, Marc. I agree. Great summary, and obviously there's still something to learn about the kinetics of the response and so on. And also, I suppose it raises the question of whether those patients who still have detectable levels should be switched at the end of therapy to some kind of preemptive second-line therapy. And these are obviously all questions for the future, but it's going to be very interesting to watch this space, I think, and see how this story develops. Dr. Marc Braunstein: Absolutely. And my colleagues in the solid tumor space are already using circulating tumor DNA, for example, in colon cancer, to help with surveillance. So perhaps this could be a tool to use to predict relapse also in patients who are on surveillance after their treatment. But again, as you alluded to, we need more data to address that.  Dr. John Sweetenham: Well, thanks so much, Marc, for sharing your insights with us today on a really interesting set of abstracts coming up at the June meeting. And thanks for joining us on the ASCO Daily News Podcast. Dr. Marc Braunstein: Thank you for inviting me.  Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstracts discussed today in a transcript of this episode. Join us again after the annual meeting for key takeaways on the late-breaking abstracts and other key advances from the ASCO Annual Meeting. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. John Sweetenham Dr. Marc Braunstein @docbraunstein   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn  Disclosures: Dr. John Sweetenham:Consulting or Advisory Role: EMA Wellness Dr. Marc Braunstein:Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb/Celgene, Adaptive Biotechnologies, GlaxoSmithKline, ADC Therapeutics, Janssen Oncology, Abbvie, Guidepoint Global, Epizyme, Sanofi, CTI BioPharma Corp Speakers' Bureau: Janssen OncologyResearch Funding (Institution): Janssen, Celgene/BMS

CardioNerds (Amit and Dan) join Dr. Khaled Abdelrahman, Dr. Gurleen Kaur, and Dr. Danny Pipilas from the Brigham and Women's Hospital Residency Program for Italian food and cannolis at the North End in Boston as they discuss the case of an elderly man with primary cardiac lymphoma. They review an approach to intracardiac masses, discuss advantages and disadvantages of various imaging modalities for the evaluation of intracardiac masses, and also delve into anthracycline toxicity. The E-CPR segment is provided by Dr. Ron Blankstein, Associate Director of the Cardiovascular Imaging Program and Director of Cardiac Computed Tomography at Brigham and Women's Hospital. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig. A 76-year-old man with a history of hyperlipidemia presented with one month of progressively worsening fatigue, weight loss, and dyspnea on exertion. Physical exam was notable for a 3/6 systolic murmur at the left upper sternal border, a flopping sound along the sternum heard throughout the cardiac cycle, and JVP elevated to the level of the mandible. TTE revealed a large heterogeneous echodensity in the right ventricular (RV) free wall that extended into the pericardium and into the RV myocardium with mobile components in the RV cavity and obstruction of the RV outflow tract. Nongated CT chest showed a solid nodule in the periphery of the left lower lung lobe. Gated cardiac CTA revealed a large heterogenous mass in the right atrioventricular groove that encased the proximal thoracic aorta and pulmonary artery and invaded the RV myocardium and RV outflow tract along with a large pericardial effusion. On cardiac MRI, the mass was isointense to the myocardium on T1-weighted images, hyperintense on T2-weighted images, and had heterogenous enhancement on late gadolinium enhancement images. Overall, the imaging findings were highly suspicious for cardiac lymphoma which was confirmed with biopsy of the lung nodule; pathology showed a large B cell lymphoma. The patient was treated with R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), and TTE after 6 cycles of chemotherapy demonstrated resolution of the RV mass. CardioNerds is collaborating with Radcliffe Cardiology and US Cardiology Review journal (USC) for a ‘call for cases', with the intention to co-publish high impact cardiovascular case reports, subject to double-blind peer review. Case Reports that are accepted in USC journal and published as the version of record (VOR), will also be indexed in Scopus and the Directory of Open Access Journals (DOAJ). CardioNerds Case Reports PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Case Media 1.  There is a large homogeneous mass in the right atrioventricular groove that extends anterior to the right ventricular outflow tract, pulmonary artery, and ascending aorta, measuring up to 9.4 x 7.1 cm (axial) x 13 cm (craniocaudal). The mass encases the proximal thoracic aorta and pulmonary artery. The mass invades the right ventricular myocardium, the right ventricular outflow tract, the pulmonary artery, and proximal main pulmonary artery. There is severe stenosis of the right ventricular outflow tract due to obstruction by the mass. The mass encases the right coronary artery, without compression of the artery. There is enhancement of this mass on delayed contrast imaging. Collectively, these findings suggest cardiac lymphoma. 2.  There is a large pericardial effusion, circumferential, measuring up to 2.2 cm adjacent to the right atrium and up to 2.3 cm anterior to the intraventricular septum. There is pericardial enhancement, indicative of pericardial inflammation. 3.  This study was not optimized for the assessment of the coronary arteries. However,

In this episode, we discuss the management of newly diagnosed DLBCL with Dr. Pallawi Torka. We also have a few bonus ASH22 updates on DLBCL. Links to articles and abstracts discussed in the episode are as follows: 1. A comprehensive review article on DLBCL:https://pubmed.ncbi.nlm.nih.gov/33657296/ 2. RCT testing CHOP vs Three Intensive Regimens in DLBCL:https://www.nejm.org/doi/full/10.1056/nejm199304083281404  3. RCT testing R-CHOP vs CHOP in DLBCL in older adults:https://www.nejm.org/doi/full/10.1056/nejmoa011795  4. RCT testing R-CHOP vs CHOP in young (MINT):https://pubmed.ncbi.nlm.nih.gov/21940214/  5. PHOENIX trial: R-CHOP +/- Ibrutinib:https://pubmed.ncbi.nlm.nih.gov/30901302/ 6. R-CHOP +/- Lenalidomide (ECOG-ACRIN E1412):https://pubmed.ncbi.nlm.nih.gov/33555941/  7. R-CHOP vs Pola-R-CHP (POLARIX Trial):https://www.nejm.org/doi/full/10.1056/NEJMoa2115304 8. Comparison of 3 IPI scores in DLBCL:https://ashpublications.org/blood/article/135/23/2041/452696 9. RCT testing R-CHOP vs Dose-Adjusted R-EPOCH (CALGB 50303):https://ascopubs.org/doi/full/10.1200/JCO.18.01994 10. Timing of CNS Prophylaxis in DLBCL:https://pubmed.ncbi.nlm.nih.gov/34995350/ 11. RCT testing R-CHOP vs R-CHOP + Bortezomib (REMoDL-B):https://pubmed.ncbi.nlm.nih.gov/30948276/ 12. Interim PET in DLBCL? https://ashpublications.org/bloodadvances/article/5/9/2375/475850 13. RCTs in Limited Stage DLBCL: CHOP x 8 vs CHOP x 3 + XRT (S8736):https://ascopubs.org/doi/10.1200/JCO.2015.65.4582 CHOP x 4 + Rituximab x 6 vs R-CHOP x 6 (FLYER):https://pubmed.ncbi.nlm.nih.gov/31868632/ PET-adapted therapy with R-CHOP (S1001):https://pubmed.ncbi.nlm.nih.gov/32658627/ 14.   ASH 2022 updates:REMoDL-B update: https://ashpublications.org/blood/article/140/Supplement%201/1770/493225 Glofitamab update: https://ashpublications.org/blood/article/140/Supplement%201/1062/491024 Epcoritamab update: https://ashpublications.org/blood/article/140/Supplement%201/9443/488543

Dr. Aaron Goodman discusses treatment options for patients who relapse after R-CHOP first line treatment.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Christopher Flowers covers new research in non-Hodgkin lymphoma presented at the 2022 American Society of Hematology Annual Meeting, held December 10-13 in New Orleans, Louisiana. Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. View Dr. Flowers' disclosures at Cancer.Net. Dr. Flowers: Hello and welcome to this Cancer.Net podcast. I'm Dr. Christopher Flowers, professor and chair of the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center. And it's my great pleasure to talk to you today about updates in lymphoma from this year's American Society of Hematology meeting in December of 2022. I have a number of disclosures related to my work as a consultant for companies in the development of therapies for lymphoma. I will not talk about agents specifically related to those companies, but 2 companies that overlap with some of the areas that I'll talk about in bispecific antibodies includes Genentech, Roche, and Genmab, as well as research support from those companies for research that is performed at MD Anderson. So this year's American Society of Hematology meeting had a number of highlights. I was very fortunate to be the introducer for one of those key highlights, and that was the abstract presented at this year's plenary session. This was actually the first abstract presented in the plenary session where I introduced the abstract and set the context, and Dr. Martin Dreyling from the German group described the TRIANGLE study. So the TRIANGLE study was a randomized controlled clinical trial, meaning that the trial was performed in a randomized fashion to be able to test 3 particular strategies for patients with mantle cell lymphoma. Mantle cell lymphoma, as many of you may know, is a relatively uncommon form of non-Hodgkin lymphoma. It's a kind of lymphoma that can be quite aggressive, and particularly for younger patients who are suitable for aggressive therapy, the role of autologous stem cell transplantation has been something that's been important for the first-line therapy for mantle cell lymphoma. This study evaluated the use of a standard regimen of giving R-CHOP chemotherapy alternating with R-DHAP chemotherapy. So a chemotherapy regimen that includes Ara-C as their component followed by autologous stem cell transplantation. And it compared using that same regimen to giving it with ibrutinib added to the R-CHOP portion of the chemotherapy, followed by ibrutinib maintenance after the stem cell transplant or another experimental arm that added ibrutinib to the R-CHOP portion of the chemotherapy and gave 2 years of ibrutinib maintenance without stem cell transplantation. I think, importantly, this arm compared to each of those 2 experimental arms versus the standard of care and showed graphically that both of the arms that contained ibrutinib, the BTK inhibitor, looked to have improved failure-free survival compared to the standard stem cell transplant arm. Formal statistical tests were performed to compare the arm that included transplant plus ibrutinib showing that that was superior to transplant alone. And it remains to be seen whether that arm is superior to the arm that used ibrutinib alone. But those 2 arms look fairly similar in terms of their outcomes, and also the toxicity associated with the transplant obviously was substantially more than performing the therapy without transplant. This suggested perhaps autologous stem cell transplantation can be removed from frontline therapy for patients with aggressive mantle cell lymphoma and provides provocative data that may help to change practice, both in Europe and in the United States, as well as the rest of the world. A few other abstracts that were presented at this year's ASH meeting presented provocative data about ways to be able to improve the ways that we predict outcomes for patients. Matt Maurer presented the results of the Follicular Lymphoma International Prognostic Index 24, or the FLIPI24, as a risk factor to try and predict patients who might have early progression of disease with follicular lymphoma. One of the things that we know is that when you look at patients with follicular lymphoma, those patients who have progression of their disease within 24 months of the start of chemoimmunotherapy are patients that have markedly worse outcomes. And Dr. Maurer and our colleagues led an international study showing that a new prognostic factor model that included age, hemoglobin, white blood cell count, normalized lactate dehydrogenase, and beta-2-microglobulin, so all laboratory values that are connected within routine clinical practice, along with age, were a better predictor of this early progression of disease. This may serve as a useful model moving forward to help patients and their providers to understand who are the patients who are at higher risk of having aggressive behaving follicular lymphoma, and eventually, we can make strategies that help to address that for those patients. A second provocative model for using integrated genomics helps to identify patients who also have early progression of disease, and those are for patients with diffuse large B-cell lymphoma. This was presented by Kirsten Wenzel from the Mayo group, where Anne Novak was the senior author for this publication. What they did was they integrated the genomics into the clinical prognostic factors and found that there was a particular RNA-seq profile that helped to identify those patients who had early progression of disease with diffuse large B-cell lymphoma. They compared this approach to other prognostic models and suggested that these approaches may be able to improve upon the prediction of outcomes and be incorporated into the ways that we predict treatment strategies for patients with diffuse large B-cell lymphoma in the future. While these are still early on in their development, I think this holds promise for the future management of patients. And then the other class of agents that I'll mention from this year's ASH meeting are the bispecific antibodies. There were several abstracts that addressed this, both in patients with relapsing, refractory, diffuse large B-cell lymphoma, and in patient populations with relapsing refractory follicular lymphoma. One of those highlighted came from Nancy Bartlett, who discussed the role of a specific bispecific antibody for patients with relapsed follicular lymphoma. And I think these agents hold broad promise. So I appreciate your time and attention and hope you enjoyed this podcast and look forward to talking to you in the future about new developments in lymphomas broadly. ASCO: Thank you, Dr. Flowers. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Diffuse Large B-Cell Lymphoma or DLBCL is the most common type of lymphoma. Much progress has been made in treatment of the disease lately, particularly with emergence of CAR T-cell therapy, but not all patients are benefiting from it. This episode of Cancer Topics features Drs. Loretta Nastoupil and Chijioke Nze exploring treatment approaches for two cases of refractory DLBCL: a 60-year-old man with no comorbidities (1:30) and a 39-year-old woman with HIV (18:35). The guests also discuss improving patient access to CAR T-cell therapy and managing its toxicities (10:35), as well as emerging therapies for DLBCL (14:30). To learn more about management of refractory DLBCL, check out the ASCO course linked bellow. Guest Disclosures:Loretta Nastoupil, MD: Honoraria – Gilead Sciences, Novartis, Bayer, Janssen Oncology, TG Therapeutics, Bristol-Myers Squibb, ADC Therapeuitcs, Morphosys, Epizyme, Genmab, Takeda, Genentech/Roche; Research Funding – Janssen Biotech, Celgene, Genentech/Roche, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Chijioke Nze, MD, MPH: No Relationships to Disclose Resources: ASCO Course: Second-line Therapy for Relapsed/Refractory Diffuse Large B-cell Lymphoma (Free to Full and Allied ASCO Members) ASCO Podcast: Cancer Topics - New Therapies for Lymphoma (Part 1) ASCO Guideline: Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor (CAR) T-Cell Therapy ASCO Article: Navigating the Evolving Treatment Landscape of Diffuse Large B-Cell Lymphoma If you liked this episode, please follow the show. To explore other educational content, including courses, visit education.asco.org. Contact us at education@asco.org.  TRANSCRIPT The disclosures for guests on this podcast can be found in the show notes. Dr. Loretta Nastoupil: So, I do have optimism that as we have more and more treatment options entering into the treatment landscape, we'll have fewer patients that are experiencing a refractory disease, and potentially succumbing to the lymphoma. Hello, my name is Dr. Loretta Nastoupil, I'm an Associate Professor and Deputy Chair of the Department of Lymphoma and Myeloma, at the University of Texas MD Anderson Cancer Center. Welcome to this ASCO Education podcast episode. It's my pleasure to welcome Dr. Chijioke Nze. Dr. Chijioke Nze: Hello, everyone. I'm Dr. Chijioke Nze, a Hematology/Oncology fellow at MD Anderson, I'll be co-hosting this episode with Dr. Nastoupil. Dr. Loretta Nastoupil: We've seen notable advances in diffuse large B-cell lymphoma research lately, with novel treatments including CAR T-cell therapy, offering the prospect of long-term remission for some patients, yet many patients are not even receiving second-line or later therapy, and even fewer are treated beyond the second line. How do you approach a patient with refractory diffuse large B-cell lymphoma? In today's episode, we'll explore strategies for management of refractory diffuse large B-cell lymphoma through two patient cases. So, Dr. Nze, walk us through our first case. Dr. Chijioke Nze: Our first case is Frank. Frank is 60 years old and has no comorbidities. He presented with severe back pain in September 2021, and was evaluated locally. He had a CT scan that showed retroperitoneal mass, prompting further evaluation. He had a biopsy of the left retroperitoneal mass in November 2021, which was consistent with diffuse large B-cell, germinal center B-cell of phenotype Ki-67 of 90%. He had a subsequent PET-CT scan, which showed a large conglomerate, and invasive left retroperitoneal hypermetabolic mass with satellite nodularity and contiguous bulky retroperitoneal adenopathy. He had bulky, FDG-avid metastatic retrocrural and intrathoracic adenopathy as well. He was treated with R-CHOP for six cycles, and at the end, achieved complete remission. He had a PET-CT a year later that showed new and worsening intensely FDG-avid abdominal adenopathy. This was new from a PET scan he'd had in January 2022 of the same year. He had a biopsy of this retroperitoneal adenopathy, which was consistent with relapsed diffuse large B-cell germinal center phenotype, also Ki-67 of 90%. Locally, he was treated with ICE, times five cycles, and had a follow-up CT scan at the end, which showed persistent bulky nodal disease with periaortic regional nodes with double 5, consistent with persistent disease. He also was found to have new and more conspicuous nodes in other areas as well. He presented for his first visit at MD Anderson in September 2022. Dr. Nastoupil, when you see a patient like this coming into your clinic, what's your typical approach? Dr. Loretta Nastoupil: For a diffuse large B-cell lymphoma, we are always hoping for cure with frontline rituximab, containing anthracycline-based chemotherapy. And so, it's always a gross disappointment when patients experience relapse. The timing of that relapse right now informs our current approach. And the reason I mention that, is because there have been three large randomized studies conducted and reported out just in the last year demonstrating that CAR T-cell therapy is the preferred option for patients who experience either primary refractory disease, or relapse within 12 months. And that is because they resulted in better outcomes than standard salvage-based chemotherapy and high-dose therapy autotransplant in the setting of chemosensitive disease. I have to acknowledge, of the three studies that were done, two were positive trials, so that's why currently, we have axi-cel or Axicabtagene ciloleucel, or Lisocabtagene maraleucel, and not tisa-cel or Tisagenlecleucel, as CAR T-cell therapy options. And again, that's because two of the three studies were positive trials. Now, the challenge is why would we have two positive studies in one negative trial? There are a lot of caveats to how those studies were conducted, but I think one of the biggest important lessons to be gained is that if you're going to consider CAR T for these high-risk patients, you want to do it as soon as possible, because that delay from identifying CAR T as a preferred option to actually infusing cells in a disease-- in a case particularly like this, where patients may have bulky, aggressively-behaving disease - that prolonged time may actually have an impact on outcomes. Dr. Chijioke Nze: Excellent. Thank you. So, you've mentioned he had an early relapse. How would you define early relapse in this patient population? Dr. Loretta Nastoupil: Thinking back to how we've been approaching diffuse large B-cell lymphoma over the last two decades, the PARMA study, which was done prior to Rituximab, suggested that for patients who had chemosensitive disease to a platinum-based salvage chemotherapy, which generally, was at least a partial response on CT, if they went on to high-dose therapy autologous stem cell transplant, 50-60% of those patients could anticipate cure. Whereas for the folks who continued on salvage chemotherapy, 10-20% of those patients had favorable outcome. So, we generally do try salvage-based chemotherapy, and for patients with chemosensitive disease, go on to high-dose therapy autotransplant. However, in the modern era where we've approached patients who've had rituximab as part of their frontline therapy, at least two studies - the ORCHARD study, and the CORAL study suggested that only 20% of patients who relapse in the post-rituximab era, particularly within 12 months, were successfully salvaged with platinum-based chemotherapy and high-dose therapy autologous stem cell transplant. Now, fortunately for patients who fail salvage, we have had CAR T-cell therapy as an option based off of three pivotal phase II studies, demonstrating about 40% of patients could anticipate a cure with CAR T-cell therapy. So, it only made sense to try and move that therapy up into second line, and the preferred population was those that had progressed within 12 months of frontline rituximab and anthracycline-based chemo. Now, to qualify for those studies, patients had to be considered fit for the control arm, which was salvage and auto transplant. Nonetheless, I do think for a patient like this, who's 60, without any other significant comorbidities, whose biggest challenge to longevity of life is his aggressive lymphoma, CAR T-cell therapy should be considered as soon as possible for this patient. Dr. Chijioke Nze: Is there still a role for high-dose therapy and autologous transplant in the new era, given the efficacy shown with CAR T-cell therapy? Dr. Loretta Nastoupil: I think there is. And the reason why I say that is, the trials that were done really did focus on the highest-risk patients, which were those with primary refractory disease or those who progress within 12 months of frontline. Now, there are patients that will have later relapse. And so, I do think for those patients, particularly those who are young and otherwise fit, should be approached first with a platinum-based salvage chemotherapy, in the setting of chemosensitive disease, proceed onto high-dose therapy and autologous stem cell transplant. Now, what do we do for those patients who have a late relapse but are otherwise older, or who have comorbidities that would make them suboptimal candidates for the high-dose therapy preceding stem cell transplant? I have a couple other options for those patients - so, there was a trial done with liso-cel for patients who were otherwise older, or not fit for intensive therapy. It's a single-arm phase II without a randomized comparison, but also demonstrated that liso-cel in second-line, later relapsed patients who are not fit for intensive therapy, resulted in comparable outcomes to what we would anticipate on that third-line or later setting. We also have other non-CAR T-cell therapy options, such as tafasitamab, which is a naked CD19 antibody, which has been combined with lenalidomide in the L-MIND study, again, for patients without primary refractory disease and who would not be appropriate candidates for intensive therapy. So, I do think we have alternative options, it's just when we look at the totality of the data right now, my conclusion is that CAR T-cell therapy, particularly for high-risk patients, is the most likely chance to result in cure. Dr. Chijioke Nze: Excellent. In a patient who we are considering CAR T-cell therapy, what are some of the short-term and long-term consequences, or toxicities that we should worry about? Dr. Loretta Nastoupil: One of the challenges right now with CAR T, and why it's still only available in specialized centers, is the acute toxicity, which is really a derivative of its mechanism of action. We take patients' own T-cells, we use a viral vector to introduce extracellular receptor, but also a co-stimulatory molecule. So, once these cells engage their antigen, sort of prime to react to that, and that can lead to pretty rapid T-cell expansion, release of cytokines, recruitment of other inflammatory cells to that tumor bed, and as a result, a large portion of patients can anticipate to experience cytokine release syndrome, which again, is the result of the activation of these T-cells, the expansion and the recruitment of other inflammatory cells. Fortunately, for most patients, this results in fever alone that can be managed with supportive measures. Occasionally, they'll have concomitant hypoxia or hypotension, and unfortunately, few patients will have significant or severe toxicity. The other toxicity that's less easily manageable or less predictable is the neurotoxicity that can vary according to patient-specific characteristics, such as age, and the amount of tumor burden, their performance status going into CAR, but even more importantly, the construct that's utilized, with highest rates of neurotoxicity associated with axi-cel. Again, likely speaking to its construct and the CD28 costimulatory domain that is unique to axi-cel. As a result of these acute toxicities, patients are required to stay within two hours of their treating center for the first four weeks, and they're also discouraged from operating heavy machinery, such as driving, for the first eight weeks following CAR T. So, I do you think this creates some barriers to access to this therapy, particularly the patients that are treated in community settings that may reside long distances from these certified CAR centers. Dr. Chijioke Nze: So, you mentioned that obviously, given the specialized care needed for the CAR T therapy, that they're kind of localized in certain sites. What are some of these issues with access that you're noticing both in the logistics of giving CAR T, and also in patient access? Dr. Loretta Nastoupil: I'm hoping we're going to address one of those issues right now, which is, education and awareness, because we've had these three randomized studies, and two being positive readouts just in the last year. It's important to get the message out that CAR T-cell therapy for high-risk early relapsed refractory large cell lymphoma patients can result in a significant improvement in event-free survival and progression-free survival over the standard of care. And so, being aware that this therapy can result in more favorable outcomes is step one. Step two is, we have to ensure that there are minimal barriers to getting those patients into these treating centers as quickly as possible. So, recognizing who delivers the care - is it your traditional stem cell transplant physician? Is it a lymphoma doctor? What centers are certified? Some of these issues can be addressed with quick internet searches. So, for instance, in our center, we have a 1-800 number for anyone who's interested in CAR T-cell therapy that connects them directly to a CAR T coordinator who can help them understand do they meet the FDA-approved indication? Would they be interested in seeking consult? And we try and prioritize getting those patients in the door as soon as possible since time likely does have an impact on outcomes. And then, partnering with our community oncologist - you're going to be the primary oncologist for these patients leading up to CAR, and then after that four-week window, when we're keeping the patients in close proximity to our centers, we often send them back. And so, making sure that they're comfortable knowing what potential late toxicities to be on the lookout for, which include B-cell aplasia and risk for infection, or prolonged cytopenias, beyond just lymphopenia. And so again, there's a need for education and partnering with our community sites to make sure that there is successful handoff of these patients back after they've completed the monitoring for the acute toxicity. And then, really trying to explore opportunities to utilize some of the better tolerated CAR T, such as liso-cel, in your non-traditional academic centers. Those that are equipped to handle phase I studies or stem cell transplant, for instance, may not be affiliated with the university. So, I think those are all types of strategies that could be employed to try and improve access for patients. Dr. Chijioke Nze: And then, you mentioned the liso-cel, but in some of the toxicities, are there ways of predicting which patients will do better or worse? Are there ways to reduce toxicities? And is there any hope for things such as outpatient administration of CAR T? Dr. Loretta Nastoupil: So, my answer today may improve over time as we get larger numbers and more experience, but what we currently understand is that the patient performance status, their degree of tumor, how quickly that tumor is increasing, LDH and some inflammatory markers such as CRP or ferritin pretreatment can provide some insight into a higher risk of toxicity. And then obviously, the construct that's utilized. Again, axi-cel has higher rates of neurotoxicity. All will have some form of cytokine release syndrome, generally speaking, but rates of grade three or higher are quite infrequent, particularly with liso-cel and tisa-cel. So, it's multifactorial. That then raises the question, can we do anything to alter those modifiable risk factors? Can we reduce the disease burden? Can we improve the performance status? Can we do anything to reduce the inflammatory markers pre-treatment? And so, those are strategies that are being discussed, and I think in general, as we get more effective therapies that enter into the treatment landscape, it's probably some of the best ways to try and reduce some of those risk factors. Dr. Chijioke Nze: Rounding that up, are there any exciting developments or things to look out for, for exciting therapies in the relapse setting? Dr. Loretta Nastoupil: A couple of things beyond CAR T that I think we should all be aware of and anticipate to be in our toolkit relatively soon; probably, one of the most exciting, is the development of the bispecific antibodies. So, another challenge with CAR T is the requirement to collect these patients' own T-cells and send them off to a central manufacturing site, and the turnaround time can be anywhere from 3-4 weeks. And again, in a situation where you have an aggressive disease, that can be a long time to wait. And so, is there any treatments that are more readily available, that again, will be effective at reducing disease burden? And so, by specifics kind of fit those unmet needs to some extent - you have essentially two heads; one head is going to bind the endogenous T-cells that eliminates the need to leukapherese these patients and manufacture, and then the other head is going to generally engage CD20, which we know is an effective targeted antigen, particularly in B-cell lymphomas. And there are a number that are under development. We saw preliminary phase II data with glofitamab, epcoritamab, as well as combination strategies with mosunetuzumab. So, I do have optimism that the bispecific antibodies will potentially enter into the treatment landscape. I anticipate they'll probably be used first post-CAR T, but will likely move their way into earlier lines of therapy. I've already mentioned tafasitamab in combination with lenalidomide, which is an effective non-chemotherapy option. We have antibody-drug conjugates, such as Loncastuximab, which is a CD19 antibody-drug conjugate. It's essentially targeted delivery of chemotherapy, and it looks to have a pretty promising activity as a single agent in that third-line or later space, and then polatuzumab, which is a CD79b antibody drug conjugate, in the relapse setting has been combined with bendamustine and rituximab, but also demonstrated significant improvement in the frontline setting in the POLARIS study where vincristine was replaced with polatuzumab. So, I do have optimism that as we have more and more treatment options entering into the treatment landscape, we'll have fewer patients that are experiencing refractory disease, and potentially succumbing to the lymphoma. Dr. Chijioke Nze: And then, one additional question: How do you approach a patient who is not quite as fit, in thinking about what their options are for later-line therapies? You already mentioned some of these, but which of those would you prioritize in this setting? Dr. Loretta Nastoupil: Again, as we get more experience, we develop skills that help us sort of navigate all these different options. In my practice, if I'm even considering CAR T, I'm going to delay bendamustine until after I've collected those cells. I think that's one caveat that-- we do get nervous about the quality of those autologous CAR Ts if they're generated in someone who's had recent exposure to bendamustine. So, that may help me sequence that later on. We have questions right now about what's the optimal sequencing of CD19-directed therapy because we have several options beyond just CAR T-- As I mentioned, we have Lonca, we've got tafasitamab and lenalidomide. Currently, we don't have prospective data that really informs that question, and there's a number of research studies underway to try and help us understand if there is a preferred sequence, or even if it matters how we handle CD19 targeting. For my older, frailer patients where I'm really worried, they're not going to be able to tolerate something like liso-cel, or they're not going to be able to have that caregiver, and they're uncomfortable relocating to an area where CAR T might be available, my general approach right now is to consider tafasitamab and lenalidomide first in that relapse setting, followed by either Lonca or Pola-BR. Selinexor is another option. It's an oral agent, though again, in my opinion, if we look at the totality of the data, may be less effective than the other options. So, I might reserve that as a last option for someone, again, with relapsed/refractory large cell. Dr. Chijioke Nze: Excellent. Thank you. This has been very helpful. Dr. Loretta Nastoupil: All right. So, Dr. Nze, now I'm going to turn the table and ask you some questions. I'm going to change this up a little bit - she's now a 39-year-old female. She has significant comorbidities. She has HIV, and again, large cell lymphoma. So, let me walk you through her case, and then we'll discuss some of the challenges, again, in a very different scenario, albeit a similar disease. So, our female is, I mentioned 39, pre-existing HIV, she's treated frontline with six cycles of R-CHOP and intrathecal methotrexate for CNS prophylaxis. Because of her comorbidities, again, not well controlled HIV, she also has a poor functional status at the time of relapse. This was a couple years ago, and CAR T was not an option in second line, though she is someone who had a relapse that was beyond 12 months. So, for her second-line approach, because of her comorbidities, she actually receives rituximab in combination with high-dose cytarabine, dexamethasone, and oxaliplatin for three cycles, and actually achieves a chemosensitive disease and is referred to our stem cell transplant colleagues. Unfortunately, at that time, due to comorbidities, she was deemed not to be an appropriate candidate for high-dose therapy, and she's been monitored for signs of relapse. Despite being in the minority, she actually does not have a recurrence of her lymphoma but has a number of other, again, challenges in regards to her comorbidity, including multiple infections, resulting in recurrent hospitalizations. And so, it's always been a challenge for me in being intimately involved in her case, deciding when she's presenting, how alarmed to be about recurrent lymphoma versus infection, and how I might approach her in the setting of relapsed large cell lymphoma. So, what role does prior type and response to therapy play in treatment selection at your next line of treatment? Dr. Chijioke Nze: I think in this patient, it sounds like she got one adequate therapy on and the initial presentation with R-CHOP, and then with IT chemotherapy as well. She looked like she had a good response. I think the fact that she achieved a complete response and the duration of her response, lets me know that she likely has chemosensitive disease. This, in turn, helps me to pick what to do next. As you mentioned previously, we know how efficacious the CAR T therapy is, but in someone like her who had a long duration, trying salvage therapy and proceeding to autologous transplant might make sense. I'd be interested in your thoughts. Dr. Loretta Nastoupil: Yeah, I agree. And I think part of the challenge, particularly when we're facing patients with HIV, they're often excluded from prospective studies. And so, we're often in a scenario where we may not have the wealth of data to inform our treatment decision. But I do think in general, comorbidities play a major role-- we're navigating treatment options. Because again, traditionally, we've used intensive chemotherapy as our mainstay of treatment, and there are clear criteria that patients generally should meet that help us predict how likely they are to have significant or severe toxicity from high-dose therapy. And this is a prime example of even though she was young, her comorbidity made her a poor candidate for intensive therapy. I think the other sort of non-clinical factors that we sometimes take into consideration, because CAR T was approved off of single-arm phase II studies, again, none of which would've included someone like her, because of her HIV status, how do we extrapolate-- for instance, if she had relapsed in that third-line space, and suggesting that she did not have significant infection or other significant comorbidities, do we have experience to proceed with an autologous CAR in that setting? So, again, there've been a few cases where we have case reports where people have reported on their standard of care outcomes, particularly with CAR T in patients with active HIV disease, but one of the concerns I have in these scenarios is very selected. If you have active infection, that can make the acute toxicity with CAR significantly worse. And so again, we're trying to navigate a sort of limited data zone to try and help her and choose the right therapy. Again, you've met this patient with me, you helped care for her for some time, and you have a unique experience of also practicing in a county hospital where comorbidities, particularly, like HIV, can be much more common. What is your perception regarding barriers to accessing CAR T as it pertains to social factors, clinical factors, and again, this is a case that highlights some of those issues. Dr. Chijioke Nze: You mentioned at first that she had uncontrolled HIV. So, I think which, one, speaks to her treatment reference of her non-malignancy-related diseases, and trying to get that under control would be one of the first things I could think about. Thinking about how her care is managed and what kind of support she has are very important for us to think about as well. The other thing that's very important is, a lot of patients who we're seeing in the community may not have access to such specialized centers such as MD Anderson, where patients do have access to clinical trials and CAR T therapy. So, patients who are unlike her, who might qualify, may not actually be able to get these therapies as well. Part of the reason is, it can be insurance status, which is what we see in a lot of our patients. So, a barrier to get into the door. And then too barriers, lack of social support can be a big issue as well. And then there's also a big push in the community to improve the trust and awareness of these novel therapies, as you've mentioned. So, in a lot of the community practice, some of the community practitioners may not be comfortable with these, and a lot of the patients may not have heard of these new technologies, and also want to defer trying new therapies before having other people try new therapies before they consider them themselves. I think all these things present specific significant barriers to patients in the community. One, their ability to adhere to care, two, their insurance and their ability to get care and the financial toxicities associated with that. And then third, really understanding the options that are available. Dr. Loretta Nastoupil: And again, just to try and illustrate a couple other points. You know, we use a case here, which is a real case, with significant comorbidities such as HIV, which again, is something that is not frequently encountered, and will have a large impact on treatment selection. What if I just told you this patient has comorbidities, but she has moderate type-2 diabetes, and as a result, she has mild renal insufficiency, ejection fraction is actually adequate, would you have done anything different in this case? Dr. Chijioke Nze: No. I think in this particular case, I do think the fact that she did have a good response for a long duration of time, and did seem to have chemosensitive disease, I would probably still have tried a salvage therapy and autologous transplant in this patient. In the event that she was refractory, or had early relapse, and in that case, I would consider her to not be chemosensitive and would definitely have sought some more active therapies such as CAR T cell therapy through available products. Dr. Loretta Nastoupil: And then one last question for you: What if we just changed her age and we made her 79, but no other significant comorbidities, how would that have impacted your approach? Dr. Chijioke Nze: I'm going to turn that one over to you, I'm not exactly sure how I would treat with older patient with the same disease. Dr. Loretta Nastoupil: That's fair. So, if you have an older patient who has a late relapse, but not necessarily someone you would consider appropriate for salvage chemotherapy and high-dose therapy, then I think tafasitamab and lenalidomide would be probably my first choice in that setting, just based off of the L-MIND study. Dr. Chijioke Nze: Thank you, Dr. Nastoupil, for a great discussion of the management of diffuse large B-cell lymphoma. And thank you to all our listeners. We appreciate you tuning in to this episode of the ASCO Educational podcast.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.

Featuring perspectives from Drs Jonathan Friedberg, Brad Kahl, David Maloney, Loretta Nastoupil and Sonali Smith, including the following topics: Diffuse Large B-Cell Lymphoma (DLBCL)  Introduction (0:00) Case: A woman in her early 60s with DLBCL with renal and subcutaneous involvement — Erik Rupard, MD (2:36) Cases: An otherwise healthy woman in her mid 80s with an orbital mass diagnosed with Stage IE DLBCL and a man in his early 80s with Stage IIIB DLBCL, GCB type and LVEF 35% to 40% due to prior myocardial infarction and coronary artery disease — Bhavana (Tina) Bhatnagar, DO and Yanjun Ma, MD (7:10) Dr Friedberg presentation (11:54) Follicular Lymphoma  Case: A man in his late 60s with progressive Grade I/II follicular lymphoma after observation for many years — Neil Morganstein, MD (29:07) Case: A woman in her early 60s with Grade II follicular lymphoma who received bendamustine/rituximab and maintenance rituximab — Jennifer L Dallas, MD (33:11) Dr Nastoupil presentation (38:36) Hodgkin Lymphoma  Case: A woman in her early 80s with newly diagnosed classical Hodgkin lymphoma — Kapisthalam (KS) Kumar, MD(51:21) Cases: A woman in her late 30s with newly diagnosed classical Hodgkin lymphoma and a man in his early 60s with newly diagnosed Stage IV classical Hodgkin lymphoma who receives brentuximab/vedotin with AVD (doxorubicin/vinblastine/dacarbazine) — Susmitha Apuri, MD and Amany R Keruakous, MD, MS (55:21) Dr Smith presentation (1:10:17) Chimeric Antigen Receptor (CAR) T-Cell Therapy for Non-Hodgkin Lymphoma   Cases: A man in his late 50s who presents with a large cecal mass and mesenteric adenopathy and is diagnosed with “double hit” DLBCL and a woman in her early 70s with DLBCL treated with R-CHOP, now with progressive disease 6 months later — Vignesh Narayanan, MD and Rahul Gosain, MD (1:14:56) Case: A woman in her early 70s with rapid relapse after R-CHOP then R-ICE (rituximab/ifosfamide/carboplatin/etoposide) and ASCT who achieves a complete response with CAR T-cell therapy but experiences significant pancytopenias — John Yang, MD (1:22:10) Dr Maloney presentation (1:25:24) Mantle Cell Lymphoma (MCL)  Case: A man in his late 70s with high-risk relapsed MCL after BR and maintenance rituximab x 3 years — Raman Sood, MD (1:39:10) Case: A man in his mid 80s who received prior treatment for prostate cancer and presents with low-volume indolent MCL with a TP53 mutation — Spencer H Bachow, MD (1:42:47) Dr Kahl presentation (1:45:29) CME information and select publications

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, ASCO experts and members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, our guests will discuss new research in lung cancer, lymphoma, and childhood cancer that was presented at the 2022 ASCO Annual Meeting, held June 3-7 in Chicago, Illinois. First, Dr. Charu Aggarwal will discuss 3 studies looking at treatment options for people with non-small cell lung cancer. Dr. Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer. You can view Dr. Aggarwal's disclosures at Cancer.Net. Dr. Aggarwal: Hello and welcome to this Cancer.Net podcast. I'm bringing you updates from the Annual Meeting of the American Society of Clinical Oncology, held in Chicago in 2022. I'm Dr. Charu Aggarwal. I'm the Leslye Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania's Abramson Cancer Center. I will be discussing updates on 3 studies today that offer insights and new advances in the management of patients with non-small cell lung cancer. I don't have any direct relationship with any of these companies or studies, and you can view a list of my disclosures on the Cancer.Net website. First off, I would like to talk a little bit about advances in the management of patients with EGFR exon 20 mutations. We know that a lot of advances have been made in the management of patients with non-small cell lung cancer, and much of that has been attributed to the fact that we are now able to deliver targeted therapy for a subset of patients. EGFR mutations form one such subset where we have a lot of oral drugs that are available, and we can offer these that improve survival, and patients can avoid chemotherapy, immunotherapy, and other IV infusional therapies. Within the subset of EGFR mutations lies this unique subset of EGFR exon 20 insertion mutations, which have been historically harder to target with currently available EGFR inhibitors. And over the last 5 years, we have seen tremendous growth of opportunities, targets, and new drugs for this subset of patients. The mutations in this subset forms about 2% to 5% of all non-small cell lung cancers. But now we have 2 FDA-approved drugs in this space, one being intravenously administered, amivantamab, and another that is orally available, mobocertinib. We covered this in a podcast as well as a blog, so please check those out on our Cancer.Net website. But building upon that progress, there is now another drug that was reported at ASCO. This drug is called CLN-081. And we saw preliminary activity in a phase 1 and 2 study of this molecule or this drug in patients with EGFR exon 20 insertion mutations. It's an orally available drug. The top line data is that it is safe, it is effective, it was tested in different doses. It was tested at less than 65 milligrams, 100 milligrams, and 150 milligrams, again, as I mentioned, administered orally, and we saw responses and patients that had previously received other therapies and may have progressed on other therapies. And what we found was that this drug also tends to have activity against brain metastases, which I think is this huge unmet need in the management of such patients. So I think more to come, but again, I think offers us an insight into what may be in the future, an attractive drug for our patients with EGFR exon 20 insertion mutations. So stay tuned, more on that in the future. Shifting gears, I would like to now talk about one of the common mutations. So we talked about EGFR exon 20, which is about only 2% to 5%, but the largest subset of mutations in non-small cell lung cancer really revolves around KRAS mutations, and these form about 30% to 35% of all mutations in non-squamous, non-small cell lung cancer. And amongst this group there is another subset which is KRAS G12C non-small cell lung cancer, that forms about 13% of all lung cancers. We have 1 approved drug already in this space by the name of sotorasib that is FDA approved for the management of patients with this particular mutation after having received 1 prior therapy, be it chemo-immunotherapy or immunotherapy. At this year's ASCO meeting, we heard data from a study called KRYSTAL-1, which looked at the activity and safety of another molecule called adagrasib, which is an orally available drug targeting KRAS G12C, again, in a similar population of patients with advanced and metastatic non-small cell lung cancer harboring a mutation. We found that this drug is again effective, the overall response rate was about 43%, the majority of the patients had stabilization of disease, about 80%, and many patients were able to remain on treatment with stabilization of disease. We found that this drug does have side effects and adverse events and most commonly of this were diarrhea, nausea, vomiting, and fatigue. Many patients did require dose reductions, but the activity of the drug remained despite dose reductions. Now, what would be the advantage of this drug against the currently available sotorasib? In another smaller study reported at ASCO, there seemed to be activity in the brain, including intracranial penetration with the use of this molecule, adagrasib, which has not been demonstrated before with other KRAS G12C inhibitors, so I think that makes it a potentially attractive option. Again, I will say that the report of this intracranial activity was in a very small subgroup of patients, so I think needs to be further corroborated in a larger study. Shifting gears again and talking about our last study, so I would like to highlight what do we do if, in case, patients don't have a targetable mutation. I want to highlight that we do have a lot of available options, and we are continuing to improve upon available options. The way we treat such patients is by using immunotherapy, either alone or in combination with chemotherapy. But what do we do after this treatment stops working? Researchers from the Southwestern Oncology Group, or SWOG, launched a massive national effort called Lung-MAP, which is basically a clinical trial that evaluates several different strategies all at once, either for patients with targetable mutations or for patients without a targetable alteration. And they reported results from a study that evaluated the combination of pembrolizumab with ramucirumab in patients that may have progressed after frontline immunotherapy. Now, pembrolizumab is immunotherapy, so the concept was, can we continue immunotherapy beyond progression and perhaps get some synergistic activity by using ramucirumab, which is a drug that prevents blood vessels from forming in the tumor itself. It's an anti-angiogenic agent, meaning that it is a targeted molecule that prevents blood vessel formation and promotes tumor death. What they found was that patients that received pembrolizumab and ramucirumab were more likely to live longer, so overall survival was longer for patients with this combination compared to a physician investigator discretion choice, such as chemotherapy in combination with ramucirumab or other chemotherapies that are otherwise used in the second line setting. And interestingly, we did not find a significant improvement in shrinkage with this combination of pembrolizumab and ramucirumab or a significant reduction in the time of progression-- or, sorry, prolongation of the time of progression of disease. But the overall survival findings are interesting, and I think that's why we are including them in this podcast because that's one of the approaches that is leading to an improvement in survival and improvement in outcomes. I will point out that this is a phase 2 study. These results would need to be validated in a large prospective phase 3 trial so that we can account for certain confounding factors that may have led to these results. Having said that, I think there's a tremendous excitement, there's tremendous excitement in this field. I gave you examples of, or highlighted, 3 studies: one in patients with EGFR exon 20 insertion mutations, another in KRAS G12C mutations, and the third in patients who may have already received either immunotherapy or chemoimmunotherapy. We will continue to update our Cancer.Net website with updates as they come through, new advances, new studies, so thanks for following, thanks for listening, and more to come. Stay tuned. Thank you. ASCO: Thank you, Dr. Aggarwal. Next, Dr. Christopher Flowers will discuss new research in treating people with different subtypes of lymphoma, including mantle cell lymphoma and diffuse large B-cell lymphoma. Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. He is also the 2022 Cancer.Net Associate Editor for Lymphoma.   You can view Dr. Flowers' disclosures at Cancer.Net. Dr. Flowers: Hello and welcome to this podcast that is a review of late breaking abstracts from the ASCO Meeting and recent updates in lymphoma. I'm Dr. Christopher Flowers, professor and chair of the Department of Lymphoma and Myeloma and Interim Division Head for Cancer Medicine at The University of Texas MD Anderson. And it's my great pleasure to discuss with you some of these late breaking abstracts. I do have some disclosures that are related to the content that I will present from this year's ASCO Meeting and recent studies in lymphomas. Those are available at Cancer.Net. Those relate to my role as a consultant for the development of clinical trials in lymphomas and research funding that MD Anderson has received from companies related to my role in clinical trials in lymphoma and clinical trials across cancers. So, the ASCO Meeting had a host of new information that was presented. Some of that information centers around key clinical trials. One that was a pivotal clinical trial, the SHINE clinical trial, looked at patients with mantle cell lymphoma, a rarer lymphoma subtype, that looked at the combination of bendamustine and rituximab, a standard chemoimmunotherapy combination, compared to that same chemoimmunotherapy combination, bendamustine, rituximab, plus the Bruton's tyrosine kinase inhibitor ibrutinib. Ibrutinib, as some of you may know, is a kind of therapy that is typically used in the relapse setting for patients with mantle cell lymphoma when they have their disease come back. And the SHINE clinical trial was looking at adding it to frontline therapy. What this randomized, controlled trial in the phase 3 setting found was that patients who received the combination of bendamustine, rituximab, plus ibrutinib had improvement in their progression-free survival, meaning that the time that it took for their disease to come back or them to have deaths related to the lymphoma was longer for patients who received this combination. About 2.3 years longer than the group that received bendamustine, rituximab, plus placebo. And in total, that led to a median progression-free survival of 6.7 years. That study has now been published in the New England Journal of Medicine and was led by my colleague Dr. Michael Wong from MD Anderson. Dr. Wong also led another study that was presented at the ASCO Meeting looking at CAR T-cell therapy for patients with mantle cell lymphoma. That study has now been published in the Journal of Clinical Oncology, and it looks at brexucabtagene autoleucel, a kind of CAR T-cell therapy, where that-- the CAR T-cell therapy was successfully manufactured for 71 of the 74 patients in the trial. 68 of those patients received an infusion and the median progression-free survival, so the average amount of time that it took for patients to have progression of their disease, was about 25 months. And so a marked benefit for those patients who were receiving CAR T-cell therapy when their mantle cell lymphoma came back. There also were major breaking abstracts at the ASCO Meeting in the area of diffuse large B-cell lymphoma. As many of you may know, diffuse large B-cell lymphoma is the most common type of lymphoma that occurs in the United States. And there was a breaking trial that was presented in December at the American Society of Hematology Meeting describing polatuzumab, a CD79b antibody drug conjugate, as a new drug in the substitution of frontline therapy for patients with diffuse large B-cell lymphoma in combinations with rituximab, cyclophosphamide, adriamycin, and prednisone, or the pola-R-CHP arm, that compared favorably to rituximab and CHOP chemotherapy, which has been the standard of care for patients with diffuse large B-cell lymphoma. And that trial showed an improvement in progression-free survival. At this year's ASCO Meeting, Franck Morschhauser presented results from looking at subsets of that patient population. Those patients who had BCL2 by immunohistochemistry that was positive or MYC expression by immunohistochemistry that was positive, or both of those, what we call double-expressor lymphomas, those who have poorer risk than standard groups. And those double-expressor lymphomas, treated with pola-R-CHP, had improvement in progression-free survival compared to R-CHOP with a hazard ratio of 0.64 in that group. We also saw in a multitude of analysis that that supported the benefit of pola-R-CHP in patients with both BCL2-positive and MYC-positive diffuse large B-cell lymphoma. Another area that has been very hot in diffuse large B-cell lymphoma clinical trials is the role of bispecific antibodies. Bispecific antibodies are antibodies that bind both to CD20, a marker on the diffuse large B-cell or the lymphoma cells, and to the marker CD3, which is a marker on T-cells which brings the normal T-cells of the immune system in close proximity to the lymphoma cells and then leads to immune-directed killing of lymphoma cells. The agent glofitamab is an agent that was presented by Michael Dickinson at this year's ASCO Meeting in an abstract. And in this study, 107 patients who received more than 1 dose of steady treatment went on to have complete responses in about 35% of patients. And this showed that glofitamab induced durable complete responses and had a very favorable safety profile in patients with relapsed and refractory diffuse large B-cell lymphoma. And in this trial, they compared that also for patients who had prior exposure to CAR T-cells and showed that responses were also good in those patients. Another set of studies has also looked at bispecific antibodies and a whole host of other areas with multitude of other agents. Another study that was presented at this year's ASCO Meeting explored the use of bispecific antibodies in the frontline setting in combination with the R-CHOP regimen that I just discussed. In that study, Lorenzo Falchi presented results of the subcutaneous bispecific antibody epcoritamab in combination with R-CHOP. This was a relatively small study of 33 patients that showed that the combination of epcoritamab plus R-CHOP was something that was safe and tolerable. There were no new treatment emergent adverse events that led to discontinuation of epcoritamab in the study. And there are some adverse events that are of special interest that we see with the bispecific antibodies, and those include the kind of immune-mediated adverse events that we can also see with CAR T-cells, like cytokine release syndrome, or CRS, or neurologic toxicities that we can see there that are also called ICANS. What we've seen in this trial, that about 42% of patients had some form of cytokine release syndrome, but that most severe form of cytokine release syndrome, those that were greater than grade 3 in severity, was only in 3% of patients. And likewise, the neurologic toxicities, or ICANS, that were grade 2 was in only 3% of patients. Relatively few patients completed all therapy by the time that this was presented. Only 10 patients had completed 6 cycles of therapy, but that showed an overall response rate that was quite high in that patient population. There were a whole host of other trials that were presented at this year's ASCO Meeting, and those portend improved kinds of outcomes on the horizon for patients with lymphomas across the spectrum. And I think it's an exciting time moving forward for clinical trials in lymphoma and hopefully, to see new therapies that emerge for the management of this disease. One of those new therapies that happened outside of the ASCO Meeting was the recent FDA approval of CAR T-cell therapy in the relapse setting for follicular lymphoma. And this was based on the ELARA clinical trial. And I think the future is quite bright for therapies and for patients with lymphomas broadly. ASCO: Thank you, Dr. Flowers. Finally, Dr. Daniel Mulrooney will discuss new research in childhood cancers, including a study comparing treatment options for Ewing sarcoma, and several studies on neuroblastoma. Dr. Mulrooney is an Associate Member in the Division of Cancer Survivorship at St. Jude Children's Research Hospital. He is also the Cancer.Net Associate Editor for Pediatric Cancers. You can view Dr. Mulrooney's disclosures at Cancer.Net. Dr. Mulrooney: My name is Dr. Dan Mulrooney from St. Jude Children's Research Hospital. I'm the Deputy Director of the After Completion of Therapy Clinic at St. Jude and primary care for survivors of pediatric solid tumors. The annual ASCO Meeting is typically quite busy and full of research presentations sharing knowledge and advances in cancer treatment and care. Today, I'd like to highlight some of the exciting presentations in pediatric cancer. Please note, I do not have any relationships to disclose related to any of these studies. At this year's meeting, one of the highlights was a European study in patients with relapsed or refractory Ewing sarcoma. Ewing sarcoma is a rare bone cancer that typically occurs in adolescents or young adults. While challenging to treat, it is difficult to cure in patients who have relapsed, and studies are needed to improve the care of these patients. Investigators from 13 European countries and Australia and New Zealand studied the most common relapsed therapies, which include irinotecan and temozolomide, gemcitabine and docetaxel, topotecan and cyclophosphamide, or high-dose ifosfamide. The study enrolled 451 patients between 2014 and 2021 and randomly assigned them to one of these four treatments. Based on response rates, the first 2 arms were dropped and the study was largely a comparison between topotecan cyclophosphamide and high-dose ifosfamide. The main outcome was event-free survival. Event-free survival is a common way in a clinical trial to see how well a treatment works. It measures the time from treatment that the patient remains free of complications, such as return or progression of the cancer. But investigators also looked at overall survival, toxicity, and quality of life. The 6-month event-free survival was better for high-dose ifosfamide at 47% compared to 37% for topotecan cyclophosphamide. The median overall survival was also better for high-dose ifosfamide compared to topotecan cyclophosphamide. The results were best for children younger than 14 years old versus those 14 or greater. Toxicities included fever and neutropenia, nausea, vomiting, and diarrhea. Patients receiving high-dose ifosfamide had more neurologic and kidney toxicities, which might be expected since ifosfamide is known to affect these organ systems, while only descriptive measurements of quality of life appeared higher for those children treated with high-dose ifosfamide compared to topotecan and cyclophosphamide. The strength of this trial is its large size, particularly for a rare cancer, and the fact that it randomized patients to the most commonly used treatment regimens for relapsed Ewing sarcoma. Importantly, data did not previously exist comparing these different treatments. While the results of this study are promising, clearly more needs to be done, and there was a lot of discussion at the ASCO Meeting about how to further improve survival in these patients. This study provides some information for doctors and patients, but importantly, provides data to advance future trials, which will concentrate on incorporating new targeted drugs with high-dose ifosfamide. This study is ongoing and is adding additional arms to continue to improve the outcomes for patients with relapsed or refractory Ewing sarcoma. In addition to this study in Ewing sarcoma, several studies investigating neuroblastoma were presented. Neuroblastoma is the most common extracranial solid tumor in children and for children with high-risk disease requires intensive and prolonged treatment, including chemotherapy, surgery, radiation therapy, and stem cell transplantation. Treatment for these patients has improved since the introduction of immunotherapy, particularly an antibody directed at a particular antigen named GD2 on the neuroblastoma cells. One study showed improvement in outcomes using this antibody for children with relapsed or refractory neuroblastoma, and another study demonstrated feasibility of using this antibody earlier in treatment, which was not previously known to be safe and tolerable. In what is called the BEACON study, investigators tested whether the antibody, called dinutuximab, would be effective when combined with chemotherapy for relapsed or refractory neuroblastoma. They enrolled 65 patients from 2019 to 2021 and randomized these patients to either chemotherapy alone or chemotherapy plus dinutuximab. The median age of these children was 4 years. The overall response rate, which means either a complete or partial response, was 18% for the chemotherapy-only arm but improved to nearly 35% for those treated with chemotherapy and dinutuximab. The progression-free survival was 27% for chemotherapy only and improved to 57% for those treated with chemotherapy and the antibody. There was no change in overall survival, though investigators think this may have been due to some patients who had progressive disease and crossed over to the antibody arm of the study. This presentation was followed by a study from the Children's Oncology Group, which investigated the feasibility of adding antibody treatment earlier in the treatment regimen for neuroblastoma. Prior studies had used antibody later in treatment when the tumor burden is thought to be lower. The endpoint of this study was tolerability measured by toxic deaths or unacceptable toxicities, such as adverse reactions to the medication. For example, sustained low blood pressure requiring a ventilator or breathing machine, or severe neuropathy. 42 high-risk neuroblastoma patients were enrolled from 8 different children's hospitals between 2019 and 2021. 41 of the 42 were able to complete the induction chemotherapy plus the antibody. There were no toxic deaths or unacceptable toxicities. Importantly, 85% were able to complete the next phase of treatment, called the consolidation phase, and 79% were able to complete the following phase after consolidation, called post-consolidation. One-year event-free survival was 83%, and 1-year overall survival was 95%. Now, it's important to know these are still early results, and the trial recently closed, and some of the patients have only completed therapy within the last year. Both of these studies add to the knowledge of chemoimmunotherapy for children with high-risk neuroblastoma. These studies provide a foundation for larger randomized trials that will further advance the care of these children. And finally, another study looked at race, ethnic, and socioeconomic disparities among children treated for high-risk neuroblastoma on Children's Oncology Group studies. There were no differences in event-free survival, but there were differences in overall survival based on ethnicity. The 5-year survival was lowest for Hispanic patients at 47%, 50% for non-Hispanic other ethnicities, which included Asian, Native American, Native Hawaiian, or Pacific Islanders, and 62% for non-Hispanic Black and non-Hispanic White children. Importantly, these investigators also studied household and neighborhood poverty. Overall, survival was lower for children living in poverty, though some of these differences went away when accounting for other factors, such as stage of disease or high-risk features. This study is important because it highlights the increasing need to collect data on clinical trials that may contribute to inequities in outcomes. While most studies collect data on the race and ethnicity of participants, other factors known as social determinants of health, such as income, neighborhood, education, access to health care, and insurance coverage, may also contribute to outcomes in pediatric cancer patients. Overall, the studies highlighted here and presented at this year's ASCO Annual Meeting focused on difficult-to-treat cancers, such as relapse or refractory disease, and they have laid the groundwork for future investigations to continue to improve survival rates for all children diagnosed with a malignancy through improved therapies and by addressing potential social barriers. Thank you for listening to this brief summary of the new research in pediatric oncology presented at the 2022 ASCO Annual Meeting. ASCO: Thank you, Dr. Mulrooney. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Partners in cancer care – who are advanced practice providers? In the first episode of ASCO Education's podcast series on Advanced Practice Providers (APPs), co-hosts Todd Pickard (MD Anderson Cancer Center) and Dr. Stephanie Williams (Northwestern University Feinberg School of Medicine), along with guest speaker, Wendy Vogel (Harborside/APSHO), discuss who advanced practice providers are, share an overview of what they do, and why they are important to oncology care teams. If you liked this episode, please subscribe. Learn more at https://education.asco.org, or email us at education@asco.org   TRANSCRIPT Todd Pickard: Hello everyone, and welcome to the ASCO Education Podcast, episode number one of the 'Advanced Practice Providers' series, 'APPs 101: What and Who Are Advanced Practice Providers?' I'd like to introduce my co-host for this series, Dr. Stephanie Williams. My name is Todd Pickard. I'm an advanced practice provider, I'm a PA, and I work at MD Anderson Cancer Center in Houston, Texas. I'm also the Executive Director of Advanced Practice and my clinical practice is in urology. Dr. Williams, how about you introduce yourself? Dr. Stephanie Williams: Thanks, Todd, and thanks for this opportunity to present this incredibly important topic. I am currently retired from clinical practice. I had been in practice for over 35 years both in an academic setting, a private practice, and more recently in a large institutional, multi-specialty institutional type of practice. My primary clinical care has been in stem cell transplants and cellular therapy. And we have used APPs, both PAs and NPs for a couple of decades in our particular area. Todd Pickard: Great, thanks for that. I'd also like to introduce you to our guest panelist today, Wendy Vogel from Harborside, who is a certified oncology nurse practitioner with over 20 years of clinical experience and expertise. We're excited to be chatting with Wendy today about the basics of advanced practice providers and who they are. This will be an introduction for the rest of the upcoming episodes of APP Podcasts. Wendy, why don't you tell us a little bit about yourself and your practice. Wendy Vogel: Thanks, Todd. It is a pleasure to be here. I appreciate you asking me to talk. I am an oncology nurse practitioner as you said. I do a high-risk cancer clinic and do that a couple of days a month. And I am also the executive director of APSHO, the Advanced Practitioner Society for Hematology and Oncology. Todd Pickard: Great! We're looking forward to a robust and informative discussion today between the three of us. So, I'd like to get started with some basics. Wendy, do you want to always start with a definition of advanced practice registered nurse? Wendy Vogel: Okay, great question! So, APRNs or advanced practice registered nurse include nurse practitioners. It can include clinical nurse specialists, nurse anesthetists, and nurse midwives. And generally, APRNs hold at least a master's degree in addition to some initial nursing education as a registered nurse. Some APRNs have doctorates like the DNP or Doctorate of Nursing Practice. But licensure for APRNs generally falls under the State Board of Nursing.   So, we're also required to have a board certification, usually as some sort of generalist as in family medicine, pediatrics, geriatrics, women or acute care. But in oncology, many APRNs also carry oncology certification. Todd Pickard: Excellent! Thanks for that. I'll go ahead and add to the conversation by defining physician assistant. So, physician assistants are individuals who are trained in the medical model and are licensed to practice medicine in team-based settings with physicians. Very much like advanced practice registered nurses, we come from a variety of backgrounds, and our education model is really focused on thinking about the patient the same way that our physician colleagues do. We're trained in really taking a very broad look at patient care, and our education as a generalist model. PAs are certified by the National Commission on Certification of Physician Assistants, which is one national certification that includes all of the content areas in which we will practice. Dr. Stephanie Williams: For those out there who don't know, what are the differences between a physician assistant and an APRN? Or are there differences in practical terms, in terms of how we practice our field? Wendy Vogel: That is a great question, Stephanie, thanks for asking that. We function very much the same. The main difference is just in our educational background, where nurse practitioners come from a nursing background and the nursing model of care, and I'll let Todd speak to where PAs come from, but basically, our functions are very much the same. Todd Pickard: I very much agree. If you are in a clinical setting, and for some reason, Wendy or myself failed to identify who we are, you wouldn't really detect a distinction between the care either of us provide, because we are there in that provider setting and we're really there to assess the conditions you have like appropriate history in physical examination, think through differential diagnosis or a workup, create a diagnosis and then a therapeutic plan and also to educate you as the patient or to make an appropriate referral. So, really, when APPs, PAs, and NPs work side by side, there's really not a lot of difference in what people detect in what we're doing and how we're doing things. But there are some educational differences, which are pretty minimal. So, for example, one small difference is that PAs include surgical assisting as part of our core fundamental training, and our APRN colleagues generally don't. So, in my institution, we do have nurse practitioners that go to the OR and do assisting, but in order to get there, they did a Registered Nursing First Assist Program, it's a certification. So, they learn those fundamentals of sterile technique and surgical technique. So, in essence, there's really not a whole lot of difference. Dr. Stephanie Williams: I think what I was struck with about the difference was the history and the fact that PAs came out of the Mobile Army Surgical Hospitals. To me, that was just fascinating. I think Duke was the first graduating class. Wendy Vogel: You know, the role of the APRN has really changed drastically. It began in the 1960s, because there were not enough primary care providers, particularly for children in the urban and rural areas of the US, and the first nurse practitioner program was in 1965, at the University of Colorado. So, gosh! Have we come a long way since then, both the PA role or the NP role. When was the first PA role, Todd, when was that? Todd Pickard: We were born at the same time in 1965, we just happened to be at Duke University and y'all were in Colorado. You know, I think that the most important thing about working with advanced practice providers is that you look to work with somebody who has the competencies, the skills, interpersonal communication, and the pertinent experiences because honestly, I know fantastic APRNs, I know fantastic PAs, and I know some of either profession that really just don't quite fit a particular role. And so, there is some kind of mythology around PAs and APRNs, and who should work where, like PAs should be more procedural and more in surgery, and nurse practitioners should be more in medicine in the hospital. And really, there's nothing in our training that defines that per se, I think it's just a natural progression of we're over 50 now, so our professions are middle-aged. And we're starting to really have our feet underneath us. And I think people who've worked with PAs or NPs really understand, it's about the individuals and what they bring to the table. It's not really about the initials behind our names, because honestly, that's not what makes me do good work. It's not that I have the PA or NP behind my name. It's my commitment and dedication to my patients and supporting the rest of my team. Wendy Vogel: I think Stephanie, that's why we use the term advanced practitioner, advanced practitioner provider because it doesn't single out either one of us because we are functioning in the same manner. It's easier to say than say, PAs and NPs, so we just say, APPs. Todd Pickard: Yeah. And it doesn't mean that we don't identify as individual professions, because we do. I mean, I'm a PA, but I am part of a larger group. And part of that larger group is identifying as advanced practice provider because, at my institution, there are over 1000 of us, and we are a community of providers, and that's the way that we sense how we function within the team and within the institution. And so, it's really about that kind of joint interprofessional work. And speaking of work, Wendy, tell us a little bit about what are typical things that advanced practice providers do? Wendy Vogel: It might be easier to say what we don't do. I've got a list. Do you want to hear my list? Todd Pickard: Yeah, lay it on us. Wendy Vogel: Okay, here you go. Staff and peer education, survivorship care, palliative care, hospice care, pain management, acute care clinics, case management, research, cancer patient navigator, genetic services, lung nodule clinics, quality improvement. We're writers, we're authors, we're speakers, we mentor, and we do all kinds of public education. We can have clinical roles with faculty and professional organizations. We do procedures like bone marrows, paracentesis and suturing, and all that kind of stuff. We do a lot with all the other things like diagnosing, all the things you said earlier, diagnosing, ordering lab tests, ordering chemotherapy, etc. Todd Pickard: I think what's amazing about advanced practice providers is the flexibility we have to fill in gaps on teams or in service lines, no matter what that is. You know, I like to say and I'm sure everybody thinks that they originated this, but I feel that advanced practice providers are the stem cells of the team because we differentiate into whatever is necessary. At my institution, we recently had a gap in how our peer-to-peers were handled. Many times, you order an MRI or a PET scan, and the payer will, the day of or the day before, say, ‘Oh, I need to talk to somebody.' How that gets to the clinical team and when the clinical team has time to do that, it's really hard to coordinate. So, we created a team of advanced practice providers who spend one day a week doing the regular clinical roles, but then the rest of the time, they are dedicated to facilitating these peer-to-peer conversations. They have over a 95% success rate. And the payers, the medical directors, have actually gotten to know them. And so, they'll say, ‘Hey, I want to talk to so and so because she's fantastic and knows our program, and it's really easy to have these conversations.' And so, patients are taken care of and these business needs are taken care of, and then our clinical teams can really focus on what they're there for, which is to see those patients in and out every day. So, that's the power of advanced practice, its flexibility, filling in gaps; we can bend and morph to whatever we need to do because one of the things that's in our DNA is part of PA and advanced practice RN, we're here to serve, we're problem solvers or doers, too. When we see something, we pick it up and take care of it. That's just in our nature. Stephanie, tell us a little bit about your experience working with an advanced practice provider, is what Wendy and I are saying ringing true, or what's your experience? Dr. Stephanie Williams: Oh, absolutely! As I look back on my career, I'm not certain that I could have accomplished much of what I did, without my team members and advanced practice providers, both PAs and NPs. We also use them in an inpatient setting. And I can't remember Wendy mentioned that to take care of our stem cell transplant patients, because of residency, our requirements were removed from our services, and they became the go-to's to taking care of the patients. It actually improved the continuity of care that the patients received because they would see the same person throughout their 4 to 6-week course in the hospital, they also helped run our graft versus host clinics. I hate that term physician extender because they're really part of our health care team. We are all healthcare professionals working together, as Todd beautifully mentioned, for a common goal to help that patient who's right there in front of us. And not only that, from a kind of selfish viewpoint, they help with a lot of the work, doing the notes, so that we could all split up the work and all get out on time and all have at least some work-life balance. And I think that's a very important part of any team is that we can each find our own work-life balance within the team. So, I feel that they're a very important part of the oncology healthcare team. And I would recommend that everyone who wants to take care of patients, incorporate them into their team. Wendy Vogel: Can I say something right here that you mentioned that I'm so glad you did, which was physician extender. That is a dirty, dirty word in the AP world now because we don't know what part we're extending, that is not what we do. And also, we don't want to be called mid-level providers because – you can't see but I'm pointing from my chest to my belly - I don't treat just the mid-level, nor do I treat in mid-level care. I give superior care. I just give different care. And I give care on a team. And the last one is a non-physician provider. That is also a no-no because I wouldn't describe a teacher as a non-fireman, nor would I describe you, Stephanie, as a non-nurse practitioner. So, I don't want to be a non-physician provider either. Todd Pickard: It is an interesting phenomenon that even after 50 years, so many different places, whether it's the Joint Commission, or the Centers for Medicaid and Medicare Services, whether it's a state legislator, an individual state, an individual institution like Memorial Sloan Kettering or an MD Anderson or a Moffitt, everybody comes up with these different terms. And it's so interesting to me. Physicians are either physicians, doctor, sometimes they're called providers. But as a PA, who's an advanced practice provider, those are the two things that resonate with me: either call me PA or call me advanced practice provider. All these other names seem to just be, it's an alphabet soup, and it really doesn't carry any meaning because some places just come up with these strange terms. And I agree, physician extenders has been the one that always has amused me the most because it reminds me of hamburger helper. Am I some noodles that you add to the main meal so that you can extend that meal out and serve more people? I think what Wendy and I are really trying to get at, I know this has been with a little bit tongue in cheek, but we are part of the team. We work with physicians in a collaborative team-based setting, just like we all work with social workers and schedulers and business people and pharmacists and physical therapists. I think the main message here is that oncology care and taking care of patients with cancer is a team effort because it is a ginormous lift. It's a ginormous responsibility and our patients deserve a full team that works collaboratively and works well and has them in our focus like a laser, and I know that's what APPs do. Dr. Stephanie Williams: I think that's well said, Todd. What I enjoyed in the clinic in particular, was sitting down and discussing patient issues and problems with my APPs. And we worked together to try to figure out how to resolve issues that would come up. But we also learned from each other, you're never too old to learn something from people. I just felt the interaction, the interpersonal interaction was also very satisfying as well. Wendy Vogel: I think that the job satisfaction that comes from being a team player and working together is so much higher and that we're going to experience so much less burnout when we're working together each to the fullest scope of our practice. Todd Pickard: So, Wendy, one of the things that people ask a lot about when they work with advanced practice providers is, ‘Well, gosh! How do I know that they have this training or this experience or this competency?' And then the question arises about certification. So, let's talk a little bit about certification and what that means and what it doesn't mean. So, tell me, are advanced practice providers certified? And are they required to get a variety of certifications throughout their career? Let's talk a little bit about that. Why don't you open up the dialog. Wendy Vogel: Okay, happy to! So, to be able to practice in the United States, I have to have a board certification. And it can vary from state to state, but generally, it has to be either a family nurse practitioner certification, acute care nurse practitioner, geriatrics, women's health, pediatrics, there are about five. So, you are generally certified as one of those. There are a few oncology certifications across the US, board certifications to be able to practice at the state level, but not all states recognize those. So, most of us are educated in a more generalist area, have that certification as a generalist, and then can go on to get an additional certification. So, many nurse practitioners in oncology will also get an advanced oncology nurse practitioner certification. So, that's a little bit different. It's not required to practice. But it does give people a sense that, ‘Hey, she really knows what she's doing in oncology.' Todd Pickard: The PA profession has one national certification, and it is a generalist certification. It's probably similar to USMLE, where you really are thinking about medicine in its entirety. So, whether that be cardiology, orthopedics, family medicine, internal medicine, geriatric, psychiatry, or ophthalmology. I mean it's everything – and oncology is included as well. And that certification really is the entree into getting licensure within the states. It's basically that last examination that you take before you can get that license just to make sure that you have the basic knowledge and fundamentals to practice. And so, I always respond to this kind of question about certification, I say, ‘Well, is it really the experience and the onboarding and the training that one gets on the job and the mentoring and the coaching that one gets from our physician colleagues and other advanced practice providers that brings them the most value? Or is it going through an examination, where basically you're responding to a certain amount of information, and you either pass it or you don't, and you can get a certification? I'm not saying there's not value in that, but I'm also making the argument that if you are working with your APPs well, and they have good mentors, and they have good resources, they're going to be excellent clinicians. And having an additional certification may or may not make some huge difference. Many times I see people use it as a differentiator for privileges or something. It's really an external kind of a pressure or a desire, it doesn't really have anything to do with patient care. I mean, Wendy what has your experience been around that need for additional certification? Wendy Vogel: I've seen it used in practices to merit bonuses, which isn't really fair when a PA does not have that opportunity to have a specialty certification per se. So, I've seen it used negatively. I'm a great believer that any additional education that you can get is beneficial. However, I will say just like you said, if you are getting your mentoring, you have good practice, you're doing continuing education, then it's essentially the same thing. To be able to have an oncology certification, I had to practice for a year and I had to take a test that really measured what I should know after one year. And that's what a certification was for that. Is it beneficial, do I want it? Yeah, I want it. Do I have to have it to practice? No. Todd Pickard: I think that is a great way to segue to having a brief conversation about how you bring APPs in? I mean, just at a very high level, should people expect for an APP to come in right out of school and just hit the ground running without any additional investment? And I could ask the same question about a resident or a fellow who completes an oncology training program. Do you just put those people to work? Maybe that's an older model, and now really mentorship and that additional facilitated work is, I think, critical. So, I'll start with Stephanie, tell us a little bit about what's your experience been with advanced practice providers, or even young physicians as they enter the workforce? What's the role of onboarding or mentoring program? Dr. Stephanie Williams: So, it's important. We had a set process for bringing on our new APPs and it pretty much followed the guidelines from the American Society of Cellular Transplantation in terms of the knowledge base that they would need to know. So, it was a checklist. And we would also have them do modules from ASCO's oncology modules, as well looking at primarily hematologic malignancies, so they could get a background there. And then we would slowly bring them on board. Usually, they would start taking care of autologous patients, a certain subset of patients, and then move on to the more complicated patients. We did the same clinic, whether they were clinic or inpatient APPs. So, it took us about three to four months to onboard our APPs. In terms of a fellow becoming an attending physician, I'd like to say that there's specific onboarding there. Unfortunately, sometimes they're just, ‘Okay, these are your clinic days, this is when you start.' I mean, you're right Todd, we really need to work more on onboarding people. So, that one, they like their jobs, they're not frustrated, and they want to stay and continue to work in this field. I see many times after two or three years, if they're not onboarded properly, they just get frustrated and want to move on to a different area. Wendy Vogel: We know that most of the advanced practitioners who come into oncology don't have an oncology background, PA or NP.  They just don't, and we don't get a lot of that in school. So, it takes months, it would probably, I dare say, take 12 months of full-time practice to feel comfortable in the role. But how many practices particularly in the area that I've practiced in you get this AP, and you throw them in there, and in four weeks, you're supposed to be seeing patients. How can you make those decisions when you haven't been properly mentored? So, absolutely important to have a long onboarding time till that APP feels comfortable. Todd Pickard: Yeah, I think that it is critically important that we set up all of our team members for success, whether they be physicians, or PAs, or nurse practitioners or nurses, or pharmacists, and I think that is the role of onboarding and mentoring, having people who will invest time and energy in what you're trying to accomplish. You know, Wendy is spot on. Advanced practice providers have specific types of training within their educational program. As a PA, my focus in oncology was to screen for and detect it. So, to understand when a patient presents with a mass or some symptoms that may make you think that, oh gosh, maybe they've got acute leukemia or something else and looking at those white counts and, and understanding. But that transition from identifying and screening and diagnosing cancers is very different than how do you care for specific types of tumors and specific disciplines, whether it be radiation oncology, surgical oncology, medical oncology, cancer prevention. There's a lot that folks need to be brought up to speed about the standards of what do we do in this practice and how do we care for these types of cancers? And that really is the role for the onboarding and mentoring. You know, you may be lucky, you might get an advanced practice provider who used to work at a big academic cancer center in the same field, whether it be breast medical oncology or GI, and yeah, that's a much easier task. That person probably really needs mentoring about the local culture, how we get things done, what are the resources, and which hospitals do we refer to. But for the most part, working with an advanced practice provider means that you've got a PA or an NP, who has a strong foundation in medical practice. They know how to care for patients, they know how to diagnose, they know how to do assessments, they know how to critically think, they know how to find resources, and they know how to educate. But they may not know how long does a robotic radical prostatectomy patient going to be in the hospital? And how long does it take to recover and what are some of the things you need to be considering in  their discharge and their postoperative period? That is very detailed information about the practice and the local resources. Every advanced practice provider is going to need to have that kind of details shared with them through mentorship, and a lot of it is just how do we team with each other? What are the roles and responsibilities? Who does what? How do we have backup behaviors to cover folks? So, a lot of this really is just deciding, ‘Okay, we've got a team. Who's doing what? How do they work together and how do we back each other up?' Because at the end of the day, it's all about the team supporting each other and that's what I love about advanced practice. Wendy Vogel: Very well said, yes. I had an AP student yesterday in clinic, who told me - I was asking about her education in oncology and what she got - and she said, ‘Well, so for lymphoma, we treat with R-CHOP. So, a student, of course, raised their hand and said, ‘What's R-CHOP? She's like, ‘Well, the letters don't really line up with what the names of the drugs are, so, just remember R-CHOP for the boards.' So there you go. That's kind of what a lot of our education was like specific to oncology. And again, I'm a little tongue in cheek there also. But Todd, are you going to tell everybody about the ASCO Onboarding tool that's now available? Todd Pickard: Absolutely! ASCO has done a really great job of trying to explore what advanced practice is, and how teams work together. All of us are part of the ASCO Advanced Practice Task Force. One of the things we did was really to look at what are some best practices around onboarding, orientation, scope of practice, and team-based cancer care, and we created a resource that is available on the ASCO website, and I think that it is a great place to start, particularly for practices, physicians, or other hospital systems that don't have a lot of experience with advanced practice. It's a  great reference, it talks about the difference between orientation and onboarding. It gives you examples of what those look like. It talks about what are the competencies and competency-based examinations. So, how you assess people as they're going through the onboarding period. It has tons of references, because ASCO has done a lot of great research in this field, around collaborative practice and how patients experience it, and how folks work on teams, and what do those outcomes look like. So, I highly recommend it. Wendy, thank you for bringing that up. It's almost like you knew to suggest that. Well, this has been a really, really good conversation. I'm wondering, what are some of those pearls of wisdom that we could all provide to the folks listening? So, Stephanie, what are some of your observations that, you know, maybe we haven't just thought about, in your experience working as a physician with advanced practice providers? Dr. Stephanie Williams: One, it's important to integrate them into the team, and, as Wendy mentioned, to mentor them – mentor anybody correctly, in order for them to feel that they're contributing the most that they can to the care of the patient. I think there are other issues that we'll get into later and in different podcasts that come up that make physicians hesitant to have nurse practitioners or physician assistants. Some of those are financial, and I think we'll discuss those at a later time. But really, that shouldn't keep you from employing these particular individuals for your team. It really is a very rewarding type of practice to have. You're not alone. You're collaborating with other providers. I think it's just one of the great things that we do in oncology. Todd Pickard: I wanted to share a moment as a PA, advanced practice provider, when I most felt grateful for the opportunity to work as an advanced practice provider. My clinical practice has been in urology for the past 24 years for the main part. I've had a few little other experiences, but mainly urology, and I'll never forget a patient who was a middle-aged lady who had been working with transitional cell bladder cancer. It was superficial. So, the treatment for that is BCG and repeat cystoscopies and surveillance. And I walked into the room and I was going to give her BCG installation, and she was so angry. I wanted to know what was going on. I thought, gosh, should I make her wait too long or something else? So, I asked her, I said, ‘How are you doing today? You seem to be not feeling well.' And she said, ‘Well, I'm just so tired of this. I don't understand why y'all don't just fix me. Why don't y'all just get this right? Why do I have to keep coming back?' And as I looked at the medical record, this patient had had superficial bladder cancer for years. And I thought, ‘Has nobody ever really kind of sat down and mapped this out for her?' So, I asked her to get off the examining table, and I pulled the little paper forward, so I had someplace to draw. And I drew a big square and I said, ‘This is a field, just think of any big field anywhere near you. And it's full of weeds.' And I drew some weeds on there. And I said, ‘You know we can pull them out and we can pluck them, and we can put some weed killer in that field,' I said,  ‘do you think that if you come back in three months and there will be any weeds on that field?' She said, ‘Of course, there will be. There are always weeds because they always come back. It's very hard to get rid of.' And I said, ‘Well, this field is your bladder. And the type of cancer you have are like these weeds, and we have to constantly look for them, remove them, and then put this treatment down, that's why you come.' And she started crying. And I thought, ‘Well, I've blown it.' Because this was in the first couple of years of working as a PA in urology. And I said, ‘I'm so sorry. I really apologize.' She said, ‘Don't you dare apologize to me.' I said, ‘Man, I've really blown it now.' She said, ‘Todd, I've had this disease now for this many years. This is the first time I've ever fully understood what's happening to me. I am so grateful to you.' I will never forget this patient. I will never forget this experience. And I'm extraordinarily proud. It's not because I'm the smartest person in the world. I just happened to investigate, take the time, and I drew it out. I explained it in the simplest of terms because I wanted her to understand. And then whenever she came back, she always wanted to see me. So, it was great. I really developed a really lovely relationship with this patient. It was very rewarding. Wendy, can you think of a story that you have about an advanced practice provider that makes you particularly happy or where some big lesson was learned? Wendy Vogel: Yeah. I love your analogy. That's a great analogy. I think that part of what I love to do is similar to you, Todd, in that I like to make things understandable because I consider myself an East Tennessee southern simple person, I want to understand things in the language that I understand. So, I like using a language that a patient understands. I think if I was to say about some of the proudest things, or what makes me so excited about oncology is what we've seen in our lifetime. So, Todd, you and I practice probably about the same number of years and we could say we remember when Zofran came out, and how that revolutionized chemotherapy nausea and vomiting – Stephanie's nodding here, too. We all know that. And then wow! When we found out that we could maybe cure CML, that we're having patients live normal lives in our lifetime, that we've seen non-small cell lung cancer patients living past a year that are metastatic – Oh my gosh! This is such an exciting field and we learn something every day. There's new drugs, there's new treatments, there's new hope, every single day, and that's what makes me proud to be a part of that. Todd Pickard: Yeah, I think that oncology and the work that we get to do as a team is so incredibly rewarding. It's challenging, and we have losses, but we also have wins, and those wins are amazing, and transformative, not only for us but for our patients. So, some final pearls of wisdom. I'll share and then Wendy, I'll turn it over to you. One thing that I really want to convey to folks is to know about the state that you work in and what are the practice acts for advanced practice providers. Because, unlike our physician colleagues who have a very standard scope of practice across the country, advanced practice can drastically change from state to state and place to place even from institution to institution. So, be aware of that, so that you can build your team-based practice around what are the constraints, what is the scope of practice, and you can comply with that. It just takes a little bit of pre-work at the beginning. It's not daunting. These things are written in English. We're all smart folks. We can understand them and we can build our teams in the right way. So, just keep that in the back of their mind. It is not an obstacle. It's the instruction manual of how to build your team. That's all it is if you just think about it simplistically like that. So, Wendy, what's one or two things that you would say you really want our listeners to understand about advanced practice? Wendy Vogel: I loved what you said, Todd, both of our PA Associations and our Nurse Practitioner Associations have that information online, so it's very easy to find. But I think I would say, don't be afraid to stand up for yourself as an advanced practitioner or as a physician who wants an advanced practitioner. Don't be afraid to stand up for yourself and your scope of practice, know what you can do, know what you can't do, know and demand the respect that you deserve. I would always say that just don't forget that ‘no' is the first step to a ‘yes,' and keep on trying. Todd Pickard: I think we can all appreciate that sentiment, whether we be a PA an NP or a physician. Many times, we're advocating for our patients within our systems or our practices or with our payers or insurance providers. And yeah, sometimes you start from a place of ‘no' and then you work until you get to that ‘yes', or at least a compromise, if you can get to a 'maybe,' that's a good place too. Stephanie, any particular last words of wisdom or wrap us up with our conclusion? Dr. Stephanie Williams: Thanks, Todd and Wendy, for sharing your insights today. It's always a pleasure chatting with you both. Stay tuned for upcoming episodes where we plan to dig deeper into the various types of APPs, how they are trained, what a day in the life looks like for an oncology APP, their scope of practice, and the importance of team-based care, especially in oncology. Thank you to the listeners as well. Until next time. Thank you for listening to the ASCO Education Podcast. To stay up to date with the latest episodes, please click subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive education center at education.asco.org.   The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product , service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Visit this link to complete the CE request form & evaluation:  https://www.ceconcepts.com/DLBCL-GR-PodcastThis activity will review the failure rates of traditional therapies for DLBCL, such as R-CHOP, and evaluate patient-centric factors that contribute to disease progression and/or relapse. Expert faculty will then guide attendees through an evidence-based examination of the exigent need for more effective front-line therapeutic options in DLBCL, emphasizing practical clinical pearls and notable distinguishing features of novel and emerging treatment agents and their potential to optimize patient outcomes.Supported by an independent educational grant from Genentech.

Featuring perspectives from Dr Andrew Evens, including the following topics: Introduction (0:00) Case: A woman in her late 80s with Stage II classical Hodgkin lymphoma (HL) — Spencer Henick Bachow, MD (5:43) Case: A woman in her early 30s with sclerosing HL who achieved a complete response to ABVD — Priya Rudolph, MD, PhD (19:53) Case: A man in his late 20s with Stage IIA HL — Raman Sood, MD (28:14) Case: A woman in her late 60s with transformed diffuse large B-cell lymphoma (DLBCL) after R-CHOP with a complete response — Justin Peter Favaro, MD, PhD (37:35) Case: A woman in her late 70s with relapsed DLBCL — Ranju Gupta, MD (47:28) Case: A woman in her early 60s with Stage IIA, Grade IIIB follicular lymphoma — Neil Morganstein, MD (57:06) CME information and select publications

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Dr. Christopher Flowers covers highlights from the 2021 American Society of Hematology Annual Meeting, held December 11 to 14 in Atlanta, Georgia. He discusses new treatments for diffuse large B-cell lymphoma, advances in immunotherapy, and a session on improving inclusivity in clinical trials. Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. He is also the 2022 Cancer.Net Associate Editor for Lymphoma.   View Dr. Flowers' disclosures at Cancer.Net. Dr. Flowers: Hello. I'm Dr. Christopher Flowers, Chair of the Department of Lymphoma and Myeloma and Interim Division Head for Cancer Medicine at The University of Texas MD Anderson Cancer Center. And it's my pleasure to talk to you today about the highlights from this year's American Society of Hematology meeting. The ASH meeting this year was a very exciting meeting for lymphoma broadly across all of the lymphomas, with particular highlights around diffuse large B-cell lymphoma where there were some changes that may be changes in the standard of care in the year ahead. I was involved in one of these studies, the POLARIX study that I'll spend some time talking about, where I was the North American lead, and I've served as a consultant for Genentech-Roche in the conduct of that study and other studies related to drugs in their portfolio. The other set of studies that I will talk about are the studies around CAR T-cell therapy. And 2 of those studies, Dr. Jason Weston from my institution and MD Anderson were involved with and Dr. Weston was the senior leader on 2 of those 3 studies that I will talk about. So let's first talk about the first line in diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma, as many of you may be aware of, is the most common type of lymphoma and the most common type of aggressive lymphoma. Back in the 1970s and 80s, the standard of care for CHOP therapy was developed. And that through the 90s, through a number of comparisons of clinical trials for chemotherapy, emerged as the de facto standard of care. In early 2000, the drug rituximab, the anti-CD20 antibody therapy, so our first form of immunotherapy, was added to CHOP. And R-CHOP therapy became the standard of care around 2002. And so it's really been about 20 years that that has been the standard of care for all patients or for most patients in the front line for diffuse large B-cell lymphoma. That's not been without challenges. There have been a number of clinical trials from 2002 to the present that have challenged R-CHOP, either by adding new therapies, like new targeted therapies looking at intensifying the CD20 antibody component, adding things like stem cell transplant or intensifying the chemotherapy-- and in some cases, focusing on subsets of diffuse large B-cell lymphoma, like the activated B-cell-like subset that are at poorer outcomes in the general population. However, none of those clinical trials really emerged to change the standard of care. And R-CHOP had remained the standard of care for patients. This year, as one of the late breaking abstracts presented at the American Society of Hematology meeting and followed up by a publication in the New England Journal of Medicine, one of our top premier journals, there was a study that looked at the substitution of vincristine, one of the drugs in CHOP, for the drug polatuzumab vedotin. Polatuzumab vedotin is what we call an antibody-drug conjugate, where that antibody binds to a cell surface marker on the lymphoma cells CD79B. And with that, binding is internalized into the cell. And the conjugate is a form of chemotherapy, MMAE, that is then taken into the cell with the antibody. And that antibody-drug conjugate was substituted for vincristine in the study. In the POLARIX study, it showed that it met its primary endpoint for the study, which was an improvement in progression-free survival, where the patients who got the polatuzumab in their chemotherapy with R-CHP had an improvement in progression-free survival of approximately 26% over the group that got R-CHOP. This is the first time to show an improvement in front-line therapy for patients with diffuse large B-cell lymphoma. And regulatory bodies will be looking at this to see whether this is approved in the first line in the relatively near future. The other major trials that were presented at this year's American Society of Hematology meeting in diffuse large B-cell lymphoma were trials looking at the second line of therapy for patients with diffuse large B-cell lymphoma. And in that second line, for patients who were fit and able, stem cell transplant has formed as standard of care for patients after R-CHOP therapy. As many of you may know, diffuse large B-cell lymphoma is a disease where the goal of treatment is cure. And with that first-line therapy, the therapies that are able to produce benefits in terms of progression-free survival are expected to go on to cure for those patients if those responses are durable in 5 years. Even when patients have relapse after their first-line therapy, there's the potential of cure in the second line. And stem cell transplant has been that curative approach that we've taken for many patients in the past. In this year's ASH meeting, there were 3 trials that compared the concept of moving on, after first-line therapy, to intensive chemotherapy followed by a stem cell transplant or to performing CAR T-cell therapy as that second-line therapy. As some of you may know, CAR T-cell therapy has emerged as really an exciting form of immunotherapy, a cellular therapy, that is approved for patients who are with lymphomas and some leukemias and being explored in other diseases. CAR T-cell therapy is a form of immunotherapy where we actually re-engineer cells. So we take the cells from the patient and then genetically re-engineer those cells so they attack a marker on the cell surface. I talked about CD20 antibody therapy. All of these CAR T-cell therapies are cellular therapies against the marker on the lymphoma cells called CD19. And so in these 3 trials that compared CD19 CAR T-cell therapy versus autologous stem cell transplant, 2 of those trials, 1 presented in the plenary session—and that was one of the ones that Dr. Weston participated in—was a study that showed that there was a benefit in progression-free survival for those patients who received CAR T-cell therapy over the approach to do stem cell transplant as that second-line therapy. There was a second trial, the TRANSFORM trial, that was also presented in one of the oral abstract sessions. That one presented interim analysis of their trial. They also showed a benefit in terms of progression-free survival. And then there was a third trial that was looked at in the late breaking abstract session. That one did not show a benefit for CAR T-cell therapy in that setting, using  tisagenlecleucel as a form of CAR T-cell therapy in that study. And perhaps the reasons why that did not show a benefit or differences in the trial design between those 3 trials, not as many of the patients were able to go on to CAR T-cell therapy in that third trial. And that was really expertly described and compared by Alex Hariri in a discussion of the plenary session. So really, 4 major trials in diffuse large B-cell lymphoma that we expect will change the standard of care. Likewise, there were a number of other exciting new immunotherapies that have been presented at this year's annual meeting, namely studies looking at bispecific antibodies. And so these are antibody-based therapies in a number of different trials that both engage a portion of the lymphoma cell. And then as the other portion of the bispecific, so meaning two, that other portion engages T cells. So it brings T cells into the tumor to be able to attack the lymphoma cells. And so there are a number of exciting therapies that are on the horizon for lymphomas looking at that. And those were also presented at the ASH meeting. The last thing that I'd like to highlight from this year's annual society meeting was a joint session that looked at the role of clinical trials and ways that we can actually improve clinical trial design for patients-- 1, to increase the diversity, equity, and inclusion that we see across clinical trials to make sure that all patients who are eligible are having equal access to trials and being able to participate, but also in terms of being able to modify the eligibility criteria that we use for clinical trials. One of the things that we've explored, particularly for those challenges that I described without advances in the front line for diffuse large B-cell lymphoma in the past, have been that some of the eligibility criteria for our past trials really were not including all the patients who were most likely to benefit from trials. And so Tom Witzig at this year's annual society meeting really presented an outstanding look at the eligibility criteria that we use for lymphoma trials, and trying to be able to address those in ways that help to allow more patients to participate in trials, and those who are most likely to need a trial to be able to benefit from the activities that are engaged in a trial. So I really appreciate all of your attention to this podcast. Exciting meeting this year for the American Society of Hematology Annual Meeting. And lots of things that will come to patients in the near future. And hope to be able to create advances that will help all of you in terms of your quality of life and well-being. So thank you all for your attention. ASCO: Thank you, Dr. Flowers. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Guest host, Dr. John Sweetenham, associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and Dr. Syed Abutalib, medical director of the Hematologic Malignancies and Stem Cell Transplant Program at the Cancer Treatment Centers of America in Zion, Illinois, discuss advances in CAR T-cell therapy in the management of lymphoma, the toxicities associated with CAR T, and emerging bispecific antibodies for the treatment of lymphomas.   Transcript Dr. John Sweetenham: Hello, and welcome to the ASCO Daily News podcast. I'm John Sweetenham, the associate director for Clinical Affairs at UT Southwestern Harold C. Simmons Comprehensive Cancer Center and guest host of the podcast. I'm delighted to welcome my friend, Dr. Syed Abutalib, the medical director of the Hematologic Malignancies and Stem Cell Transplant Program at the Cancer Treatment Centers of America in Zion, Illinois. He's also associate professor at the Rosalind Franklin University of Medicine and Science, and founder and co-editor of Advances in Cell and Gene Therapy. Today, we're going to be discussing some of the recent advances in the use of CAR T-cell therapy in the management of lymphoma. Our full disclosures are available in the show notes, and disclosures relating to all episodes of the podcast can be found in our transcripts at asco.org/podcasts. Syed, it's great to have you on the podcast today. Thanks for coming. Dr. Syed Abutalib: Thank you, John. It's my honor. Dr. Sweetenham: Syed, the emergence of CAR T-cell therapy is having a transformed impact on the treatment landscape for hematologic malignancies in general, and for lymphoma in particular, and I'd like to give our listeners a sense of where we're at with CAR T-cell lymphoma. Can you tell us a little about the FDA approved agents which are now being used for the management of patients with malignant lymphoma? Dr. Syed Abutalib:  Sure, so there are, at this time, about five agents that are approved based on mainly a phase 2 single arm study controlling them with the historical data from Scholar One in diffuse large B-cell lymphoma. They are axicabtagene ciloleucel. We'll be calling this axi-cel, which was approved after the data ZUMA-1 for the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy. In this group, there were diffuse large B-cell lymphoma NOS, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and transformed diffuse large B-cell lymphoma from follicular lymphoma. The next agent that was approved was--let's see if I can pronounce it. It's the most difficult name--tisagenlecleucel which is tisa-cel was based on the JULIET trial. This drug was approved again for the adult patients with a relapsed/refractory large B-cell lymphoma after two lines of systemic therapy for the same indications as patients in ZUMA-1 trial except tisa-cel is not approved for the primary mediastinal large B-cell lymphoma. The next agent is lisocabtagene maraleucel. We will call this liso-cel. This agent was approved after the pivotal trial TRANSCEND NHL 001. And the unique thing about this trial was also there were two patients with CNS lymphoma in this trial. And again, the indications were similar to the axi-cel indication. And the fourth indication is for axicaptagene lisoleucel based on the ZUMA-5 trial, which was FDA approved for adult patients with relapsed/refractory follicular lymphoma after two or more lines of systemic therapy. And the last agent that has been approved is based on the trial of ZUMA-2, which is brexucabtagene autoleucel, brexu-cel. And this is approved for adult patients with relapsed or refractory mantle cell lymphoma. Dr. John Sweetenham: Syed, thanks for providing that background. As you've shown, there are multiple agents which have been through early phase clinical trials. They've been applied to various subtypes of malignant lymphoma. And furthermore, they've been used at various stages in the treatment algorithm for these lymphomas, albeit mostly in the relapsed and refractory setting. We've all been waiting for some time to start to see data emerging from prospective randomized trials of CAR T-cell therapy versus standard of care. And of course, we were exposed to some of the early data from these randomized trials at the American Society of Hematology Annual Meeting in December. And overall, there was the suggestion of a possible benefit to CAR T-cell therapy. Could you tell us a little bit about the data that caught your attention and your insights into how to interpret those data? Dr. Syed Abutalib: Yeah, definitely. So as I alluded earlier, right now, the FDA approval is mainly for patients after two lines of therapy in diffuse large B-cell lymphoma. Now what is happening is that this CAR T-cell is trying to move forward into failure after first line of therapy. And in order to do that it is important that they have a comparative arm, which they tried to do in three trials by comparing it with so-called standard of care therapy. However, it must be noted that the standard of care therapy in diffuse large B-cell is not that straightforward for all patients who relapse. So just to give you the background, about 30% to 40% of the patients with diffuse large B-cell lymphoma experience relapse, and 10% are refractory to first line therapy. Now out of these patients, the standard of care therapy applies in real world practice as to the patients who are transplant eligible. For the remaining patients who are transplant ineligible, there is no standard of care therapy. And the list is very long if you look at the NCCN guidelines for those patients. And the patients who are transplant eligible; if 100 patients go to transplant, 50% are cured. And there is a very good track record for this. And the ones who are cured are mainly the ones who are sensitive to chemotherapy, mainly platinum-based chemotherapy. So what these trials that were presented at ASH, one has to understand that what they call standard of care in their comparative arm because what happens is that if you have a comparative arm that is weak, that is not transplant-eligible patients, or the patients don't go to transplant, then your trial would look much better than what it really is. So there were three trials that caught my attention. One is, of course, ZUMA-7, the axi-cel and the second one is the TRANSFORM trial with liso-cel. And the third one is the BELINDA trial, tisa-cel.  ZUMA-7 and BELINDA trial have been published in the New England Journal of Medicine already. So what is important to acknowledge here is that the patients in ZUMA-7 were refractory to frontline therapy. About 74% of those patients were refractory, meaning that they did not respond to [INAUDIBLE]. Now we don't know how bad the refractory disease was, and ideally, these patients, if they are transplant eligible, which most of the patients were, would have gone to auto transplant, and 50% of them historically would be cured and the other patients who are relapsed within 12 months to frontline therapy. Now in ZUMA-7, they assumed that these patients who are early relapse will not respond to standard of care transplant. They divided those patients to CAR-T versus transplant or non-transplant. The reason I say non-transplant, because only 36% of the patients who were on ZUMA-7 received what you call, ‘standard of care therapy,' high dose chemotherapy with transplant. So I don't think it was a fair comparison to standard of care therapy. Now the other thing is the follow up is not too long as it is for the auto transplant. So it remains to be seen how things will evolve. In the TRANSFORM trial, which was with the liso-cel, the large cell lymphoma group were either primary refractory or relapsed within 12 months. Again, they assume that the patients who relapsed early will not respond to platinum-based therapy. Ideally, these patients should go for auto-transplant. In BELINDA trial, what is significant is that only 23% of the patients received auto transplant. And out of the three transplants, BELINDA trial was the only one which did not show improvement in median event-free survival compared to the standard of care. The hazard ratio was 1.01. So it's difficult to say that these trials are truly positive for CAR-T over auto transplant because they did not compare auto transplant in the CAR-T. They compared all patients with relapsed or refractory disease who could have gotten transplant also to CAR-T, favoring the experimental arm. Dr. John Sweetenham: Yeah, thanks Syed. So I think the take-home message that I'm hearing from you is that there are some interesting signals in these randomized studies about the potential efficacy of CAR-T. It's probably a little bit early to claim victory just yet, and we need to let these studies mature out a bit more and I guess ultimately wait for some overall survival endpoints. You're absolutely right that there is still some uncertainty surrounding the interpretation of these results and the long-term effectiveness of CAR T-cell therapy. One thing there's no doubt about is that CAR T-cell therapy is associated with significant toxicities, the most common being Cytokine Release Syndrome and Immune Effector Cell Associated Neurotoxicity Syndrome, or ICANS. But of course, the list of adverse events is much longer. We recognize late toxicities, including prolonged cytopenias. So right now, CAR T-cell therapy is mainly performed at larger tertiary care centers, but obviously, things are changing as regional facilities begin to do CAR T-cell therapies themselves. And even if they don't actually provide CAR T-cell therapy, a lot of physicians are going to be seeing their patients locally after they have developed toxicities from this treatment. How far have we come, do you think, in managing the toxicities of CAR-T, and how can we better manage those adverse events in our patients as we move forward and it becomes a more widespread intervention? Dr. Syed Abutalib: I believe we are getting better in managing these therapies, but of course, the CAR T-cell therapy is at its infancy, and we are learning. In any case, it is important to understand what are the main toxicities-- as you had mentioned, the CRS and the neurotoxicity and the chronic B-cell achalasia or hypogammaglobulinemia, which basically reflects the persistence of CAR T-cell therapy. So, in an effort to improve on recognition and treatment of these side effects, ASTCT, which is the American Society of Transplant and Cellular Therapy, had the workshop in 2018 in Washington DC, and they published a paper subsequently in trying to educate everybody about these toxicities. What is important in CRS is early recognition, and CRS is divided into different grades according to the ASTCT criteria from grade 1 to grade 4. Grade 1 is when you have fever. Many patients that we will admit or who we will treat who are very sick patients will get fever. One should not assume that it is CRS. We should always exclude the infection and start the appropriate antibiotics. And as a transplanter, we are very well-aware of how to tackle this or as treating hematologic malignancies with a lot of neutropenic fevers. So, if you have fever, appropriate workup should be done. Grade 2 ASTCT criteria is fever with hypotension that does not require pressors or hypoxia that requires low-flow nasal-cannula oxygen. Grade 3 is worsening of the hypotension, requiring pressors without vasopressin or hypoxia getting worse. And grade 4 is an extreme with multiple pressures requirement for hypertension and hypoxia requiring CPAP or BiPAP. So all this requires close monitoring and one should also recognize the risk factors prior to the admission of the patient or prior to giving the CAR-T. What are the risk factors for this CRS. The risk factors, which include our high pre-infusion tumor burden, so it is important sometimes to debulk the patient.  Early onset of fever, presence of underlying inflammatory process or presence of infection--these things will help manage the CRS. The other thing is the neurotoxicity. And similarly, there has been criteria developed for that too.  There's an algorithm at our institution, we have developed a card that has this criteria and algorithm imprinted on it. So, there is an ICE criteria which basically checks for patient orientation. And you have certain questions about ability to name three objects, following commands, writing, and attention. You give them certain points. And then you have them go into the neurotoxicity domain and check the level of consciousness and/or their seizures or motor findings or elevated cerebral intracranial pressures. So based on that, you find out what is their neurotoxicity grade. Having said that, it is also important to have toci, which is IL-6 inhibitor, on hand. And according to the regulatory authorities, these drugs are approved under the REMS program. So you have to have at least two doses of tocilizumab in-house before you give any patient these drugs. So, to answer your question in a nutshell now is that close hemodynamic monitoring is very important, and it is important to have trained staff on board who can check on patients at regular, frequent intervals to recognize these toxicities early and intervene early to prevent morbidity and mortality. Dr. John Sweetenham: Yes, thanks. And I think it emphasizes the fact that the initial patient selection for CAR T-cell therapy is extremely important bearing in mind not just the patient's disease state but also age, performance status, co-morbidities, and so on in the same way, really, as with transplant. I want to change gears just for a moment. There is no doubt that cellular immunotherapies like CAR-T remain of limited availability in part because of cost and effectiveness barriers. And without getting into a long discussion about that, I wonder if you could comment a little bit on other emerging therapies that in time could potentially, if it's the right expression, challenge CAR T-cell. I'm thinking in particular about some of the bispecific T-cell engaging antibodies which are now coming online. Dr. Syed Abutalib: Sure. So the bispecific antibodies are basically protein constructs with a specificity to two different antigens. And they commonly bind immune effector cell antigens and tumor-specific antigens, creating what we call an immune synapse, which results in activation of the effector cells, which are T-cells, and cause direct cytotoxic activity. For example, we have an FDA-approved agent in ELL, and it's also listed in NCCN as an-- in transplant-ineligible patients, which is blinatumomab, which is a CD3 and CD19 construct. Now in the clinical trials, there are many bispecific antibodies that are in development. The benefit of this is manifold, in my opinion. They are off-the-shelf immunotherapy. They have strategies to mitigate CRS and neurotoxicities such as that they are given those adjustments with lower rates of doses early on and then the dose is escalated. And we see less CRS and neurotoxicity in patients. The third advantage is they might be preferable, especially in older adults.  I'm not sure if they are going to replace the auto transplant at this time. The other advantage is that there is data emerging that they are effective even after CAR T-cell therapy failures although the data is not mature yet. And still, we need them to be approved and see how they will be in the real world setting. So some of them I will talk about. The one that really caught my attention was mosunetuzumab, which is called mosun. The unique thing about this is that it's IV, and there is a step up dosing to mitigate the CRS and neurotoxicity as I mentioned.  And it is a time limited therapy. It's not that you have to keep going, and that is important because of the cost effectiveness of the therapy. And this is a CD3 and CD20 construct. It is being tested in the third line follicular lymphoma as monotherapy in combination of Revlimid. The important thing is that the CR grade 3 and grade 4, very few patients, 2 patients out of 90 in follicular lymphoma, and no grade 4, grade 5 events occurred whether with monotherapy in follicular lymphoma with a CR rate of about 58%. They are also being combined with polatuzumab, which is an anti-CD79 antibody and also in relapsed/refractory diffuse large B-cell lymphoma as a subcutaneous dose because of, again, further trying to mitigate the CRS with a slow release form. The other important biphasic antibody is glofitamab, which is being tested in relapsed/refractory follicular lymphoma, relapsed/refractory mantle cell lymphoma after BTKI, failures. And also, the data in more than 200 patients was presented in patients with diffuse large B-cell lymphoma, mantle cell lymphoma, transformed follicular lymphoma, Richter syndrome. So these two are very important to watch for. There are others, such as epcoritamab, which is also C3 and CD20 bispecific antibody, which is also in a phase III trial, what is the standard of care in relapsed/refractory diffuse large B-cell lymphoma, and is also being tested upfront with R-CHOP. So I think these three are important to watch out for, and in my opinion, which might be incorrect, these are, as I alluded earlier, are more convenient, less laborious, can be less CRS, and might have about similar-- might have similar activity as CAR-T, might win the game over CAR-T. But it's too early to say. It's just an opinion. Dr. John Sweetenham:  Thanks, Syed. And I think however this plays out, however, ultimately, these bispecific antibodies line up versus CAR T-cell therapy, I think two things are true for sure. The first of those is that patients with aggressive lymphomas and indolent lymphomas now have available to them a number of treatment options they didn't have before, which, of course, is great news. The second thing which is undoubtedly true is at least for a while, CAR-T therapy is with us to stay. Syed, it's been a pleasure having you on the podcast today and hearing your insights into how CAR T-cell therapy is evolving and its potential to improve patient outcomes in the future. Dr. Syed Abutalib: Thank you, John. Dr. John Sweetenham: And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate, review, and subscribe wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness   Dr. Syed Abutalib: None Disclosed   Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Chadi invites a trio of lymphoma experts to weigh the importance of the POLARIX trial – which was presented at the ASH Annual Meeting and looked at frontline therapy for patients with DLBCL. Matthew Matasar, MD, Memorial Sloan Kettering Cancer Center, co-authored publication of the POLARIX study “Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma” in the New England Journal of Medicine and defends the its results with guests Liz Brem, MD, UC Irvine, and Daniel Landsburg, MD, University of Pennsylvania. Can polatuzumab vedotin supplant conventional R-CHOP as the standard of care for previously untreated DLBCL? As they work through the details of the study, the experts share whether they believe the data supports an immediate standard-of-care change or if more research is needed. Read the study published in NEJM https://www.nejm.org/doi/full/10.1056/NEJMoa2115304 Check out Chadi's website for all Healthcare Unfiltered episodes and other content. www.chadinabhan.com/ Watch all Healthcare Unfiltered episodes on Youtube. www.youtube.com/channel/UCjiJPTpIJdIiukcq0UaMFsA

Reviewing some big news from ASH21 concerning DLBCL that has us asking, "the more the change, the more R-CHOP remains the same?" Also, we talk CAR-T (ZUMA-7 & BELINDA), sotorasib, a possible way to predict poor response to ICI (HLA-A*03), and Evusheld as a possible way to protect those patients destined to a poor vaccine response from COVID.

Featuring perspectives from Dr Jonathon Cohen, including the following topics: Chimeric antigen receptor (CAR) T-cell therapy for non-Hodgkin lymphomas (0:00) Case: A woman in her mid-60s with relapsed diffuse large B-cell lymphoma (DLBCL) after R-CHOP and maintenance rituximab (27:20) Case: A man in his late 50s cured of DLBCL but with long-term toxicities related to CAR T-cell therapy (32:43) Case: A man in his early 60s with progressive mantle cell lymphoma after CAR T-cell therapy (38:36) CME information and select publications

This podcast will discuss data from a phase II trial evaluating the dose-adjusted EOPCH-R chemo-immunotherapy regimen for the treatment of primary mediastinal B-cell lymphoma in children.   TRANSCRIPT [MUSIC PLAYING] LISA GIULINO-ROTH: This JCO podcast provides observations and commentary on the JCO article "Dose-Adjusted Rituximab Therapy in Children and Adolescents with Primary Mediastinal B-cell Lymphoma, a Multicenter Phase II Trial" by Burke et al. My name is Lisa Giulino-Roth, and I am a pediatric oncologist at Weill Cornell Medical College in New York. My oncology specialty is lymphoma in children, adolescents, and young adults. I have no relevant disclosures. Primary mediastinal B-cell lymphoma, or PMBCL, is an aggressive non-Hodgkin lymphoma derived from thymic B-cells. While previously classified as a subtype of diffuse large B-cell lymphoma, PMBCL is now recognized as a distinct clinical and pathologic entity. Unlike diffuse large B-cell lymphoma, PMBCL has a peak incidence among adolescents and young adults and is more common in females. PMBCL also shares many molecular characteristics with Hodgkin lymphoma, including alterations in JAK-STAT pathway signaling and amplification of the 9p24.1 locus, leading to upregulation of PD-L1. Adults with PMBCL have historically been treated on regimens designed for diffuse large B-cell lymphoma, which in the US was most commonly R-CHOP and radiation therapy. More recently, adult patients have been treated with a dose-adjusted EPOCH-R regimen, which is composed of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab. This radiation-free approach is of interest, given this young and predominantly female population who are at risk for significant long-term toxicity from chest radiation. In a single center NCI-led study by Dunleavy and colleagues, dose-adjusted EPOCH-R was administered for six to eight cycles without radiation therapy and resulted in excellent outcomes with a five-year event free survival of 93% and overall survival of 97% among 51 adult patients. Pediatric patients with PMBCL have historically been treated on regimens designed for mature B non-Hodgkin lymphoma, which in pediatrics is most commonly Burkitt lymphoma or diffuse large B-cell lymphoma. These dose intensive multi-agent regimens include doxorubicin, high dose methotrexate, and intrathecal chemotherapy without radiation. Outcomes for children with PMBCL treated on these regimens are inferior to pediatric patients with diffuse large B-cell lymphoma treated on the same protocol. Children with PMBCL have a five-year event-free survival ranging from 65% to 75% in different international series. Given the excellent outcomes observed with dose-adjusted EPOCH-R in the adult NCI trial, an international phase II trial of this approach was conducted by two cooperative groups, The European Intergroup for Childhood Non-Hodgkin Lymphoma and the Children's Oncology Group. This single arm trial enrolled patients age 18 and under with primary mediastinal B-cell lymphoma. All patients were treated with six cycles of dose-adjusted EPOCH-R without radiation. The primary endpoint was event-free survival with events defined as any of the following-- viable cells in any residual mass after six cycles of treatment, relapse, progressive disease, secondary malignancy, or death from any cause. The four-year event-free survival from this trial would be compared with the event-free survival from historic controls, which was estimated at 67%. A total of 46 pediatric patients were enrolled between 2012 and 2016. All patients received six cycles of dose-adjusted EPOCH-R without RT. At a median follow-up of 59 months, there were 14 events, including four patients with viable cells in the residual mass at the completion of therapy, eight progressions or relapses, and two secondary malignancies, including one case of Hodgkin lymphoma and one case of acute promyelocytic leukemia. The event-free survival of the entire cohort at four years was disappointing at 69.6% with a 95% confidence interval of 55.2% to 80.9%. This was not statistically different than historic controls treated on pediatric mature B and HL regimens. Overall survival at four years was 84.8% with a 95% confidence interval of 71.8% to 92.4%. The authors acknowledge several limitations in the current study and challenges when comparing this study to the NCI trial. Not all patients adhered to the dose escalation rules, and 29% should have received a higher dose level in at least one course of treatment. Among the 10 cases of local relapse or primary refractory disease, five were noted to have a failure to dose escalate, including one patient with a clinical complication that precluded dose escalation. Comparing this trial to the NCI trial is challenging due to several important differences. Adults in the NCI trial were treated with six or eight cycles of dose-adjusted EPOCH-R based on the response between cycles 4 and 6. In pediatrics, eight cycles was not deemed appropriate, given the potential for greater than 600 milligrams per meter squared of cumulative doxorubicin exposure and concern for significant long-term cardiac toxicity at this exposure level. In addition, the NCI trial did not consider residual viable cells or secondary malignancy as an event, both of which were defined as events in the current pediatric trial. In a reanalysis of the pediatric data using the NCI event definitions, there was only a modest change in event-free survival with a four-year event-free survival of 73.9%. So where does this leave dose-adjusted EPOCH-R and the management of pediatric patients with PMBCL? In my opinion, there's no single superior regimen to treat pediatric PMBCL. Outcomes are similar across regimens. However, the toxicities are different. Dose-adjusted EPOCH-R offers significantly less short-term toxicity, but the potential for a higher cumulative doxorubicin dose compared to pediatric mature B and HL regimens. Regardless of the chemotherapy backbone, it is clear that for children with PMBCL, outcomes remain suboptimal, and further studies are needed to advance treatment. Given the rare nature of PMBCL and the peak incidence in the AYA population, combined pediatric and adult trials may allow us to evaluate novel agents and advance outcomes. Both children and adults with PMBCL may benefit from the incorporation of novel agents. Retrospective multicenter data from adults treated with dose-adjusted EPOCH-R have also failed to reproduce the excellent outcomes observed in the NCI trial. In two large retrospective series, adults with PMBCL treated with dose-adjusted EPOCH-R had a two- and three-year progression-free survival of 85% and 87% respectively. To advance outcomes in PMBCL across age groups, our team at the Children's Oncology Group in collaboration with Alliance and the National Clinical Trials Network is conducting a randomized phase III trial of the checkpoint inhibitor nivolumab in combination with chemo immunotherapy for adult and pediatric patients with PMBCL. Checkpoint inhibitors, including pembrolizumab and nivolumab, have demonstrated efficacy and PMBCL in the relapsed setting. And pembrolizumab is FDA approved for children and adults with relapsed PMBCL after two or more lines of therapy. However, these agents have not been evaluated in the upfront setting. In this trial, the treating physician will choose between R-CHOP and dose-adjusted EPOCH-R as the chemotherapy backbone. And patients will then be randomized to standard of care with six cycles of chemo immunotherapy alone or six cycles of nivolumab plus chemo immunotherapy. We are optimistic that this will define the role for checkpoint inhibition in the upfront management of PMBCL and work towards improved outcomes for both adult and pediatric patients. This concludes this JCO podcast. Thank you for listening. [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

In part one of this two-part ASCO Education Podcast episode, Dr. Sonali Smith (University of Chicago Medicine) and Dr. Paolo Strati (MD Anderson Cancer Center) discuss the application of recently approved therapies for diffuse large B-cell lymphoma through examination of challenging patient cases. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: education.asco.org | Contact Us Air Date: 10/20/21   TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. [MUSIC PLAYING] SONALI SMITH: Hello, and welcome to this episode of the ASCO Education Podcast highlighting new therapies for lymphoma. My name is Dr. Sonali Smith, and I'm a hematologist and medical oncologist specializing in lymphoma and clinical investigation in lymphoma. I'm also the Elwood V. Jensen Professor and chief of the hematology/oncology section at the University of Chicago, and very excited to be joined by my colleague, Dr. Paolo Strati. PAOLO STRATI: Good morning to everybody. My name is Paolo Strati. I'm a hematologist and medical oncologist and an assistant professor in the Department of Lymphoma/Myeloma, and in the Department of Translational Molecular Pathology at MD Anderson Cancer Center, Houston, Texas. And I'm also the clinical director for the Lymphma Tissue Bank. In part one of this podcast episode, we will discuss the adoption of recently approved therapies for diffuse large B-cell lymphoma, such as selinexor, tafasitamab, Liso-Cel, and Lonca-T. These therapies have transformed care for patients with this disease. And we'll start our conversation today with a patient case. SONALI SMITH: Great. Well, I'll go ahead and present a patient to you, Paulo. So this is a 78-year-old man with diffuse large B-cell lymphoma that is the germinal center-derived subtype. It is not double expressor, it is not double-hit. He has advanced stage disease with a high IPI, as well as the high CNS IPI. Luckily, his performance status is zero and he has no significant comorbidities or other health conditions. He received frontline dose-adjusted EPOC-R with intrathecal methotrexate for six cycles. But at the end, he had a partial remission. So how do you select your salvage therapy in this situation? Are you concerned about using agents targeting CD19 in the second line, given the potential need to use anti-CD19 cellular therapy, or CAR-T in the third line? PAOLO STRATI: This is a very interesting and unfortunately not uncommon case. And thank you, Sonali, for asking these very important questions. Technically, a platinum-based regimen followed by autologous transplant will be a standard answer and may be feasible. Because as you mentioned, this patient has a good performance status and non-meaningful comorbid health conditions. However, patients who are refractory to a frontline anthracycline-based regimen, such as in this case, with achievement only of partial remission at the end of frontline dose-adjusted EPOC, can potentially experience a suboptimal outcome following the standard approach with a platinum-based second line regimen. And as such, alternative strategies may be needed. To this regard, the combination of tafasitamab that, as you know, is a monoclonal antibody targeting CD19, and lenalidomide, an oral immunomodulatory agent, a combination which is currently approved by the FDA in the United States as a standard second line option for transplant ineligible patients, would be a great option in this case. Data from the three year follow-up of the phase II study that has brought to the FDA approval this combination, the L-MIND had been recently presented and have showed the complete remission rate of 40% and immediate duration of response of 44 months, including patients who received this regimen as a third line or beyond. So there is, of course, a biological concern by targeting CD19 in second line. These may potentially impact a third line use of an autologous anti-CD19 CAR-T, because CD19 downregulation may potentially be a mechanism of escape to tafasitamab. And recent data has shown the CD19 levels are strongly associated with the efficacy of CAR-T cell therapy in patients with large B-cell lymphoma. Small retrospective studies have shown that autologous anti-CD19 CAR-T can be safely and effectively used after antibodies or antibody drug conjugate targeting CD19. But we need a significantly larger and prospective data, including serial tissue biopsy in these patients before considering this combination as a standard practice in patients for whom we plan to use CAR-T as a third line. Until then, I would be cautious in using second line tafasitamab in patients, again, for whom there is a potential plan for anti-CD19 autologous CAR-T in third line. And if necessary, limited to very selective cases. Finally, recent press releases have anticipated the two autologous anti-CD19 CAR-T products, Axi-Cel and Liso-Cel, are superior to autologous settings transplanted in second line. And so in the near future, CAR-T cell therapy may become a standard second line option. And that would be an ideal option in primary chemorefractory patients as the case that you presented here. SONALI SMITH: Yeah, I agree. There are a tremendous number of options. And having anti-CD19 products as well as autologous stem cell transplant, the sequencing will be an evolution. So going back to this patient, he received tafasitamab and lenalidomide for two cycles with no significant toxicity, but unfortunately, he had further progression after two cycles based on a PET/CT scan. So what are your next steps? Would you move directly to an autologous anti-CD19 CAR-T cell therapy now? Would you re-biopsy before that? And how would you select among the three available CAR-T products? PAOLO STRATI: These are not easy questions, particularly the selection of one out of three available CAR-T products. As you said, there are currently three autologous anti-CD19 CAR-T products approved by the FDA in the United States for the treatment of large B-cell lymphoma in third line or beyond. And these are Axi-Cel, Tisa-Cel, and Liso-Cel. For all of them, the best outcome is observed for patients who have a low turmor burden at time of CAR-T infusion. And they need to either select patients with no bulky disease or to decrease it through bridging therapy. And as we define bridging therapy given between leukapharesis and CAR-T infusion. Unfortunately, there is currently no standard bridging therapy and all FDA products approved in third line can potentially be used in this specific scenario that you described, including polatuzumab with bendamustine/rituximab, selinexor, and Lonca-T, of course, beyond tafasitamab and len that has already been used in this case. Of course, when selecting a bridging therapy, there are many disease-related and patient-related factors to take into consideration, including the need to preserve the host immune microenvironment that we all know is crucial for the subsequent activity of CAR-T cells. And also, we need to give into consideration the need to preserve as much as possible, as we discussed previously, in CD19 expression. To this regard, and going back to one of your questions, I strongly recommend to re-biopsy patients if any bridging therapy is used between bridging therapy and CAR-T infusion in order to document CD19 expression before CAR-T infusion. When it comes to CAR-T product selection, as I said, it's a really difficult decision to do. And we don't have at this time randomized trials in third line. And as such, the decision is really left to the treating physician based on multiple factors. But all of the limitations of inter-study comparison, efficacy seems to be pretty much the same for the two products, maybe slightly higher based on the recent second line data. But Axi-Cel and Liso-Cel as compared to Tisa-Cel, and also as suggested by recent press release. However, due to the fact that Liso-Cel and Tisa-Cel have less potent co-stimulatory domain for 1BB instead of CD28, the rate of CRS and ICANS, the two main toxicities associated with CAR-T cell therapy, is usually lower with this to the point that some centers are able to infuse them in the outpatient setting, whereas Axi-Cel is almost always infused in the inpatient setting so the toxicity can be monitored more closely. So with older patients or those who have comorbid health condition, Tisa-Cel and Liso-Cel may be a safer option, though there's a lot of research going on trying to mitigate toxicities associated with Axi-Cel. Finally, it's important to keep in mind manufacturing time. Axi-Cel is manufactured in an average of 17 days, whereas Tisa-Cel and Liso-Cel take typically longer than three to four weeks. This can be itself a determining factor, particularly for patients who are quickly progressing and where immediate treatment is needed. SONALI SMITH: Yeah, I agree. I think there are going to be many patient product and disease-based factors that will impact both the effectiveness as well as the toxicity. And you did a really great job of explaining the role of the co-stimulatory domain potentially in some of that, as well as all of the products that are out there. It's definitely a complicated area. Going back to our patient, so he did undergo leukapharesis for Liso-Cel and received third line polatuzumab and rituximab without bendamustine. The restaging PET/CT after two cycles showed a PR with a significant decrease in tumor burden, and repeated biopsy showed high expression of CD19 by flow cytometry. He then proceeded with Liso-Cel, which was relatively well tolerated. There was only grade 1 cytokine release syndrome and no ICANS, so no neurotoxicity. And his day 30 PET/CT showed a complete remission. Unfortunately, the 90 day PET/CT showed progression. So Dr. Strati what is the outcome for patients who relapse after CAR-T? Do you recommend to re-biopsy? And what are the efficacy data for FDA approved agents for these patients? And I know this is a long question, but is there any role for repeated CAR-T or allogeneic transplant now? PAOLO STRATI: Unfortunately, currently, the outcome of patients with large B-cell lymphoma relapse or progress after autologous anti-CD19 CAR-T is suboptimal, with a life expectancy, unfortunately, shorter than six months. Hence, the need to be creative and customize treatment based on biological data. To this regard, I think it's crucial to repeat a tissue biopsy to guide subsequent therapy. As mentioned previously, there are currently four products approved by the FDA for patients with large B-cell lymphoma in third line and beyond. Two of these target CD19, tafasitamab plus lenalidomide and Lonca-T One targets CD79B, polatuzumab combined with bendamustine and rituximab. And one is an SPO1 inhibitor, selinexor. While we have no data for selinexor in patients who relapse or progress after CAR-T cell therapy, limited prospective data showed that a progression-free survival in the order of weeks is usually observed for patients who receive polatuzumab with or without bendamustine and rituximab after CAR-T cell therapy. So I would not recommend that. However, there's some interesting activity in the post-CAR-T setting for Lonca-T and for tafasitamab/len is limited to patients who still express CD19 in time of relapse. And of course, it needs to be largely and prospectively further investigated before becoming a standard approach for patients who relapse or progress after CAR-T cell therapy. When it comes to cellular therapy, repeated anti-CD19 CAR-T infusion is not shown to be successful in the original registration studies. So it is not currently something that I would recommend and is not definitely a common practice. And very limited retrospective studies have shown the use of allogeneic stem cell transplants in the post-CAR-T setting may be associated with quite elevated treatment-related mortality. So I don't suggest this as a standard practice in large B-cell lymphoma at this time. This is different from B acute lymphoblastic leukemia, where instead, allogeneic stem cell transplant is becoming progressively a standard approach. And we definitely need more data before using this consistently. While we strive to identify the optimal cell batch therapy for large B-cell lymphoma patients who relapse or progress after CAR-T cell therapy. I think the priority should be given to clinical trials, including CAR-T targeting molecules other than CD19, such as CD20, CD22, CD79B, allogeneic CAR-T there are immediately available, so without the need to wait for manufacturing times. And K-CAR, that may be less toxic than CAR-T and other non-cellular therapy biological agents. So definitely, clinical trials are, at this time, the best approach in patients who relapse after CAR-T cell therapy, as the case that you described. SONALI SMITH: Thank you Dr. Strati. As an update, this patient had repeated biopsy showing a CD19 positive relapse. He consented for a clinical trial with a novel NK-CAR targeting CD19, achieving CR which is still ongoing at nine months. And this case really does represent some of the most exciting advances that we've had for this disease for patients who can tolerate aggressive therapies and have access to clinical trials. PAOLO STRATI: Dr. Smith, I'd like to hear your opinion about another patient with diffuse large B-cell lymphoma. This patient is an 81-year-old man with a history of coronary artery disease and well-controlled diabetes mellitus, who noticed a right cervical lymph node while shaving that seemed to have popped up. He was evaluated by his primary care physician and given a course of antimicrobials. 10 days later, the lymphoma seems to be enlarging and he is referred to ENT pharyngeal biopsy. The specimen is small but shows follicular lymphoma in a portion of the sample. However, there is also concern for larger cells and possible transformation. The patient is also beginning to note night sweats and a decreased appetite. And labs are notable for elevated LDH, 500, and thrombocytopenia with a platelet count of 110. So Dr. Smith, in your opinion, is this specimen sufficient to start treatment? Or should treatment be delayed to get a larger and maybe excisional biopsy? SONALI SMITH: Yeah, thank you for this question. I think this is a challenge we have in the clinic all the time, which is what is a sufficient biopsy specimen to make a diagnosis that allows us to subtype lymphoma? As we know, every lymphoma subtype, the treatment is really guided by the histology and not so much the stage or some other factors. So having a needle biopsy is unfortunately often insufficient. In this case, we have a very strong concern for a possible transformation. And as we know, both follicular lymphoma and diffuse large B-cell lymphoma can mark very similarly when it comes to immunophenotype. Certainly, the germinal center type of diffuse large B-cell lymphoma or any transformed follicular lymphoma will be CD20 positive, CD10 positive, and it really requires architecture to be able to tell whether or not there are sheets of large cells. So the ideal outcome for this patient would be to have a biopsy that is done promptly that allows us not only to confirm whether or not there is histologic evidence of transformation, but also to conduct FISH studies to determine if there's acquisition of a MYC rearrangement. At its core, all follicular lymphoma patients essentially have a transformation of 14;18, leading to BCL2 rearrangement and BCL2 overexpression. During the transformation process, there can be an acquisition of a MYC rearrangement, which would then make this a double-hit lymphoma and certainly has a much worse prognosis and may also prompt a change in treatment if the patient can tolerate more intensive therapy. So my recommendation would be to have a biopsy. Now one other aspect is that sometimes, we don't really have the time to proceed with a biopsy, or the lymph node may be in an inaccessible area. And in that case, there are some other criteria that we can use to assume that somebody has a transformation. Symptoms such as profound B symptoms and elevated LDH, and sometimes, a PET scan with multiple areas of very high avidity, can lead you to feel or suggest that this person has a transformation. There is some controversy over the use of PET and we know it does not confirm a diagnosis of transformation. But in my opinion, this is very suggestive if there are many areas of high SUV. PAOLO STRATI: Thank you, Dr. Smith. I agree completely about the importance, when time allows, to perform either a larger core biopsy or an excisional biopsy, because as you very well-outlined, this has not just a mere diagnostic purpose, but can meaningfully affect treatment planning for patients. And actually, in this case, as you suggested, the patient eventually had multiple core biopsy that showed transformed follicular lymphoma with very evident areas of diffuse large B-cell lymphoma. FISH, as expected for follicular lymphoma, was positive for translocation for TN18, but luckily negative for MYC rearrangement. So fortunately, we didn't have to deal with a double-hit lymphoma. The remainder of his staging showed he had diffuse lymphadenopathy. And PET scan, as you mentioned, has a controversial role in the diagnosis of transformation. So there's some areas that had high avidity with an uptake with an SUV of 1215, whereas other areas were less intense with SUV 618. And usually, heterogeneity in SUV actually helps further supporting diagnosis or transformation. While meta-maps showed follicular lymphoma, no large cells. So movement was isolated in the B-cell lymphoma. So Dr. Smith, at this point, based on the provided information, what's your treatment approach in this older patient and also a patient with comorbid health conditions, but with diffuse large B-cell lymphoma? SONALI SMITH: Yes. The goal of treating any aggressive lymphoma is to obtain remission, and if the remission lasts, to hopefully offer cure to the patient. And when somebody has a transformed lymphoma, of course, there is a dual concern, which is that the aggressive component can potentially be put into remission in a durable way achieving cure. But the indolent component will always need to be monitored, although hopefully, will not be life threatening the way the aggressive component can be. Treating an octogenarian is really challenging, particularly due to comorbidities in this age group and the potential toxicity of chemotherapy. So the standard of care for diffuse large B-cell lymphoma is anthracycline-based chemotherapy. But this, of course, can have significant toxicity in older patients. And in addition, the vincristine can aggravate neuropathy. And I've personally found that the high dose steroids that are part of CHOP can also cause toxicity in older patients and patients who are frail. So unfortunately, the literature is somewhat sparse. But we do have several data sets that can guide management in this particular patient situation. The French published, over a decade ago, the development of R mini CHOP, that includes an attenuated dose of cyclophosphamide, doxorubicin, and vincristine, and leads to some durable remissions and cure. Unfortunately, the long-term overall survival is less than 50% with R mini CHOP. And so although this is an appropriate backbone, there's certainly a lot of room for improvement. And there's also toxicity even with R mini CHOP. So in their initial phase II trial, there was actual deaths related to the R mini CHOP, particularly in the first cycle or two, really necessitating some type of pre-phase help ease patients into the chemotherapy. One of the challenges that we face in the clinic is that when we meet an older patient, we both want to maximize our chance for cure, but also minimize the toxicity that is particularly pronounced. And there is very little data in terms of how to guide this at the bedside. I'm excited that SWOG, with the US Intergroup, is conducting a trial, S1918, which prospectively includes a frailty assessment tool that was developed by the Italian group in lymphoma, and then also includes serial comprehensive geriatric assessment so that we can get a better idea about quality of life both during and after treatment. So there is no great standard of care right now, but I would say that R mini CHOP, outside of a trial, is a very reasonable way to proceed. PAOLO STRATI: Dr. Smith, thank you for outlining so well what we can do to minimize toxicity and to better select patients for this type of treatment. And as an Italian practitioner in the United States, I am very excited that the Italian frailty tool will be used in this SWOG trial. Are there any other ways to further improve safety when we use chemo immunotherapy in older patients or patients with comorbid health conditions? In particular, there is a lot of concern about potentially infectious complications in these patients. And so I'm wondering if there's any routine antimicrobial prophylaxis that you recommend. SONALI SMITH: Yes. I think it's really important to maximize supportive care for our older patients with aggressive lymphomas getting intensive therapy. I did mention the pre-phase, and I would just like to mention that one more time because I do think there's data that providing a brief pre-phase can minimize toxicity with the first cycle. And how this pre-phase is given is highly variable. Again, the data is somewhat limited, but it typically includes steroids given for five to seven days with or without a dose of vincristine. And steroids themselves can have toxicity. And the dose of the steroids, I think, is somewhat controversial. In my personal practice, I use somewhere between 40 to 60 milligrams per day for five to seven days. And I do not typically use vincristine, although a prospective French trial recently did and showed that this significantly improved toxicity. Other complications that can occur really are related to infection. And so, of course, all patients should have growth factor support as per ASCO guidelines. But I also routinely give VZV prophylaxis with acyclovir or valacyclovir. And for the first cycle in particular, I have patients come back to clinic after the first dose one week later to ensure that the counts are stable and that they are doing well. This is really where our team of nurses and other providers who are part of the care team are so important and communication is also very important. PAOLO STRATI: So Dr. Smith, as you suggested, also, this patient actually received mini R-CHOP without any complications. And end-of-treatment PET/CT can showed a VL score of 3, so a complete metabolic remission, potentially. How do you interpret these findings? SONALI SMITH: So response criteria in clinical trials, and then of course, extrapolated to the clinic, have evolved in lymphoma. And the Deauville or the International Prognostic Scoring System that has been used typically defines a uptake relative to liver and mediastinal blood pool. And those patients who have a Deauville 1 to 2, which is less than that bar, is considered negative. And 4 to 5 is positive, with five being the emergence of new sites of adenopathy. The interpretation of a Deauville 3 can be somewhat more complicated, but this really outlines the limitations of just using the SUV or the PET scan uptake to measure response. For my patient and for this patient, the lymph nodes all substantially decreased in size. And having some type of combined interpretation of the uptake, as well as the size that has decreased, I think is going to be a very important part of how we approach patients going forward. So for this patient, I opted for close observation after the completion of therapy and felt that his Deauville 3, along with the decrease in the size of the lymph nodes, was very significant. PAOLO STRATI: I completely agree with that. Where PET scan is an extremely helpful tool, particularly for the management of aggressive B-cell lymphoma, can also become a major challenge when it comes to its interpretation for these borderline scenarios. And as you said, it's very important to add into the equation multiple parameters, including CT findings and overall patient performance status symptoms. So that's all we have for today. Thank you, Dr. Smith. This was a great conversation. We have learned and discussed a lot about diffuse large B-cell lymphoma, including novel biological agents, CAR-T cell therapy, management of elderly patients, and patients with comorbid health conditions and interpretation of PET/CT scan. I think this will be very helpful. And the conversation will continue beyond this podcast. In part 2 of this episode, airing in November, we will discuss new therapies for mantle cell lymphoma and for follicular lymphoma. Thank you so much to all the listeners tuning into this episode of the ASCO Educational Podcast. SONALI SMITH: Thank you. It's been a pleasure to speak with you today. [MUSIC PLAYING] SPEAKER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

During the 16th International Conference on Malignant Lymphoma (16-ICML), the Lymphoma Hub spoke with Laurie Sehn, The University of British Columbia, Vancouver, CA, and Grzegorz Nowakowski, Mayo Clinic, Rochester, US. We asked, Is frontline R-CHOP still the standard of care for DLBCL?They begin by revisiting a debate from ICML centering on what the optimal upfront therapy is for DCLB, for Sehn R-CHOP remains the standard of care in most settings and Nowakowski suggests instances where other approaches might be preferred. They go on to discuss recent clinical studies and their impact on the current treatment landscape of DLBCL. Finally they explore how to integrate the results from clinical trials and highlight a promising future for DCLB treatment. Hosted on Acast. See acast.com/privacy for more information.

Alan Skarbnik (@ASkarbnik), MD, director of the lymphoma and CLL program, Novant Health (Charlotte, NC), and Aaron Goodman (@AaronGoodman33), MD, hematologist, University of California San Diego, join the show for a long-awaited debate: treating double-hit lymphoma with R-CHOP vs dose-adjusted (DA)-EPOCH-R. The conversation gets testy when the trio describe double-hit lymphoma in terms of histology and phenotype, the limitations of retrospective analyses when it comes to establishing a standard of care for this type of lymphoma, an intense breakdown of the CALGB 50303 study as it relates to the treatment argument and toxicity profiles, and so much more.

Dr. John Sweetenham, associate director for Clinical Affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center and Editor-in-Chief of ASCO Daily News, discusses key abstracts on hematologic malignancies featured at the 2021 ASCO Annual Meeting.   Transcript ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll. My guest today is Dr. John Sweetenham, the associate director for clinical affairs at the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center. Dr. Sweetenham is also the editor-in-chief of the ASCO Daily News, and joins me to discuss key abstracts on hematologic malignancies featured at the 2021 ASCO annual meeting. Dr. Sweetenham reports no conflicts of interest relating to our discussion today, and full disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/podcasts. Dr. Sweetenham, it's lovely to have you back on the podcast. Dr. John Sweetenham: Thanks, Geraldine. It's a pleasure to be able to speak with you again. ASCO Daily News: Dr. Sweetenham, there are some really promising developments in therapies for adult patients with acute lymphoblastic leukemia. Can you tell us about these studies? Dr. John Sweetenham: Yes. There are two abstracts in particular at this year's meeting, which I think are of particular interest for adult patients with acute lymphoblastic leukemia. This is typically a difficult disease to treat in adults. And two abstracts in particular caught my eye. The first of these is Abstract 7001. And this describes a phase II study of a combination of a tyrosine kinase inhibitor, ponatinib, and a bispecific T cell engaging antibody, blinatumomab, which is directed against CD19 for patients with a particularly refractory type of ALL, and that's patients with Philadelphia chromosome positive ALL. This is a single arm phase II study for patients with both newly-diagnosed and relapsed or refractory Philadelphia-positive ALL. And in the protocol as described, the patients received up to five cycles of blinatumomab as a continuous infusion of the standard approved dose. And combined with this was ponatinib initially at a dose of 30 milligrams daily during cycle 1, and then subsequently reduced to half that dose until a complete molecular remission was achieved. Thereafter, the patient was continued on ponatinib for at least 5 years. And the treatment was also supplemented by intrathecal prophylaxis. Only 28 patients are on this small study. But nevertheless, I think the results are very intriguing. 95% of the patients responded to this treatment. And in the previously untreated patients, the response rate was 100%, compared with 88% in the relapsed and refractory group. And among the responding patients, 86% achieved a complete molecular remission. Remarkably, none of the patients in the newly diagnosed cohort required stem cell transplantation. And overall, with a median follow-up now of 14 months--so still relatively early, admittedly--the estimated 1 year overall survival rate is 94%, with an event-free survival rate of 81% for the entire study population. In the previously untreated cohort, no patients have relapsed or died. The 1-year overall and event-free survival rate in this particular subgroup is 100%. So what, to me, is really intriguing and exciting about this is a chemotherapy-free regimen for the upfront treatment of a particularly difficult-to-treat subtype of adult ALL. So these are truly encouraging and really quite remarkable results. Of course, they need to be qualified because it's very early days, small numbers, relatively limited follow-up, but intriguing nevertheless. The second study, which I think is really confirmatory of some earlier results, is described in Abstract 7002. And this describes the phase II results of the so-called ZUMA-3 study evaluating a CAR T-cell products directed against CD19 in adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia. The phase I efficacy results were previously reported a couple of years ago at ASH. And this study represents the follow-up phase II study. Eligible patients for this study all had relapsed and refractory B-cell ALL treated with CAR T-cells that the dose that was described from the original phase I study, with a primary endpoint of complete remission rates. And key secondary endpoints in the study included duration of remission, relapse-free survival, overall survival, and the presence or absence of measurable residual disease by flow cytometry. As of September 2020 when this study was originally reported, 55 of the 71 enrolled patients that received their CAR T cell products and the complete response rate combining CR and CRI rate was 71%. And 31% of the responders had ongoing responses. Looking at the median duration of response, relapse-free survival, and overall survival, these were respectively 12.8, 11.6, and 18.2 months. But for those patients who responded, the relapse-free and overall survival were respectively 14.3 months and not yet reached. So, again, relatively early results, but nevertheless very interesting, showing after a median follow-up of 16.4 months, there was clear and quite compelling clinical benefits in heavily pretreated adults with relapsed and refractory B-cell ALL, with a median overall survival not yet being reached. So, given, again, that this is a particularly difficult group of patients to treat, it's another example of a very promising result from CAR T cell therapy in a difficult clinical situation. ASCO Daily News: Absolutely, some very interesting advances there in ALL. Well, patients who have received a stem cell transplant have felt especially vulnerable during the COVID-19 pandemic. A couple of abstracts assess the outcomes of allogeneic stem cell transplant recipients amid the pandemic. What are your thoughts on these studies? Dr. John Sweetenham: Yes, thanks. So, two abstracts of particular interest, Abstract 7033 is a study which addresses the outcomes for all patients undergoing hematopoietic stem cell transplants and cellular therapy, both autologous and allogeneic, as well as a few patients with CAR T cell therapy during the COVID-19 pandemic, really just looking overall at outcomes compared with essentially, historical controls. It was a single center prospective study, which included in all, approximately 40 patients undergoing either hematopoietic stem cell therapy or other cellular therapies who were diagnosed with COVID-19 between April of 2020 and January of 2021. As I mentioned, 40 patients were included, 25 of whom underwent allogeneic transplants, 13 autologous transplants, and 2 underwent CAR T cell therapy. And these were done for a variety of hematologic malignancies. And in the allogeneic patients, a variety of STEM cell sources were chosen. And the patients had a number of treatments for their COVID-19, directed specifically at the COVID-19, which included remdesivir, convalescent plasma, dexamethasone, and some monoclonal antibodies. The bottom line from the study, and perhaps this is really not too surprising, is that the patients undergoing hematopoietic stem cell transplantation with COVID-19 had an increased risk of mortality. And that particularly related to undergoing allogeneic versus other types of cellular therapy and the presence of concurrent immune suppression. So this study demonstrated something which I think is intuitive, but for which there hasn't been a lot of literature yet, essentially saying that patients who undergo transplant in the presence of active COVID-19 have relatively poor outcomes compared with those who are non-COVID-19 positive. The other abstract which drew my attention was Abstract 7032, a very different abstract in many ways, in that it looked at the association of COVID-19 with distress and the quality of life for patients undergoing hematopoietic stem cell transplantation. And this was a cross-sectional analysis of data from 205 patients with hematologic malignancies undergoing stem cell transplantation and enrolled in a multi-site randomized supportive care trial that they compared baseline pre-transplant distress which included depression, anxiety, and post-traumatic stress disorder symptoms, and quality of life between participants enrolled pre-COVID-19 and during the COVID-19 pandemic. Prior to the COVID-19 pandemic, 124 participants enrolled, and then 81 enrolled during the COVID-19 pandemic. Interestingly enough, in multivariate regression models, enrollment during COVID-19 was not associated with pre-transplant depression, anxiety, PTSD symptoms, or quality of life. So the conclusion is interesting in that this study reports that contrary to the generally held notion that the COVID-19 pandemic has worsened distress in patients with cancer, there was no difference in distress or quality of life in these patients with hematologic malignancies prior to or during the COVID-19 pandemic. ASCO Daily News: Yes, that's an interesting conclusion as you say, and a little unexpected. Well, let's focus on chronic lymphocytic leukemia. Are there any new therapies on the horizon for patients with CLL? Dr. John Sweetenham: So, two abstracts this year's ASCO [Annual Meeting] describe what I think is significant advances with newer therapies, which I think are now really finding their place in the therapeutic algorithm for CLL. Abstract 7500 reports the results of a large randomized comparison on a head-to-head basis between ibrutinib, the first in class Bruton tyrosine kinase inhibitor, and a more selective tyrosine kinase inhibitor, acalabrutinib. This was a randomized, head-to-head non-inferiority study which compared acalabrutinib with ibrutinib in patients with previously treated CLL of all risk groups. And overall, 533 patients were randomly assigned between these two therapies. And at the median follow-up of around 41 months. Now, acalabrutinib was found to be non-inferior to ibrutinib, with a median progression-free survival of 38.4 months in both arms of the study. But importantly, acalabrutinib was found to be superior to ibrutinib in terms of toxicities, which included the incidence of atrial fibrillation. Among the other secondary endpoints of the study were incidences of grade 3 infection, which were comparable between the two arms, as was the rates of Richter's transformation. Not surprisingly, because the routine tyrosine kinase inhibitors are such effective drugs in CLL, the median overall survival was not reached in either arm of the study. Acalabrutinib demonstrated a lower incidence of hypertension, arthralgia, and diarrhea compared with ibrutinib, but a somewhat higher incidence of headache, 34% versus 20%, and cough at 28% versus 21%. And of note, adverse events led to treatment discontinuation in just over 14% of patients on acalabrutinib versus 21% of those treated with ibrutinib. So in summary, acalabrutinib demonstrated a non-inferior progression-free survival with less cardiotoxicity and fewer discontinuations due to adverse events when compared with ibrutinib. So I think that this does pave the way for some of the later generation tyrosine kinase inhibitors, which certainly appear to maintain the efficacy of ibrutinib, but appear to have somewhat lower toxicity. This study was conducted in the relapse refractory setting. And clearly, the next question is going to be whether in the frontline setting, we would expect to see similar findings with acalabrutinib. The other study of note, I think, from the CLL abstracts this time is Abstract 7501. And this is a summary of the so-called CAPTIVATE study. This is a multi-center phase II study of first line ibrutinib combined with venetoclax, a BCO2 inhibitor, for patients with CLL. The study is important because it uses a fixed duration regimen. And to give that some context, many of the newer treatments, oral treatments for CLL with ibrutinib being the initial drug of this type, have been given continuously into either disease progression or until the patient becomes intolerant of the treatment because of side effects. And so there has been an ongoing series of investigations looking at whether it's possible to give these treatments in a fixed duration way rather than indefinitely because of the risks of long-term toxicity and so on. So in this study, patients less than age 70 with previously untreated CLL received three cycles of ibrutinib, and then 12 cycles of the combination of ibrutinib plus venetoclax, and then study was completed at the end of those 12 cycles. The primary endpoint of this study was the complete response rates with secondary endpoints of overall response rate, duration of response, minimal residual disease rate, and then progression-free and overall survival. To date, 159 patients have been enrolled on this study, with a median time on study of around 27.9 months. With a fixed duration combination, the complete response rate was reported at 55%, and the overall population was consistent across all of the high-risk groups, including those with adverse cytogenetic findings. Of the 88 patients who achieved a complete response, 78, representing 89%, had a duration of greater than 1 year. And the overall response rate for the entire group was 96%. And as I mentioned, there was no difference in those patients who had a 19p deletion, so another example of a novel first line regimen given at fixed duration which is chemotherapy-free and is providing really quite remarkable and intriguing results in the upfront setting for patients with CLL. ASCO Daily News: Great. Thanks for highlighting those two interesting studies on CLL. So focusing on Hodgkin lymphoma, can you tell us about advances using PET-directed therapy? And how do you see this evolving in the future? Dr. John Sweetenham: Yeah, absolutely. So, Abstract 7507 describes what I think is a very important study further investigating the use of functional imaging in therapy of that adaptation in patients with Hodgkin lymphoma. So typically, in the early-stage setting for patients with non-bulky early-stage Hodgkin lymphoma, there is now a wealth of evidence that interim PET scanning after a couple of cycles of ABVD chemotherapy, or other induction therapy, is a strong predictor of eventual outcome and can enable you to tailor the use of radiotherapy and potentially omit radiation therapy in patients who are PET negative early in the course of their chemotherapy. In patients with bulk early-stage Hodgkin lymphoma, that's been a little more controversial as to whether PET scanning on an interim basis early in the course of treatment is really reliable. So this is really quite an important Alliance study, CALGB 50801, which has tested the PET adapted approach in patients with bulk Hodgkin lymphoma. So eligible patients had stage IA through IIB classical Hodgkin lymphoma with disease bulk, which was defined as greater than 10 centimeters or more than 1/3 of the maximum intrathoracic diameter on a conventional chest X-ray. And the patients received two cycles of ABVD chemotherapy followed by a centrally viewed PET scan. If the PET scan was negative, defined as Deauville 1 through 3, patients who were PET negative received four additional cycles of chemotherapy but no radiation therapy. If the PET after two cycles was positive, the patients received intensified chemotherapy with escalated BEACOPP plus 30 Gray of involved site radiation therapy, with a primary endpoint in this study of progression-free survival. 101 patients have been enrolled on the study, of whom 94% were evaluable. 78% of these patients were PET negative after two cycles of ABVD. And in this group, the progression-free survival is 93.1. Of the remaining patients who were PET positive after two cycles of ABVD and went on to receive more intensified chemotherapy plus radiation therapy, the progression-free survival was also impressive at 89.7%. The overall survival in the study is also excellent. But the take-home message here is that excellent progression-free survival outcomes can be observed in patients with early-stage bulk Hodgkin lymphoma if they are PET negative after two cycles of ABVD, go on to complete six full cycles, but did not receive radiation therapy. And this is really a further important advance and omits the long-term risks of radiation therapy for a very significant proportion of these patients with bulk disease. Similarly, for those who are PET positive after two cycles and their treatment has escalated to more intensive chemotherapy retaining radiation, their long-term progression-free and overall survival is excellent. So, I think this is one more piece of evidence for the usefulness of functional imaging as a biomarker for response in patients with Hodgkin lymphoma which can lead to de-escalation of therapy in those patients with a good prognosis, and escalation of therapy for those who are likely to need more intensive therapy to achieve an equivalent outcome. ASCO Daily News: Excellent. Well, that's great news. Well, my last question is about mantle cell lymphoma. There's an interesting study that has real-world data for outcomes in MCL in community-based practices across the United States. What can you tell us about this study, Abstract 7504? Dr. John Sweetenham: Yes, thanks. So, as you mentioned, this is a study which is retrospective in nature and included patients with adult mantle cell lymphoma [who were] treated over a 10-year period from 2011 through the end of 2020. Just over 3,400 patients were included in this analysis, of whom 85% had been treated in a community oncology setting, and 85% were patients undergoing front line therapy. From a demographic point of view, the disease characteristics were very consistent with published data. Chemoimmunotherapy was the most common first line treatment, usually with either bendamustine and rituximab or R-CHOP. And the cytarabine-based regimens comprised a minority with only 14% of patients receiving these. 667 patients received rituximab maintenance in this study, and 243 received a frontline stem cell transplant in first remission, most of these transplants being autologous. The median follow-up for survival on this study was 45.3 months. The 36-month overall survival for the entire group was 67%. This large real-world cohort of patients primarily treated in community-based practices demonstrates outcomes which are somewhat inferior to those which we've seen reported from prospective trials. This suggests the need to focus on developing treatments that can be delivered effectively in the community setting. And perhaps the best example of this is that the use of stem cell transplantation in a community setting was uncommon even in those patients who are less than age 65. And what this gives us a clue to is the fact that maybe real-world considerations, including access to trials, access to treatments as a whole, suggests that these considerations may influence the eligibility for stem cell transplantation and some of the other more intensive approaches to treatment. ASCO Daily News: Absolutely. Well, thank you so much, Dr. Sweetenham, for highlighting these interesting advances in therapy for hematologic malignancies. It's always a great pleasure to speak with you. Dr. John Sweetenham: Thanks, a pleasure to speak with you too, Geraldine. And thanks for giving me the opportunity to talk about some of these exciting data. ASCO Daily News: Of course. And thank you to our listeners for your time today. If you enjoyed this episode, please take a moment to rate and review us wherever you get your podcasts.   Disclosures: Dr. John Sweetenham: None disclosed Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Featuring an interview with Dr Gilles Salles on the following topics: Novel and emerging strategies for diffuse large B-cell lymphoma (DLBCL) (0:00) Available efficacy and safety data with the antibody-drug conjugate polatuzumab vedotin for DLBCL (1:01) Mechanism of action of selinexor, the novel selective inhibitor of nuclear export; key efficacy and safety findings from the pivotal Phase II SADAL trial of selinexor for relapsed/refractory (R/R) DLBCL (8:15) Emerging data with tafasitamab and biologic rationale for combining it with lenalidomide for DLBCL; benefits and risks of tafasitamab/lenalidomide for patients with R/R DLBCL (14:58) Role of chimeric antigen receptor (CAR) T-cell therapies in the management of DLBCL (25:18) Therapeutic algorithm for patients with DLBCL (31:35) Biologic rationale for the investigation of the novel bispecific antibody mosunetuzumab; activity and tolerability of mosunetuzumab in DLBCL (38:46) Efficacy of the antibody-drug conjugate loncastuximab tesirine and the anti-CD47 antibody magrolimab; role of venetoclax-based therapy for DLBCL (45:34) Case: A man in his late 60s with DLBCL receives polatuzumab vedotin in combination with bendamustine/rituximab (B/R) after disease progression on 3 lines of therapy, including autologous stem cell transplant and CAR T-cell therapy (53:30) Sequencing of tafasitamab/lenalidomide, polatuzumab vedotin/BR and selinexor for patients with R/R DLBCL (1:01:32) Response to bispecific antibodies in patients with DLBCL (1:04:59) Case: A woman in her mid-70s receives tafasitamab and lenalidomide after experiencing disease relapse on R-CHOP for Stage IV DLBCL (1:09:22) Case: A man in his early 70s presents with DLBCL with C-MYC and Bcl-2 translocation (1:11:21) CME information and select publications

This podcast considers the impact of exclusion criteria on clinical trials, generalizability, and the complexity of modernizing eligibility while maintaining trial integrity.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Impact of Organ Function-Based Clinical Trial Eligibility Criteria in Diffuse Large B-cell Lymphoma (DLBCL) Patients. Who Gets Left Behind?” by Khurana et al. My name is Richard Little, and I am at the National Cancer Institute. My oncologic specialty is lymphoid and myeloid malignancies. I am a federal employee with no conflicts of interest to disclose.    The authors have contributed a timely and provocative analysis examining the lack of generalizability and disappointing results of repeatedly negative randomized phase 3 trials conducted over the past 15 years failing to improve on R-CHOP.  The authors have proposed that these failures may be in part explained by enrollment onto clinical trials patients who are not really representative of those with the disease, because eligibility criteria too often unnecessarily eliminate patients with laboratory values that reflect organ impairment not pertinent to the agents under study.  To test this inference, the authors leveraged a unique resource:  The Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence, or SPORE. This SPORE is an NCI-funded research project initiated in 2002 and collects data in a uniform manner among consenting participants with newly diagnosed DLBCL who undergo treatment managed by their physician. This rich database enabled the evaluation of data in patients treated with R-CHOP or R-CHOP-like immunochemotherapy.   The investigators were able to categorize the SPORE participants in reference to the eligibility criteria of the important phase 3 studies recently conducted as either meeting eligibility of the phase 3 studies or not meeting eligibility due to out-of-range laboratory values.  Additionally, the SPORE data in some ways mimics clinical trial data in that events such as disease progression and death are captured, and these outcomes could be evaluated comparatively between patients categorized as clinical trial eligible and not eligible.  They indexed 7 trials, and for example, found that 12.9% of the SPORE participants did not meet eligibility for the PHOENIX study—that is the phase 3 trial of ibrutinib-R-CHOP vs placebo-R-CHOP showing no benefit of the addition of ibrutinib. Not surprisingly, those scored as ineligible had worse outcomes compared to those scored as eligible. For example, indexing eligibility for the PHOENIX trial, the overall survival hazard ratio for those scored not eligible versus eligible was 1.49 with a p-value of .002. The median survival of the SPORE cohort scored as ineligible for PHOENIX had a median overall survival of around 80 months, and the median survival for those sored as eligible had not yet been reached. Interestingly, treatment-related deaths were not found to be increased in the SPORE patients scored as ineligible compared to those scored as eligible,  but death due to progressive lymphoma was higher among those scored as ineligible.    So how does this relate to the inability to improve upon standard DLBCL therapy?    Khurana and colleagues' data highlight several features of clinical trials conduct related to trial outcomes.  The unnecessary exclusion of patients based on criteria not specific to the treatment can translate into eligible patients having a more favorable prognosis compared to individuals with the disease who are excluded from studies, but who nevertheless are treated with standard therapy used as a control in DLBCL clinical trials.  Populating randomized trials with the best prognosis patients can lead to reduced power to detect an outcome difference, even if one exists.  But what about the unnecessary exclusion of patients from clinical trials based on laboratory values that reflect organ dysfunction and poor outcomes as shown in the SPORE patients?  The authors document unequivocally that those patients deemed ineligible are at higher risk of death due to treatment failure: that is they die due to progressive lymphoma more than the SPORE patients scored as meeting clinical trial eligibility criteria. What we don’t know from the study as presented, is whether there were more dose delays and dose reductions among those scored as ineligible. This is fundamental toward an improved understanding of how to repair our clinical trials enterprise in DLBCL.  And what I mean by repair, is to broaden and expand clinical trials access to as many patients as possible and to have rigorous design and conduct of trials to detect true signals. There are two essential elements to address, and this data points the way but does not fully answer the questions.  To make trials generalizable, we must include as broadly as possible those patients with DLBCL.  However, if the SPORE outcomes are explained by an inability to administer therapy as planned in those scored as trial ineligible, then just broadening eligibility criteria could undermine the ability to detect a difference with new effective treatment by including too many patients unable to tolerate the therapy.  For example, some have suggested the negative results of the PHOENIX trial may be due to treatment intolerance among those aged 60 years and over. So it appears that trials increasing generalizability and reaching a positive trial endpoint for a novel treatment have a complex interaction, to say the least. It will be essential as diffuse large B-cell lymphoma therapeutic trials are developed to be mindful of differential prognosis and perhaps interrelated treatment tolerance of patients due to multiple factors, including degree of organ dysfunction.  The exclusion of patients with the disease understudy from clinical trials should be minimized.  Efforts to modernize clinical trial eligibility are being embraced by most stakeholders, and in my opinion is an essential social and medical responsibility for clinical trialists to meet.  The challenge is how to accomplish this important objective and appropriately design studies to enhance the ability to detect the desired study endpoint. To answer the question posed by the authors, we must endeavor to leave no one behind. We can accomplish this through statistical designs such as stratification of the randomization,  powered for the groups of interest -- as one such solution. Separate and specific trials for older or more frail patients is another solution.  And I dare say, we should focus on efforts to eliminate the CHOP backbone and develop better-tolerated therapy that those with organ dysfunction can benefit from. The VIPOR regimen presented by Melani and colleagues at the 2020 ASH meeting provides an example of the type of DLBCL research that could be of interest. The challenge of generalizability and its relevance to negative clinical trial results is becoming clearer if only to recognize the increasing complexity in meeting the needs of our patients.  But isn’t that what motivates us?   This concludes this JCO Podcast. Thank you for listening.

In this week’s episode, we will review a study that describes the pathogenic relevance of retinoic acid-responsive CD8+ T-cells in gastrointestinal graft-versus-host disease, learn more about how storage-induced disturbances of platelets is linked to changes in the number and sphingolipid content of platelet extracellular vesicles which predispose to transfusion related acute lung injury, and lastly, review the findings of a phase II study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma.

FDA 批准新型的核输出蛋白抑制剂用于治疗多发性骨髓瘤和弥漫大B细胞淋巴瘤LANCET 利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤Blood DIC时常出现的新型的凝血机制塞利尼索（selinexor）塞利尼索（selinexor）一种口服选择性核输出蛋白抑制剂，2019年被FDA批准上市用于治疗复发或难治性多发性骨髓瘤；2020年7月，适应症扩展到弥漫大B细胞淋巴瘤。《口服塞利尼索-地塞米松治疗三重难治性多发性骨髓瘤》 New England Journal of Medicine，2019年8月 (1)研究旨在评价塞利尼索对三重难治性多发性骨髓瘤的疗效和安全性。纳入122名、中位年龄65岁、至少一种蛋白酶体抑制剂、一种免疫调节剂和达雷木单抗耐药的、多发性骨髓瘤患者。给予每周两次口服塞利尼索80mg+地塞米松20mg治疗。26%的患者出现部分或更好的缓解，2名患者完全缓解；39%的患者轻微缓解或有所好转。中位缓解时间为4.4个月，中位无进展生存期为3.7个月，中位总生存期为8.6个月。血小板减少是常见的严重不良反应。结论：塞利尼索-地塞米松使现有治疗方法难以治愈的骨髓瘤患者延长了生存期。《SADAL研究：塞利尼索（selinexor） 在复发或难治性弥漫性大B细胞淋巴瘤患者中的应用》Lancet Haematology，2020年7月 (2)SADAL研究的目的是评估单药塞利尼索对复发或难治性弥漫大B淋巴瘤患者的疗效这项多中心、跨国、开放标签的2b期研究，纳入已经接受了2 - 5种治疗、自体干细胞移植后或不适合进行自体干细胞移植的、复发难治性弥漫大B细胞淋巴瘤患者共267人，随机接受塞利尼索60mg和塞利尼索100mg治疗，研究中期100mg剂量被终止。塞利尼索的总有效率为28%，12%的患者完全缓解，17%的患者部分缓解。最常见的3-4级不良事件是血小板减少、中性粒细胞减少、贫血等。最常见的严重不良事件是发热、肺炎和脓毒症。结论：塞利尼索单药治疗复发或难治性弥漫大B患者有一定的疗效，且不良事件可控制的。弥漫性大B细胞淋巴瘤弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，占25%。最常见的症状为颈部或腹部淋巴结肿大，约30%的患者出现全身性症状（发热、体重减轻、盗汗）。骨髓受累和结外髓外病变的发生率在30%和40%。弥漫大B细胞淋巴瘤的肿瘤细胞通常广泛表达B细胞抗原（CD19、CD20、CD22和CD79a）。《XPO1的表达会恶化不利的弥漫大B细胞的预后，而在没有p53突变体的情况下，塞利尼索可以有效地靶向该细胞》Journal of Hematology Oncology，2020年11月 (3)XPO1抑制剂塞利尼索（selinexor）最近被批准用于复发/难治性的弥漫大B细胞淋巴瘤，研究的目的是评价XPO1对患者的预后影响以及高危患者的合理联合治疗方案。来自厦门大学医学院的研究人员发现XPO1高表达的544例患者，均出现显著的预后不良的情况，尤其是在BCL2过表达的患者中。通过对30个、具有不同分子和遗传背景的弥漫大B细胞淋巴瘤的、细胞株进行研究后发现，塞利尼索具有很强的细胞毒性，特别是在BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤（HGBCL-DH）中。然而，p53基因突变显著降低了塞利尼索在整个细胞系、以及BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中的细胞毒性。塞利尼索联合BET抑制剂INCB057643对MYC/BCL2双重打击的、高级别B细胞淋巴瘤的治疗效果显著增强，克服了p53基因突变的耐药性。结论：XPO1降低了BCL2过表达和双重打击等预后不良因素的、弥漫大B细胞淋巴瘤患者的生存，这与塞利尼索在这两个细胞系中显示出的更好的疗效是一致的。在MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中，联合使用INCB057643处理，可以克服p53基因突变导致的塞利尼索耐药的情况。《弥漫性大B细胞淋巴瘤的国际预后指标：IPI、R-IPI和NCCN-IPI的比较》Blood，2020年6月 (4)弥漫大B细胞淋巴瘤的患者生存率存在很大的异质性。目前临床上常用的预后评分系统包括：国际预后指数（IPI）、修订的IPI（R-IPI）和国家综合癌症网络IPI（NCCN-IPI）。这三种评分系统纳入一些简单临床参数（年龄、乳酸脱氢酶、受累个数/部位、分期、表现状态）。研究人员近20年来，接受利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和强的松治疗的2124例患者的数据用于评估哪个评分系统能最准确的预测生存率。使用IPI、R-IPI和NCCN-IPI的5年生存率估计分别为54%至88%、61%至93%和49%至92%；三组评分的一致性指数分别为0.626、0.59和0.632。NCCN-IPI在高风险、低风险和生存期评价方面都表现更高；而且NCCN-IPI风险类别与生存期显著相关(P≤.01)。结论：NCCN-IPI的预测准确性较高，NCCN-IPI低风险的患者的生存结果良好，但如果能将肿瘤的分子特征和微环境特征整合到NCCN-IPI或IPI中，可能将提高其准确性。弥漫性大B细胞淋巴瘤的治疗初始标准治疗是联合化疗（如CHOP方案，环磷酰胺、多柔比星、长春新碱和泼尼松）+抗CD20单抗（利妥昔单抗），即R-CHOP方案。复发难治性弥漫大B细胞淋巴瘤首选自体干细胞移植。治疗进展：2017年，FDA批准Axicabtagene ciloleucel（商品名Yescarta，一种自体抗CD19嵌合抗原受体CAR-T细胞疗法）治疗复发难治性弥漫大B细胞淋巴瘤。《回顾性研究：R-CHOP方案治疗原发性纵隔大B细胞淋巴瘤》Blood，2020年6月 (5)原发性纵隔大B细胞淋巴瘤的治愈率随着利妥昔单抗的结合而提高；然而，放射治疗的作用仍不明确。2005年之前，通常建议患者接受R-CHOP方案放疗；2005年之后，只有治疗结束后PET扫描呈阳性的人才接受放疗。文章回顾性的分析了共159例患者，总体的5年生存期为89%，在不同的治疗时期相似，总体来说只有10%是难治性的。2005年后，共有113例患者进行了PET扫描，其中63%阴性，37%阳性，5年生存率为97%对88%。对于PET扫描评分较高的患者，预后也较差。结论：经R-CHOP治疗的纵隔弥漫大B淋巴瘤患者的结果是良好的，使用PET评估决定是否放疗减少了不必要的放疗。《HOVON-84研究：利妥昔单抗联合早期利妥昔单抗强化治疗弥漫性大b细胞淋巴瘤的3期临床研究》Journal of Clinical Oncology，2020年10月(6)该研究的目的是评估了R-CHOP方案的、前4个周期早期、强化利妥昔单抗治疗与标准R-CHOP方案比相比是否能改善预后。研究纳入574例、弥漫大B细胞淋巴瘤的患者，给予6个或8个周期的R-CHOP-14方案治疗，随机早期强化利妥昔单抗治疗（RR-CHOP-14方案）或不强化治疗（R-CHOP-14）。R-CHOP-14组和RR-CHOP-14组的、诱导期完全缓解率分别为89%和86%。中位随访92个月后，R-CHOP-14组和RR-CHOP-14组的、3年无进展生存率分别为74%和71%（P = 0. 15），两组总生存率分别为81%和76%（P=0.09）。在RR-CHOP-14组中，年龄在66岁至80岁的患者在前4个周期中经历了明显更多的不良事件，特别是中性粒细胞减少和感染。结论：RR-CHOP-14（在R-CHOP-14基础上早期强化使用利妥昔单抗）不能改善未经治疗的弥漫大B细胞淋巴瘤患者的疗效。Burkitt淋巴瘤Burkitt淋巴瘤是一种高度侵袭性的B细胞肿瘤，目前识别出3种不同的临床形式：地方性Burkitt淋巴瘤、散发性Burkitt淋巴瘤和免疫缺陷相关性Burkitt淋巴瘤。虽然流行病学、临床表现和遗传学特征有所不同，但是组织学上相同，并具有相似的临床行为，因此通常采用相似的方法治疗。对于大多数Burkitt淋巴瘤的成人患者，通常建议选择强化短程联合化疗，或者急性淋巴细胞白血病样的诱导+巩固+维持治疗，无法耐受的患者使用剂量调整的EPOCH化疗方案（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）。近年来的一个的热点是在化疗基础上加用利妥昔单抗（抗CD20单抗）。《随机对照研究：使用风险适应性的、剂量调整的DA-EPOCH-R方案治疗Burkitt淋巴瘤》Journal of Clinical Oncology，2020年8月(7)研究的目的是评价，经剂量调整的（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）联合利妥昔单抗（DA-EPOCH-R方案）治疗Burkitt淋巴瘤的疗效。研究纳入113名未接受过治疗的Burkitt淋巴瘤患者，中位年龄49岁，25%HIV阳性，低风险患者接受了无中枢神经系统预防的、3个周期的治疗；高风险患者接受了6个周期的治疗、以及鞘内治疗。中位随访58.7个月，低危患者无进展生存率和总生存率分别为84.5%和87.0%；高危患者无进展生存率和总生存率分别为82.1%和100%和。治疗对不同年龄组、HIV阳性和各风险组都同样有效。疾病累及脑脊液的、高危患者中，药物毒性相关的死亡或治疗失败的风险最大。5例治疗相关死亡发生在治疗期间，发热性中性粒细胞减少发生在16%的周期中，肿瘤溶解综合征是罕见的。结论：DA-EPOCH-R方案治疗对成人Burkitt淋巴瘤有效，且耐受良好，无论年龄或HIV状态如何。但疾病脑脊液的患者的治疗方案仍需商榷。《开放标签对照研究：利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤的3期临床研究》Lancet，2016年6月(8)这项随机、对照、开放标签的3期临床试验中，招募了45个中心的、>18岁的、新诊断的、HIV阴性的Burkitt淋巴瘤患者。分为B组（无骨髓或中枢神经系统受累）和C组（有骨髓或中枢神经系统受累）。治疗方案为利妥昔单抗+LMB方案化疗，以及单独LMB方案化疗。共纳入260例患者，中位随访38个月。利妥昔单抗组3年无事件生存率75%，显著优于单独化疗组；不良事件在两个治疗组之间没有差异，最常见的是感染和中性粒细胞减少。结论：在短期强化化疗方案中加入利妥昔单抗可以改善成人Burkitt淋巴瘤的无事件生存率。 《队列研究：美国30个癌症中心的、真实世界的、Burkitt淋巴瘤的治疗结果与进展》Blood，2020年7月(9)研究人员对2009年至2018年的、美国30个癌症中心的、未经治疗的Burtkitt淋巴瘤的成人患者进行了分析。研究人员分析了641例Burkitt淋巴瘤患者基线特征包括：中位年龄47岁；HIV阳性 占22%；23%的患者ECOG生活质量评分 2-4分；42%患者有>1个淋巴结外病灶；晚期78%；中枢神经系统受累19%；治疗相关死亡率为10%，最常见的原因是败血症、胃肠道出血、穿孔和呼吸衰竭。在45个月的中位随访中，3年的无进展生存率和总生存率分别为64%和70%，这与是否为HIV阳性无关。接受利妥昔单抗治疗的患者生存率更更高（3年无进展生存率为为67%比38%；总生存率为72%比44%），这与是否住院治疗无关。在学术中心治疗的患者和在社区中心治疗的患者的结果也有所改善（3年无进展生存率为67%比46%；总生存率72%比53%)。多变量模型中，预测生存率较短的因素包括：年龄≥40岁、ECOG生活质量评分2-4分、乳酸脱氢酶>3xULN和中枢神经系统受累；而且，以上因素越多，生存率越低生存率。结论：真实世界的分析中，成人Burkitt淋巴瘤的临床预后比临床研究的结果更温和。此外，疾病诊断时确定的预后相关的因素可以帮助评估真实的预后。新型的DIC中由组蛋白启动的替代凝血酶通路《基础研究：弥散性血管内凝血中，由细胞外组蛋白启动的替代凝血酶通路》Blood，2020年7月 (10)凝血酶的产生、活化对弥散性血管内凝血（DIC）的病理发展都至关重要。通常，凝血酶由凝血酶原复合物产生，包括活化的X因子（FXa）、活化的辅助V因子（FVa）和磷脂（钙离子存在的情况下清除凝血酶）。在危重症中，广泛的细胞损伤可释放组蛋白进入循环，增加凝血酶的生成，引起DIC，但其分子机制尚不清楚。在本研究中，来自利物浦大学的研究人员发现：在有组蛋白，但是没有活化的辅助V因子和磷脂的情况下，机体也能形成一种替代的凝血酶。组蛋白可以直接结合凝血酶原片段F1和F2，促进X因子裂解凝血酶原、释放凝血酶，而不需要磷脂参与。小鼠体内输注组蛋白可诱导产生DIC；但如果事先输注凝血酶原F1+F2片段，再输注组蛋白则显著降低DIC出现的可能性。在重症监护病房脓毒症患者中（n=144），DIC患者的循环组蛋白水平显著升高。这些数据均表明，组蛋白诱导的替代凝血酶可诱导血管内凝血，并揭示了凝血酶产生和DIC发展的新的分子机制。此外，在这个凝血机制中，组蛋白使X因子的需求显著减少，即使VIII因子和IX缺乏的小鼠中，也能形成血栓。结论：本研究揭示了一种具有治疗潜力的、新型的凝血机制，既可以激活全身凝血功能，又可以纠正凝血因子缺陷导致的凝血功能障碍。《COVID-19及其对血栓和抗凝的影响》Blood，2020年6月 (11)COVID-19引起的严重感染可能与凝血功能障碍有关，这在感染引起的弥散性血管内凝血功能障碍（DIC）患者中观察到的炎症变化很相似。肺是COVID-19的靶器官，患者急性肺损伤可发展为呼吸衰竭，也可发生多器官衰竭。COVID-19的初始凝血病变表现为D-二聚体和纤维蛋白/纤维蛋白原降解产物显著升高，而凝血酶原时间、部分凝血酶时间和血小板数量异常相对少见。故建议对患者进行凝血功能筛查，包括测定D-二聚体和纤维蛋白原水平。治疗上，应像对待任何危重病人一样管理，遵循对危重病人采用的血栓栓塞预防、和对脓毒症引起DIC的患者采用标准支持治疗。虽然D-二聚体、脓毒症生理学和消耗性凝血障碍是死亡的预测因子，但目前的数据不建议使用足量抗凝。尽管COVID-19相关的凝血功能障碍，但出血时间尚未见报道。如果确实发生出血，应遵循DIC和出血管理的标准指南。《回顾性观察队列研究：COVID-19患者出院后的血栓和出血时间》Blood，2020年8月 (12)COVID-19肺炎与血栓前状态相关，住院期间血栓事件发生率高；然而，出院后血栓形成的数据有限。研究人员对未接受抗凝治疗的COVID-19出院患者进行了回顾性观察队列研究。该队列包括163名患者，平均随访30天，平均住院时间为6天， 26%需要重症监护。出院后第30天血栓累积发生率（包括动脉和静脉事件）为2.5%；单纯静脉血栓栓塞发生率为0.6%；大出血发生率为0.7%，非大出血发生率为2.9%。因此，COVID-19患者出院后血栓形成率和出血率似乎相似，这强调需要更多的研究来提供全面的、出院后的血栓预防建议。参考文献1.Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019;381(8):727-38.2.Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e22.3.Deng M, Zhang M, Xu-Monette ZY, Pham LV, Tzankov A, Visco C, et al. XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53. J Hematol Oncol. 2020;13(1):148.4.Ruppert AS, Dixon JG, Salles G, Wall A, Cunningham D, Poeschel V, et al. International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 2020;135(23):2041-8.5.Hayden A, Tonseth P, Lee DG, Villa D, Gerrie AS, Scott DW, et al. Outcome of Primary Mediastinal Large B-cell Lymphoma Using R-CHOP: Impact of a PET Adapted Approach. Blood. 2020.6.Lugtenburg PJ, de Nully Brown P, van der Holt B, D'Amore FA, Koene HR, de Jongh E, et al. Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84). J Clin Oncol. 2020;38(29):3377-87.7.Roschewski M, Dunleavy K, Abramson JS, Powell BL, Link BK, Patel P, et al. Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol. 2020;38(22):2519-29.8.Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10036):2402-11.9.Evens AM, Danilov AV, Jagadeesh D, Sperling AL, Kim SH, Vaca RA, et al. Burkitt Lymphoma in the Modern Era: Real World Outcomes and Prognostication Across 30 US Cancer Centers. 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FDA 批准新型的核输出蛋白抑制剂用于治疗多发性骨髓瘤和弥漫大B细胞淋巴瘤LANCET 利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤Blood DIC时常出现的新型的凝血机制塞利尼索（selinexor）塞利尼索（selinexor）一种口服选择性核输出蛋白抑制剂，2019年被FDA批准上市用于治疗复发或难治性多发性骨髓瘤；2020年7月，适应症扩展到弥漫大B细胞淋巴瘤。《口服塞利尼索-地塞米松治疗三重难治性多发性骨髓瘤》 New England Journal of Medicine，2019年8月 (1)研究旨在评价塞利尼索对三重难治性多发性骨髓瘤的疗效和安全性。纳入122名、中位年龄65岁、至少一种蛋白酶体抑制剂、一种免疫调节剂和达雷木单抗耐药的、多发性骨髓瘤患者。给予每周两次口服塞利尼索80mg+地塞米松20mg治疗。26%的患者出现部分或更好的缓解，2名患者完全缓解；39%的患者轻微缓解或有所好转。中位缓解时间为4.4个月，中位无进展生存期为3.7个月，中位总生存期为8.6个月。血小板减少是常见的严重不良反应。结论：塞利尼索-地塞米松使现有治疗方法难以治愈的骨髓瘤患者延长了生存期。《SADAL研究：塞利尼索（selinexor） 在复发或难治性弥漫性大B细胞淋巴瘤患者中的应用》Lancet Haematology，2020年7月 (2)SADAL研究的目的是评估单药塞利尼索对复发或难治性弥漫大B淋巴瘤患者的疗效这项多中心、跨国、开放标签的2b期研究，纳入已经接受了2 - 5种治疗、自体干细胞移植后或不适合进行自体干细胞移植的、复发难治性弥漫大B细胞淋巴瘤患者共267人，随机接受塞利尼索60mg和塞利尼索100mg治疗，研究中期100mg剂量被终止。塞利尼索的总有效率为28%，12%的患者完全缓解，17%的患者部分缓解。最常见的3-4级不良事件是血小板减少、中性粒细胞减少、贫血等。最常见的严重不良事件是发热、肺炎和脓毒症。结论：塞利尼索单药治疗复发或难治性弥漫大B患者有一定的疗效，且不良事件可控制的。弥漫性大B细胞淋巴瘤弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，占25%。最常见的症状为颈部或腹部淋巴结肿大，约30%的患者出现全身性症状（发热、体重减轻、盗汗）。骨髓受累和结外髓外病变的发生率在30%和40%。弥漫大B细胞淋巴瘤的肿瘤细胞通常广泛表达B细胞抗原（CD19、CD20、CD22和CD79a）。《XPO1的表达会恶化不利的弥漫大B细胞的预后，而在没有p53突变体的情况下，塞利尼索可以有效地靶向该细胞》Journal of Hematology Oncology，2020年11月 (3)XPO1抑制剂塞利尼索（selinexor）最近被批准用于复发/难治性的弥漫大B细胞淋巴瘤，研究的目的是评价XPO1对患者的预后影响以及高危患者的合理联合治疗方案。来自厦门大学医学院的研究人员发现XPO1高表达的544例患者，均出现显著的预后不良的情况，尤其是在BCL2过表达的患者中。通过对30个、具有不同分子和遗传背景的弥漫大B细胞淋巴瘤的、细胞株进行研究后发现，塞利尼索具有很强的细胞毒性，特别是在BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤（HGBCL-DH）中。然而，p53基因突变显著降低了塞利尼索在整个细胞系、以及BCL2重排、或MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中的细胞毒性。塞利尼索联合BET抑制剂INCB057643对MYC/BCL2双重打击的、高级别B细胞淋巴瘤的治疗效果显著增强，克服了p53基因突变的耐药性。结论：XPO1降低了BCL2过表达和双重打击等预后不良因素的、弥漫大B细胞淋巴瘤患者的生存，这与塞利尼索在这两个细胞系中显示出的更好的疗效是一致的。在MYC/BCL2双重打击的、高级别B细胞淋巴瘤亚群中，联合使用INCB057643处理，可以克服p53基因突变导致的塞利尼索耐药的情况。《弥漫性大B细胞淋巴瘤的国际预后指标：IPI、R-IPI和NCCN-IPI的比较》Blood，2020年6月 (4)弥漫大B细胞淋巴瘤的患者生存率存在很大的异质性。目前临床上常用的预后评分系统包括：国际预后指数（IPI）、修订的IPI（R-IPI）和国家综合癌症网络IPI（NCCN-IPI）。这三种评分系统纳入一些简单临床参数（年龄、乳酸脱氢酶、受累个数/部位、分期、表现状态）。研究人员近20年来，接受利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和强的松治疗的2124例患者的数据用于评估哪个评分系统能最准确的预测生存率。使用IPI、R-IPI和NCCN-IPI的5年生存率估计分别为54%至88%、61%至93%和49%至92%；三组评分的一致性指数分别为0.626、0.59和0.632。NCCN-IPI在高风险、低风险和生存期评价方面都表现更高；而且NCCN-IPI风险类别与生存期显著相关(P≤.01)。结论：NCCN-IPI的预测准确性较高，NCCN-IPI低风险的患者的生存结果良好，但如果能将肿瘤的分子特征和微环境特征整合到NCCN-IPI或IPI中，可能将提高其准确性。弥漫性大B细胞淋巴瘤的治疗初始标准治疗是联合化疗（如CHOP方案，环磷酰胺、多柔比星、长春新碱和泼尼松）+抗CD20单抗（利妥昔单抗），即R-CHOP方案。复发难治性弥漫大B细胞淋巴瘤首选自体干细胞移植。治疗进展：2017年，FDA批准Axicabtagene ciloleucel（商品名Yescarta，一种自体抗CD19嵌合抗原受体CAR-T细胞疗法）治疗复发难治性弥漫大B细胞淋巴瘤。《回顾性研究：R-CHOP方案治疗原发性纵隔大B细胞淋巴瘤》Blood，2020年6月 (5)原发性纵隔大B细胞淋巴瘤的治愈率随着利妥昔单抗的结合而提高；然而，放射治疗的作用仍不明确。2005年之前，通常建议患者接受R-CHOP方案放疗；2005年之后，只有治疗结束后PET扫描呈阳性的人才接受放疗。文章回顾性的分析了共159例患者，总体的5年生存期为89%，在不同的治疗时期相似，总体来说只有10%是难治性的。2005年后，共有113例患者进行了PET扫描，其中63%阴性，37%阳性，5年生存率为97%对88%。对于PET扫描评分较高的患者，预后也较差。结论：经R-CHOP治疗的纵隔弥漫大B淋巴瘤患者的结果是良好的，使用PET评估决定是否放疗减少了不必要的放疗。《HOVON-84研究：利妥昔单抗联合早期利妥昔单抗强化治疗弥漫性大b细胞淋巴瘤的3期临床研究》Journal of Clinical Oncology，2020年10月(6)该研究的目的是评估了R-CHOP方案的、前4个周期早期、强化利妥昔单抗治疗与标准R-CHOP方案比相比是否能改善预后。研究纳入574例、弥漫大B细胞淋巴瘤的患者，给予6个或8个周期的R-CHOP-14方案治疗，随机早期强化利妥昔单抗治疗（RR-CHOP-14方案）或不强化治疗（R-CHOP-14）。R-CHOP-14组和RR-CHOP-14组的、诱导期完全缓解率分别为89%和86%。中位随访92个月后，R-CHOP-14组和RR-CHOP-14组的、3年无进展生存率分别为74%和71%（P = 0. 15），两组总生存率分别为81%和76%（P=0.09）。在RR-CHOP-14组中，年龄在66岁至80岁的患者在前4个周期中经历了明显更多的不良事件，特别是中性粒细胞减少和感染。结论：RR-CHOP-14（在R-CHOP-14基础上早期强化使用利妥昔单抗）不能改善未经治疗的弥漫大B细胞淋巴瘤患者的疗效。Burkitt淋巴瘤Burkitt淋巴瘤是一种高度侵袭性的B细胞肿瘤，目前识别出3种不同的临床形式：地方性Burkitt淋巴瘤、散发性Burkitt淋巴瘤和免疫缺陷相关性Burkitt淋巴瘤。虽然流行病学、临床表现和遗传学特征有所不同，但是组织学上相同，并具有相似的临床行为，因此通常采用相似的方法治疗。对于大多数Burkitt淋巴瘤的成人患者，通常建议选择强化短程联合化疗，或者急性淋巴细胞白血病样的诱导+巩固+维持治疗，无法耐受的患者使用剂量调整的EPOCH化疗方案（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）。近年来的一个的热点是在化疗基础上加用利妥昔单抗（抗CD20单抗）。《随机对照研究：使用风险适应性的、剂量调整的DA-EPOCH-R方案治疗Burkitt淋巴瘤》Journal of Clinical Oncology，2020年8月(7)研究的目的是评价，经剂量调整的（依托泊苷、长春新碱、多柔比星、泼尼松、环磷酰胺）联合利妥昔单抗（DA-EPOCH-R方案）治疗Burkitt淋巴瘤的疗效。研究纳入113名未接受过治疗的Burkitt淋巴瘤患者，中位年龄49岁，25%HIV阳性，低风险患者接受了无中枢神经系统预防的、3个周期的治疗；高风险患者接受了6个周期的治疗、以及鞘内治疗。中位随访58.7个月，低危患者无进展生存率和总生存率分别为84.5%和87.0%；高危患者无进展生存率和总生存率分别为82.1%和100%和。治疗对不同年龄组、HIV阳性和各风险组都同样有效。疾病累及脑脊液的、高危患者中，药物毒性相关的死亡或治疗失败的风险最大。5例治疗相关死亡发生在治疗期间，发热性中性粒细胞减少发生在16%的周期中，肿瘤溶解综合征是罕见的。结论：DA-EPOCH-R方案治疗对成人Burkitt淋巴瘤有效，且耐受良好，无论年龄或HIV状态如何。但疾病脑脊液的患者的治疗方案仍需商榷。《开放标签对照研究：利妥昔单抗和短期强化化疗治疗成人Burkitt淋巴瘤的3期临床研究》Lancet，2016年6月(8)这项随机、对照、开放标签的3期临床试验中，招募了45个中心的、>18岁的、新诊断的、HIV阴性的Burkitt淋巴瘤患者。分为B组（无骨髓或中枢神经系统受累）和C组（有骨髓或中枢神经系统受累）。治疗方案为利妥昔单抗+LMB方案化疗，以及单独LMB方案化疗。共纳入260例患者，中位随访38个月。利妥昔单抗组3年无事件生存率75%，显著优于单独化疗组；不良事件在两个治疗组之间没有差异，最常见的是感染和中性粒细胞减少。结论：在短期强化化疗方案中加入利妥昔单抗可以改善成人Burkitt淋巴瘤的无事件生存率。 《队列研究：美国30个癌症中心的、真实世界的、Burkitt淋巴瘤的治疗结果与进展》Blood，2020年7月(9)研究人员对2009年至2018年的、美国30个癌症中心的、未经治疗的Burtkitt淋巴瘤的成人患者进行了分析。研究人员分析了641例Burkitt淋巴瘤患者基线特征包括：中位年龄47岁；HIV阳性 占22%；23%的患者ECOG生活质量评分 2-4分；42%患者有>1个淋巴结外病灶；晚期78%；中枢神经系统受累19%；治疗相关死亡率为10%，最常见的原因是败血症、胃肠道出血、穿孔和呼吸衰竭。在45个月的中位随访中，3年的无进展生存率和总生存率分别为64%和70%，这与是否为HIV阳性无关。接受利妥昔单抗治疗的患者生存率更更高（3年无进展生存率为为67%比38%；总生存率为72%比44%），这与是否住院治疗无关。在学术中心治疗的患者和在社区中心治疗的患者的结果也有所改善（3年无进展生存率为67%比46%；总生存率72%比53%)。多变量模型中，预测生存率较短的因素包括：年龄≥40岁、ECOG生活质量评分2-4分、乳酸脱氢酶>3xULN和中枢神经系统受累；而且，以上因素越多，生存率越低生存率。结论：真实世界的分析中，成人Burkitt淋巴瘤的临床预后比临床研究的结果更温和。此外，疾病诊断时确定的预后相关的因素可以帮助评估真实的预后。新型的DIC中由组蛋白启动的替代凝血酶通路《基础研究：弥散性血管内凝血中，由细胞外组蛋白启动的替代凝血酶通路》Blood，2020年7月 (10)凝血酶的产生、活化对弥散性血管内凝血（DIC）的病理发展都至关重要。通常，凝血酶由凝血酶原复合物产生，包括活化的X因子（FXa）、活化的辅助V因子（FVa）和磷脂（钙离子存在的情况下清除凝血酶）。在危重症中，广泛的细胞损伤可释放组蛋白进入循环，增加凝血酶的生成，引起DIC，但其分子机制尚不清楚。在本研究中，来自利物浦大学的研究人员发现：在有组蛋白，但是没有活化的辅助V因子和磷脂的情况下，机体也能形成一种替代的凝血酶。组蛋白可以直接结合凝血酶原片段F1和F2，促进X因子裂解凝血酶原、释放凝血酶，而不需要磷脂参与。小鼠体内输注组蛋白可诱导产生DIC；但如果事先输注凝血酶原F1+F2片段，再输注组蛋白则显著降低DIC出现的可能性。在重症监护病房脓毒症患者中（n=144），DIC患者的循环组蛋白水平显著升高。这些数据均表明，组蛋白诱导的替代凝血酶可诱导血管内凝血，并揭示了凝血酶产生和DIC发展的新的分子机制。此外，在这个凝血机制中，组蛋白使X因子的需求显著减少，即使VIII因子和IX缺乏的小鼠中，也能形成血栓。结论：本研究揭示了一种具有治疗潜力的、新型的凝血机制，既可以激活全身凝血功能，又可以纠正凝血因子缺陷导致的凝血功能障碍。《COVID-19及其对血栓和抗凝的影响》Blood，2020年6月 (11)COVID-19引起的严重感染可能与凝血功能障碍有关，这在感染引起的弥散性血管内凝血功能障碍（DIC）患者中观察到的炎症变化很相似。肺是COVID-19的靶器官，患者急性肺损伤可发展为呼吸衰竭，也可发生多器官衰竭。COVID-19的初始凝血病变表现为D-二聚体和纤维蛋白/纤维蛋白原降解产物显著升高，而凝血酶原时间、部分凝血酶时间和血小板数量异常相对少见。故建议对患者进行凝血功能筛查，包括测定D-二聚体和纤维蛋白原水平。治疗上，应像对待任何危重病人一样管理，遵循对危重病人采用的血栓栓塞预防、和对脓毒症引起DIC的患者采用标准支持治疗。虽然D-二聚体、脓毒症生理学和消耗性凝血障碍是死亡的预测因子，但目前的数据不建议使用足量抗凝。尽管COVID-19相关的凝血功能障碍，但出血时间尚未见报道。如果确实发生出血，应遵循DIC和出血管理的标准指南。《回顾性观察队列研究：COVID-19患者出院后的血栓和出血时间》Blood，2020年8月 (12)COVID-19肺炎与血栓前状态相关，住院期间血栓事件发生率高；然而，出院后血栓形成的数据有限。研究人员对未接受抗凝治疗的COVID-19出院患者进行了回顾性观察队列研究。该队列包括163名患者，平均随访30天，平均住院时间为6天， 26%需要重症监护。出院后第30天血栓累积发生率（包括动脉和静脉事件）为2.5%；单纯静脉血栓栓塞发生率为0.6%；大出血发生率为0.7%，非大出血发生率为2.9%。因此，COVID-19患者出院后血栓形成率和出血率似乎相似，这强调需要更多的研究来提供全面的、出院后的血栓预防建议。参考文献1.Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019;381(8):727-38.2.Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e22.3.Deng M, Zhang M, Xu-Monette ZY, Pham LV, Tzankov A, Visco C, et al. XPO1 expression worsens the prognosis of unfavorable DLBCL that can be effectively targeted by selinexor in the absence of mutant p53. J Hematol Oncol. 2020;13(1):148.4.Ruppert AS, Dixon JG, Salles G, Wall A, Cunningham D, Poeschel V, et al. International prognostic indices in diffuse large B-cell lymphoma: a comparison of IPI, R-IPI, and NCCN-IPI. Blood. 2020;135(23):2041-8.5.Hayden A, Tonseth P, Lee DG, Villa D, Gerrie AS, Scott DW, et al. Outcome of Primary Mediastinal Large B-cell Lymphoma Using R-CHOP: Impact of a PET Adapted Approach. Blood. 2020.6.Lugtenburg PJ, de Nully Brown P, van der Holt B, D'Amore FA, Koene HR, de Jongh E, et al. Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84). J Clin Oncol. 2020;38(29):3377-87.7.Roschewski M, Dunleavy K, Abramson JS, Powell BL, Link BK, Patel P, et al. Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma. J Clin Oncol. 2020;38(22):2519-29.8.Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, et al. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016;387(10036):2402-11.9.Evens AM, Danilov AV, Jagadeesh D, Sperling AL, Kim SH, Vaca RA, et al. Burkitt Lymphoma in the Modern Era: Real World Outcomes and Prognostication Across 30 US Cancer Centers. Blood. 2020.10.Abrams ST, Su D, Sahraoui Y, Lin Z, Cheng Z, Nesbitt K, et al. Assembly of alternative prothrombinase by extracellular histones initiate and disseminate intravascular coagulation. Blood. 2020.11.Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033-40.12.Patell R, Bogue T, Koshy AG, Bindal P, Merrill M, Aird WC, et al. Post-discharge thrombosis and hemorrhage in patients with COVID-19. Blood. 2020.

0 (0s): Well, good morning, everyone. Welcome to Harvest. My name is Sherrilyn. If we haven't met yet, delighted to worship together with you all this morning, you may notice if you're in the house, we have an extra cameraman floating. We're just capturing some video. That can be part of a welcome video for folks to go to our website and are kind of looking for a picture of what it's like to worship here. So yeah, he'll be floating around, but do you just worship and you don't even have to mind him. We're just going to dive in this morning. Would you stand with me? And we'll pray. We'll dive in today. Solar. We're just so grateful just for the freedom. 0 (41s): We have to come into your house and worship. God, thank you so much for everyone who is here on campus and tuned in from home or wherever they're watching. We are one body we gathered together as sons and daughters to worship you this morning. As surely as the sun rises, God, you are faithful every morning. Great is your faithfulness towards us. So we worship you today. When we sit our hearts, our attention, our affection on Jesus this morning, we asked you to be in our midst that you would change us and she would make us more like you draws near to your heart today in Jesus name. 0 (1m 25s): Amen. 0 (1m 26s): we're not orphans anymore. 0 (12m 17s): Bod, with the prize rescue, you might know this old little chorus. Geez, geez. let's try that again. 0 (12m 59s): for your great lift for us. 0 (13m 45s): Amazing grace. 0 (13m 49s): missing that first together, still beautiful voice. 0 (17m 29s): Now we see clearly you see the receipt on Marcy's graceful. Give us the eyes to see what you're doing in and around us. I was to see what the father is doing and we can come alongside and joining you and bringing your kingdom on the earth. Just open our hearts to receive all that you have for us this morning. We welcome to your presence in Jesus name. 0 (18m 11s): Amen. It's good to see your faces. Why don't you say hello to someone around you and I'll have some announcements coming in just a few moments. 1 (18m 22s): Well, of course, those who are sitting here in the sanctuary and in the loft and behind the patio and those who tuned in online, it's amazing how, you know, we can reach out to the entire planet with live stream. And so, anyway, we want to welcome you. Hey, if it's your first time to Harvest Church or maybe you're new here, I would encourage you to go by the info center, which is just up the driveway right here and talk to the people there. They've got to give for you. I'm not going to tell you what it is, but it looks like a coffee cup, but she can put other things in it besides coffee that's up to you. Yeah. So go up to the info center. And while you're there, if you wouldn't mind filling out a communication card, we love to be able to communicate with everybody that that is, you know, Harvest is your Church home. 1 (19m 9s): And then if you, if you don't want to actually fill out a actual card, you can go online to our website. That is yeah. AIG Harvest app. And you can, you can fill it out that way as well. So the, the holidays are upon us. We've got Thanksgiving coming up real soon. We got Christmas right around the corner. So we are kind of in that, that zone of working to help out people in our community that are in need. So I've got a couple of opportunities for you. So the first one of course is Thanksgiving, which is coming up like a week and a half or something like that. So we've been putting the word out. I know many of you have contributed to our food pantry cause we're putting together a Thanksgiving baskets for families in need. 1 (19m 53s): If you remember to bring your stuff today, see today's the deadline. So if you're hearing this for the first time, you got to get up and get to the store and get back here quickly. If you forgot about it, or this is your first time hearing about it, you want to be a part of it. Go ahead and bring any items. If you, if you obviously can't get them here today, you can bring, bring them by the Church office tomorrow. And I will be there. Some of us others will be there and we can go ahead and, and have 'em collected that way. So if you want to come by the Church office, we're here between nine and four. That would be great as well. Okay. What else? Oh, back to that, if you did bring some items, drop them off at the info center, which is again, right up the driveway. 1 (20m 35s): So one of the other things we're participating in, in our community, it's called blessings to local foster adoptive families. And so we're partnering with other local churches to provide local foster and adoptive families with a meal and with gift cards for Thanksgiving. So you can check out our weekly email updates to get more information about how you can purchase a bait in that. But we love to be a blessing to foster adoptive families in our community. And then the last thing I want to make mention of, and this is sort of more looking towards Christmas is we are participating in operation Christmas child. It's a ministry under the umbrella of Samaritan's purse. Maybe you've heard about it. It's it's been going on for many years. 1 (21m 16s): So what they do is they put necessities and toys in a shoe box and then they're shipped all over the world. So with COVID the way they're doing it now is a little different than, than normal in the past. So what you would do is you would go to their website, operation Christmas child, and you can actually select the items on their website that you would like included in the box. And they've got a team of people in different places across the country. They put those boxes together on your behalf and ship them out to various people in need kids predominantly in need. And it's it's if you've ever seen the videos, in fact on their website, probably have some videos of these kids receiving these shoe boxes. You know, it's, it's, it's really stunning the impact we can have. 1 (21m 58s): And of course they include in those boxes, a presentation of the gospel of Jesus Christ. So that's all I have for you today, Steve. Let's welcome. Steve, come on up here. 2 (22m 11s): Morning. Welcome. I'm approaching from a different side of the room today. Tricking you welcome where Colossians chapter four today, galoshes chapter four verses two through 18. How about a quick joke? I was ready for a quick joke. It's a good one. This time. Trust me. So this, these two lifelong friends, Archie and Jack, they had been arguing their whole life about the color of Jesus. Archie was convinced that Jesus is black and Jack is convinced that Jesus is white. So they're arguing about this their whole life. It just so happens. They die on the same day and they get up to the pearly Gates and they go on inside and they asked st. 2 (22m 55s): Peter, Peter, tell us, we've been arguing about this for our whole life. Is Jesus black or is Jesus white? And about that time, Jesus walked up and said, Buenos D'usse Jesus, isn't black or white he's act he's middle Eastern. He's a, he's like his swarthy dark skinned man. So if you look at Rolando Rojas, that's probably what Jesus looked like. There we go. Now it's going to be hard to Pray without thinking about Rolando. But anyway, we are talking about prayer today. It's going to be a good day. How to pray one Oh one we're in Colossians chapter four, verse two. 2 (23m 40s): How to Pray one Oh one. Let's go ahead and stand up and pray as we get ready to talk about praying and we'll have Church today. Lord, thank you for the opportunity to gather, to have church, to be in your presence. Lord God, we pray that you would speak to us God, that our hearts will be open and that we, we would be responsive and receptive and happy to receive your truth. The revelation that you reveal to us Lord. So thank you for the opportunity to gather. So Lord, on the patio, in the loft, in the sanctuary, on the worldwide web, we just pray God that your word would go out with power and with clarity. 2 (24m 20s): Thank you for this time, Lord in Jesus name. Amen. Amen. Just as you get seated, we've got people in Greenland, our missionaries, Daniel, and Solvay, they're actually watching online in Greenland. So we just want to say hello to them. We've got a big audience in India as well, for some reason, big audience in India. And we've got literally thousands of people who tune in every week and watch what we're doing to participate from around the globe. And so it's kind of fun to it kind of makes the world a little bit smaller. Doesn't it? That we can have an impact all over the globe by just what we're doing here on the central coast of California. It's really, really good. 3 (24m 58s): How to pray one Oh one. 2 (24m 60s): The definition that the very definition of one Oh one means basic. It means introduction. It's kind of the beginner's guide. And so we're going to be talking about prayer today. Prayer is where you start, but also prayer is what get things gets, things done spiritually. So we never get to mature spiritually to S so we stopped praying. We pray when we get saved. When we come to faith in Christ, we pray before we know Christ that we'd come to know Christ. We, we pray all the days of our lives. If we want to continue to grow and mature in our faith. So don't ever get away from the basics. I was playing golf yesterday, actually played golf three times this week. 2 (25m 41s): I never play golf three times in the same week, but it just like everything happened. I kept getting invited to go play golf. So I was at home yesterday and I had nothing to do all day, which was a delightful problem to have. And my son called me up and said, Hey, I want to go play nine holes of black Lake. Do you want to go? And I'm like, sure, let's go play golf. So we played and we got on one particular hole. 3 (25m 59s): I am hacking it. I'm absolutely hacking it on the third hole. And 2 (26m 5s): I walked away. I started to get mad, but then I walked away and I said, you know why? I love this game. I told my son, you know why I love this game because you can't just get up there and fake it. You have to eat, you got to be present. You got to pay attention to the bank. You got to keep your head down. Like every time I bought your shot, what did I do? I lifted my head. Right, right. I'm trying to see where the ball went before. I actually had a chance to hit the ball. So I hit the ground and the ball goes two feet. And I'm hitting three before I even know. So there's something about the basics, keeping our 3 (26m 36s): Eye on the ball. That is it 2 (26m 38s): Never, ever changes. Like I could play golf for another 20 years. And what do still have to do? I still have to keep my head down. If I want to hit the ball. If I lift my head, I'm going to say, I'm going to chunk the ball all every time. Every single time, prayer is spiritually seeking. Speaking about the most important thing that we can do as followers of the Lord. Jesus Christ. Prayer is the most basic thing, but it's also the most important thing. It is super, super important. Prayer keeps our eyes on Jesus. Chapter four, verse two, Paul said devote yourselves to prayer. 2 (27m 19s): Colossians four, two devote yourselves to prayer with an alert mind, and a thankful hearts to devote means to persist in like never give up, continue to pray, to pray, devote yourselves to prayer with an alert mind and a thankful heart. Pray one Oh one number one. Pray with an alert mind. When I think about that, I thought, what does it mean to pray with an alert mind? Well, in my coach training, when I was training to be a coach, a life coach, they would talk about being present with people as you coach them, duh, right? The most basic thing in the world. 2 (27m 59s): Like you have to listen, you have to be paying attention to what somebody is telling you in order to effectively coach them. Well, that's true in any relationship. And it's obvious when somebody is to begin to drift in the relationship or in the conversation, right? So we're having a staff meeting this earlier this week and, and we're all talking about details of ministry and that sort of thing. And one of the staff members piped up with the question and we all kind of looked at him like, have you not been a part of this conversation? And then you realized, Oh man, I've been, I've been. So I've been drifting in my thoughts. And I miss part of the conversation. And that's kind of what happens if we're not present in a conversation where we start thinking about other things and we miss the important things that are being communicated in a message. 2 (28m 42s): And everybody knows when, when you are in a conversation with someone you begin to drift, you begin to look around, you begin to your mind and, and things get lost in the conversation. The same can happen and does happen in our prayer time with the Lord. We begin to drift. And so what I do, cause I know that I'm prone to drifting. I, I can drift with the best of them. And so when I know that I've got to go on a walk, I've got, I got to do something that will keep my mind focused on the Lord. So I'll just go out into our neighborhood. Or if I'm at the office here, I'll just walk around the village and just pray. I'm saying, Lord, I need to focus. So I just, I don't know why walking helps me to focus. 2 (29m 23s): Maybe that would be distracting to you, but for me, it helps me to focus. So whatever you need to do to not drift, but to be present in this conversation that you're having with the Lord to stay alert, then doing the world and the flesh and the devil is doing everything they can to get us distracted, to interrupt our alert mind. So do what you need to do to stay alert. God has got great things to communicate to us. And when we're alert, we can pay attention to those things. We can pay attention to that. Still small voice. I think sometimes we're so distracted. We're not giving God. 2 (30m 3s): We're just kind of going through our shopping lists with the Lord, right? Laura, I need this and I need this. And Lord, would you do this? And would you do that? And those things are bad, but he also wants to talk, right? It's a two way street. It's a conversation where we're saying, Lord, I need this in my life. Or I want this for someone else or Lord, I'm praying for the health of another person. And maybe just maybe the Lord will in that still small voice, download 4 (30m 27s): Comfort to us. Truth to us, 2 (30m 30s): Answers to us. If we'll just stop long enough to give him an opportunity and just listen and be present with what the Lord is saying, maybe you're up against a very difficult situation. And you're just kind of rambling at the Lord. Lord, I am so tired of this. This has been so difficult. I just need to get through this and you don't give the Lord a chance to speak. And so he isn't have the opportunity to bring 4 (30m 54s): Comfort to your soul 2 (30m 57s): Because it doesn't matter if a storm is raging. If the Lord has given you comfort, 4 (31m 1s): The storm can rage. There's comfort. Sometimes God will stop the storm. 2 (31m 5s): Most of the time, he's just going to give you a comfort in the midst of the storm, he is going to reassure you. He is going to, I love the song. Jesus loves me. 4 (31m 14s): I, that 2 (31m 16s): Is the basics, 4 (31m 18s): Right? And yet when 2 (31m 20s): We sing it, it's like, it's like food to our soul, like water to our spirits. I mean, it just refreshing 4 (31m 28s): Cash is us in such a powerful way, right? 2 (31m 31s): This same opportunity is with us. When we pray, Lord, I'm really struggling here. Lord, 4 (31m 37s): Would you do something? And then just wait. Instead of 2 (31m 40s): You're going to the next item on the list, just wait and see what the Lord will do. And then maybe take it to the next level and just journal Lord. This is what I think. 4 (31m 50s): I feel like you're doing. This is what I feel like you're saying. This is the sense I get when I'm praying about this situation. Thank you, Lord. Thank you for clarity. 2 (32m 4s): And all of a sudden we're getting answers or we're at least getting comfort to we're at least getting peace in the midst of whatever it is that we're going through. As we Pray with an alert mine, 4 (32m 19s): It's, it's difficult to focus when we're praying. It really is. And we were praying to somebody who's invisible. 2 (32m 26s): He's not like, like I can have a conversation 4 (32m 29s): With a person and it's easier, but God is invisible to us. And so we have to count on our other senses and pay attention to what the Lord will say to us, speak to us. 2 (32m 40s): And we have to be disciplined to do that and intentional about doing that. 4 (32m 46s): Stay alert, stay alert to how you're feeling as you Pray. If you're, if you're, if you're 2 (32m 53s): Feeling anxious, asked the Lord about that, say, God is I pray about this every time I do. I'm anxious. Lord, am I, am I lacking faith? Or am I lacking confidence in you? If I am Lord, I don't want to, I didn't want to pray from a place of anxiety. I want to pray from a place of faith and then God will give you the grace to do that. All something will happen in your spirit. God will meet that need. And all of a sudden you'll have a different perspective and you'll be able to pray from a different place. And instead of being anxious 4 (33m 23s): Or fearful, man, 2 (33m 26s): All of a sudden Lord nothing's changed in the circumstance, but I just have a different person 4 (33m 30s): Perspective. I can pray with faith, 2 (33m 34s): Faith that God is at work. Even though I don't necessarily see what he's doing. Faith, believing that even if he's not doing anything that I can see or perceive, now there's something coming because God loves me. God's caring about, he cares about my needs, right? He's never left me nor forsake me. So I can believe that if I've got a need, he is going to take care of it. Sometimes we pray for the same thing. For years before we see an answer, we pray for a loved one for years before we see an answer, we pray for a friend or a neighbor for years before we see an answer, we pray for somebody who's sick for months before we see an answer, God is doing something. 2 (34m 18s): So pay attention to what the Lord is doing. As you pray, pay attention to how you're feeling and what's going on. And then to address those things, maybe you're angry in your prayer, just maybe you're angry at the Lord. And that's kind of surfacing just feeling some anger because maybe the Lord hasn't done what you thought he should do. And so maybe in that anger, you just address it. Cause God knows. And you say, Lord, I I'm feeling angry about this. Like I expected something 4 (34m 47s): Else. Like why didn't why Lord, 2 (34m 52s): Just to say, Lord, I'm angry, but I don't want to be angry. I'm I'm angry, but I didn't want to live my life like this. And so you can say, Lord, forgive my anger. I confess my anger. I'm deciding to not be angry. Right? There's got to be, you got to come full circle with it. You gotta, you gotta acknowledge it and then get out of it. Like you got to acknowledge what's going on. And then just by faith, say, I'm not going to be angry anymore, or I'm not going to be unforgiving anymore, or I'm not going to be faithless anymore. And you declare that over your prayer time, over your circumstance and situation Pray with an alert mind and just watch what God will do as he kind of unpacks things and peels back layers of emotions and, and just all kinds of stuff in your life. 2 (35m 40s): Number one, Pray with an alert mind and then number two, pray with a thankful heart, all of this from birth to, 5 (35m 49s): I think it's important that, that I say to that because we're looking at 2 (35m 54s): One verse so far and God's already given us so much to consider and to ponder some, so many things, devote yourselves to prayer with an alert, mind, a thankful heart, just simple little verse B. There's so much richness there. It's true. When we pray as well in our simple 5 (36m 10s): Little quiet 2 (36m 13s): Prayer time with the Lord, there's just so much richness, so much for us to gather and to, to benefit from. And it's true with the word too. Sometimes we're just rushing through the scripture and it's better some days just to focus in on one verse 5 (36m 30s): And ask the Lord, God, what are you speaking to me 2 (36m 33s): In this one verse? I'll be honest. When I read through this text, I thought, man, I'm going to have a hard time writing a sermon out of this text because I was just kind of quickly going through it. I'm looking for something high points. And, and, and then I started talking with Jolene about the texts and she's like, man, I'm really excited about Colossians chapter four this week. I'm like, you are why. 5 (36m 53s): And so we just began to talk about it. And then 2 (36m 56s): I came back to it with a fresh perspective. I'm Molly, I'm a she's right. There's so much here. And so she wrote my sermon this week. Isn't that great. She's never written my sermons ever. So thanks. I know they, some weeks they come out so good. You think who somebody else must have wrote? It must be Jolene writing his sermon. 5 (37m 15s): We knew it all along 2 (37m 19s): First, Thessalonians five 16 in the ESV says region 5 (37m 23s): Joyce always rejoice. Always 2 (37m 30s): First Thessalonians five 17 in the ESV says Pray without 5 (37m 34s): Ceasing . 2 (37m 37s): These are easy verses to memorize by the way, five 16, rejoice always. That's the verse. Rejoice always verse 17, pray without ceasing first Thessalonians five 18. Give thanks in all circumstances for this is the will of God in Christ Jesus for you pray with a thankful heart. This is actually the will of God for you. You ever wonder what the will of God for you is this is part of the will of God for you give thanks in all circumstances for this is the will of God in Christ Jesus 5 (38m 10s): For you. If 2 (38m 12s): You're having our time with gratitude reasons to be thankful while you pray, 5 (38m 17s): Make a list. 2 (38m 19s): I met in met with an older couple this week. Haven't seen him for a few months. They used to come to the church, but they'd been home, home bound and sick in bed for well, the, the, the, the woman has, and the husband's declining as well with, with issues of his own. And so I sat with them and just in, in the bedroom there, we sat on the bed and just chatted. And I just asked how they were doing. And instead of complaining that they're stuck in bed, stuck at home, can't drive, can't get out like they used to. They said, and this is what they said. We're just thankful that we're alive. 2 (39m 1s): We're thankful that God has given us breath, right? Listen, no matter what you're going through in life, I would encourage you to make a list of all of the things that you're thankful for. I think we tend to lean toward the negative and think about all the things that we wish were different in our lives. 5 (39m 21s): If you're having a hard time, start with that. If you're having a hard time 2 (39m 27s): Being thankful, start with being thankful for your breath. I 5 (39m 31s): God, I thank you that I have breath. 2 (39m 35s): Thank you Lord that I have family. If you've got family thankful Lord for family, thank you for the roof over my head. If you've got a roof over your head, say thank you, Lord, thank you for that. Yeah. Thank you for my health. Even if you're sick, you can still thankful Lord for the health that you do have for employment. I talked with a guy on the golf course. This must have been a Friday cause I play three times this week. So, 5 (40m 4s): Okay. 2 (40m 5s): I had a great time this week playing golf. I didn't even play very well, but I had so much fun. 5 (40m 10s): Anyway, this guy had been, he's been lately 2 (40m 13s): Since about March and he's. So he's been unemployed since March and he's been struggling to try to find a job. So be thankful for your employment. If you've got a job and pray for others who don't have jobs To be thankful for your mind, if you can think and process. And remember just did a Memorial service for my friend, Dave Fletcher, who he just at the end of his life for the last four years, he just, he wasn't able with through dementia, just wasn't able to remember things. Wasn't able to remember people or recall events. He just, his mind just began to go over the last four years of his life. 2 (40m 53s): So if you, if your mind is sharp or even if it's not as sharp as it used to be, it's you still got to be thankful for that. Say thank you, Lord. If you have the ability to walk thankful, Lord, if you have the ability to see, thank the Lord, talked to the guy last week, he's here. And he's like I said, are you completely blind? And he said, well, there's this one spot in my eye. 5 (41m 18s): So if I look this way, I can see you. He's thankful for that. 2 (41m 24s): He's mostly blind, but he can see just a little bit. We can, we can find all kinds of things to be thankful for. 5 (41m 35s): So if you can tell, 2 (41m 36s): Talk, and play and work and eat and travel and smile. Yeah, 5 (41m 39s): They'll be thankful. Be thankful. 2 (41m 43s): The Psalmist wrote in Psalm one 11, verse one, praise the Lord. I will give thanks to the Lord with my whole heart. This almost understood. And this is not someone who never experienced trouble in his life, but at someone, someone who decided with my whole heart, I'm going to be thankful. I'm going to give thanks to the Lord. Psalm one 11 two in the ESB says great, are the works of the Lord. This is why he was thankful because great are the works of the Lord. I encourage you to go back and read Psalm all of one Psalm one 11 after Church street, all of Psalm one 11, especially if you're having a hard time with gratitude, you'll be filled with gratitude. After that, be thankful for God, for his faithful newness, for your salvation, for God's love, 5 (42m 32s): Thankful that you don't 2 (42m 33s): Get what you deserve. Jolene and I were talking about this, the mercy of God, 5 (42m 38s): Thankful that 2 (42m 38s): We don't get what we deserve thankful for his mercy and for his grace don't ever get away from the basics. Pray with an alert, mind, pray with a thankful heart. 5 (42m 49s): Why are, why are we to pray? God, God tells us to. 2 (42m 59s): It's a really good plan. It really it's a really, really good plan as how many times I, I just, I realize I I'm dry spiritually. If I just go Pray, there's the refreshing that comes. If I'm nervous about something and I pray about it, the nerves lift, Whatever the case may be. If I just go pray about it, all of a sudden I've got clarity. Maybe I don't have all the answers that I need, but I, I have clarity and usually confidence. It's budget time for the church. And so we're, CA hashing over numbers every year we get to budget time and I'm always nervous about budget time. 2 (43m 41s): But I told Julie, I said, no matter what the Lord has always been faithful. We've been here for going on 18 years. This is like our 18th budget, I guess. And every year we've watched the Lord be faithful in the budgeting process and in the provision that is needed for our budget. It's just been, it's profound and supernatural. And so when we're nervous about the budget, we just pray. When we're nervous about anything in life, we just pray. And then we watched the Lord just bring confidence or clarity or a change. He might say, well, do this or do that. And redirects, redirects our path. 5 (44m 20s): Okay. 2 (44m 21s): One person said prayer is as essential to our spiritual health as breathing is to our physical body. 5 (44m 29s): So if we stop breathing, we dying 2 (44m 32s): Physically, right? If we stop praying, we start dying spiritually. There's a direct correlation, a direct correlation. Pray prayer. Prayer is not optional. 5 (44m 51s): Okay? 2 (44m 51s): Prayer is essential to spiritual health and growth. Back to first Thessalonians five 17 in the new living translation. It says never stop praying, never stop praying. Another easy verse to memorize, never stop praying don't ever get away from the basics. Pray with an alert mind, pray with a thankful heart and number three, pray for other people. Pray for other people. Colossians four, three, Paul writes pray for us to, I love Paul's humility. And the fact that he recognized a couple of things, he recognized the power of prayer. 2 (45m 34s): Remember he's in chains, he's imprisoned right now, maybe going through some hard stuff in his life. So he says, pray, pray 5 (45m 46s): For us. Pray 2 (45m 48s): For us to that. God will give us many opportunities to speak about his mysterious plan concerning 5 (45m 52s): Christ he's 2 (45m 54s): In chains. And he wants more opportunity to speak about this mysterious plan. Mysterious plan about Christ is that he's the God of the Jews and the Gentiles. He's the guy, 5 (46m 3s): The whole wide world. And Paul's looking for 2 (46m 9s): Opportunity to Pray for opportunity while we're here. Pray for opportunity that we'll have the ability to speak the truth to preach the gospel. That's why I'm here in chains. He said, pray that I will proclaim the message. Verse four, as clearly as I should. 5 (46m 30s): Okay. 2 (46m 30s): Pray that I will proclaim the message as clearly as I should 5 (46m 35s): Pray for others. Pray for others, 2 (46m 40s): Especially in these toxic times that we're in Pray for those you disagree with and pray for those who disagree with you, man, it will soften your hearts. It will tend to raise you a little bit. It's hard to be mad at somebody that you're praying for. When I say Pray, I mean, pray for not Pray against brave for Pray for pray, for 5 (47m 5s): Pray for 2 (47m 7s): Especially those, with whom you disagree. And it's hard to be mad or at odds with people when we're praying for them, we just find a tenderness. 5 (47m 16s): Yes. And to love 2 (47m 19s): And the supernatural it's something that God does. I ran into a guy this week, who I used to have to be at odds with. And 5 (47m 30s): I was 2 (47m 30s): So grateful that the Lord had done a work in our relationship that both of us just, we saw each other and we, we hugged and we laughed and we talked like nothing ever happened. It was like the supernatural moment. I, I I'm I'm there. It was surreal in the moment. Cause I'm like, you know, not too long ago, we were kind of at odds with each other. We didn't really care for each other, but God did something. He did something in him and he did something in me. He did something in the relationship and we were able to hug on each other and talk like nothing had ever happened. Why? Because love keeps no record of wrong. I think I've read that somewhere. Love keeps no record of wrongs. 2 (48m 14s): So there was this, this refreshing move of God. As we talked, I walked away. I was like, Holy cow, that was a wonderful conversation. That's what heaven's going to be like. That's what heaven's going to be like. Just grace covered grace filled wonderful relationship and connection Beyond prayer. Paul gives instruction for daily living in verse five and following he said, this live wisely among those who are not believers and make the most of every opportunity live wisely. 2 (48m 54s): Make the most of every opportunity. 5 (48m 56s): Pray pray for pray for those in your life who are not yet believers. Pray for them. 2 (49m 8s): You might pray for them for a decade or two or five, but pray for them and watch what the Lord will do. And then love on them. Love on them. Be gracious to them. Live wisely among those who are not believers and make the most of every opportunity. Verse six, let your conversations be gracious and attractive. That that verse means seasoned with salt. 5 (49m 34s): Well, that's your 2 (49m 36s): Appreciation be gracious and attractive seasoned with salt so that you will have the right response for everyone seasoned with salt. We had some stew last night and we're eating the stew and it's it's okay. Julian says this needs some salt, man. Yeah. That's okay. We keep beating this dude. Like yeah, you're right. I need some salt. So he puts some salt on there, like, Oh, all of a sudden, this is pretty good stew. Right? Just need a little salt, little salt goes a long way. 5 (50m 7s): Okay. 2 (50m 7s): Your conversations to be seasoned with salt. I often pray. Lord, let my words be seasoned with salt lit, especially when going into a difficult conversation, because I can say the wrong thing, like stepping off this curb. I mean, it just doesn't take any effort at all. I can say the wrong thing. And so, but I pray and I make it my attention to speak words that are seasoned with salt, something, God just does something there. And when maybe when I want to react, I don't react. Or when I want to overreact, I don't. And then sometimes my words just plainly are not seasoned with salt. And God's grace is sufficient, but make it your intention. 2 (50m 49s): If we make it our intention, that our words, our conversation to seasoned with salt so that we have the right response for everyone. Lord, what is, how do I respond in this situation? We live in a toxic environment. How do we respond in these situations that are so difficult when people maybe disagree with us about, well, you name it, religious perspectives, beliefs, political perspectives. There's, there's a lot to disagree about. Or what is my response with this person right now? Maybe you have a healthy conversation about religion or politics. 2 (51m 31s): Maybe you don't, you just love the person. Maybe they are on a completely different track than you are, but you just love them. 5 (51m 40s): Because 2 (51m 41s): Cause being right is not the biggest deal. It's not, I mean, that's not the goal. I like to be bright. I don't have to be right when I have conversations. I, the most important thing that God has called us to do is to love people. So why don't we, why don't we have to fight? Why don't we just love on each other and let God worry about 5 (52m 4s): Our society is polarized. 2 (52m 8s): God has an assignment for us and I'll get specific. God has an assignment for you in this polarized society that we live a live wisely, live wisely among those who are not believers. That's your assignment as believers. This is your assignment to live wisely. It's going to be different for every scenario and every situation that you're in. But if it's your, if it's your heart and mind to live wisely, you just say, Lord, I, I don't know how, what would you show me a be make the most of every opportunity. 2 (52m 54s): God is going to bring people to your path. Lord make what's the best way to make the most out of this opportunity. I don't know what to do. Lord, if you ever been, I don't know what to say. I don't know how to have a connection, a conversation with this person, make those be prayerful. This is why prayer is so crucial to who we are as followers of the Lord, Jesus Christ. You can be having a conversation to be praying at the same time. I'm often up here praying as I'm preaching because I'm in desperate need of the grace of the Lord, Jesus Christ to do what I do. So I'm praying. 5 (53m 28s): And then I'm preaching talking. And then 2 (53m 32s): I'm praying. I asking the Lord for his help to, to get this word clearly out, making the most of every opportunity. See, let your conversations be gracious and attractive against seasoned with salt so that you will have the right response for everyone. A, B and C a B, and C. All of these seemingly impossible things are possible. When our lives are filled with prayer and love, 5 (54m 2s): The more we Pray 2 (54m 3s): For people, the more we'll have the capacity to love them. Last week, we looked at 14 ways. Husbands can love their wives. That's a great list. 14 ways how'd you guys do this week. 5 (54m 22s): We'll talk later. 2 (54m 25s): This list is actually a great list to keep an eye on. When loving people in general, Prayer makes this 14, this list of 14 things doable, possible. 5 (54m 45s): How can 2 (54m 45s): And we live wisely making the most of every opportunity and have the right response for everyone. W we have to remember to pray for people and love people. Love is patient. We were running late this morning and I was in the car waiting. And Jolene was just running late and get in the car and later to go, I'm like you ready to go? She's like, Oh, I need to get something. I said, well, we're in no hurry just to get what you need. She said, thanks for being patient with me. And I said, well, love is patient, 5 (55m 17s): Right? 2 (55m 17s): Some days I really nail it. Other days I totally missed the Mark. I, my arrow goes Well. That was basically, but I knew I was going to be talking about it today. So I knew that I had to be on my best 5 (55m 33s): Love is patient love is kind. 2 (55m 38s): Love is not jealous. It's not boastful. 5 (55m 45s): Love is not proud, is not rude. 2 (55m 51s): Love does not demand its own way. Love is not irritable. Love keeps no record of being wronged does not rejoice about injustice, but rejoices. When the truth, when the truth wins out, love never gives up. Love, never loses. Faith. Love is always hopeful. Love endures through every tall order, impossible in the natural impossible. Just if we're relying on our own natural strength, our own sinful man, but very possible. 2 (56m 35s): All of these things are very possible when we're prayerful and filled with the love of God, then we can love people. The way that God's asked us to love people, Because it's not boastful or proud or rude, it's just tender. And it can be direct at times, but it's not boastful or proud or rude keeps no record of being wronged. All of those things are key to healthy relationships between friends and neighbors, coworkers, spouses, siblings, you name it. 2 (57m 21s): So we wrap up here, let's look at Paul's final instruction and greetings verse seven, Paul mentions 10 people by name 10 people by name who were with him. People partnering with him, people who prayed for him and those Paul prayed for and people that he did life with. Paul did life with people. As far as we know, he's a single man during his ministry, but he was surrounded by people tickets for seven, writing to the church. , we'll give you a full report about how I'm getting along. He's a beloved brother and faithful helper who serves with me in the Lord's work. 2 (58m 5s): I have sent him to you for this purpose to let you know how we are doing and to encourage you. Paul's Paul's in chains and he's writing a letter to encourage the church. It's because it's all about life is all about perspective. It can be in chains and be thrashed, or we can be in chains and be filled with the Holy 5 (58m 25s): Spirit and not thrashed at all. 2 (58m 27s): Just so thankful. Got my breast still. I can still write letters. I can still pray. I can still do all of these things. That was Paul's perspective. It must have been there. Otherwise he wouldn't have the capacity to want to encourage others, but he did. He didn't care about the chains. He was there because he was preaching. The gospel counted worthy to suffer for the, for the King. 5 (58m 53s): It was wonderful. 2 (58m 57s): It's balls and change is he and he's encouraging them. And again, I believe this response is a result of purpleness and great love. Paul prayed for the church. He prayed for the church. He loved the church. He loved the people. Verse nine. I am sending also, I'm also sending a, Onesimus a faithful and beloved brother, one of your own people. He and will tell you everything that's happening here. So he's, he just wanted to do, to give a report. This is what's going on during the week, this last week, Daniel, and Solvay a video chatted in and got a chance. They got a chance to talk with their, their board Daniel. And Solvay kinda, they minister in Greenland. They're living in Greenland, taking the gospel to the top of the world. 2 (59m 40s): And they're yet connected to us. And they're watching on Sunday morning, the, the preaching and the service, and then they're encouraging people in their village to do the same thing. So we've got people on this Greenlandic village who are watching what we're doing here on Sunday morning. So we, we love you guys. We bless you. We love Daniel. And Solvay they called in to just give an update on what's going on. The people that they're praying for and their people that they're ministering to and the people that they're serving in their community. Why? Because we're called to do life in community. Even if we're in a Greenlandic village on the top of the world, there's connection there there's prayer exchanged. I'll often get messages from Daniel and Salva. 2 (1h 0m 21s): Hey, we're praying for you and I'll respond. I'm praying for you. God's doing good stuff all over the world. Aaron Stark is firsthand who was in prison with me. So Paul is not alone. Send you his greetings. And so does Mark Barnabas cousin, as you were instructed before, make Mark welcome. If he comes your way to Mark surface, March, the guy that Paul and Barnabas were traveling with on their missions acts chapter 13, John Mark, he went home, he went back to Jerusalem. He's like, I'm not going to continue on in the mission. And Paul was pretty tweaked by that. He's like Mark, can't travel with us any longer. And that's when Paul and Barnabas split up and went their separate way. 2 (1h 1m 5s): Something happened. Maybe like my friendship with a guy that I ran into there, there was a healing there. Why? Because, because of prayerfulness and love being extended and exchanged, remember the story. I mean, there was a, it's a big deal. It's often cited in acts. I think it's chapter 15 where they say, Hey, we're done. We're not traveling together. We're not ministering together. But here in this scenario, 4 (1h 1m 38s): Paul saying, Hey, take, take care of my brother, Mark. 2 (1h 1m 42s): We endure hardship better when we are in it with others. So we don't have time for petty disagreements. 4 (1h 1m 49s): We are brothers and sisters in the Lord. We are 2 (1h 1m 53s): Connected. We are friends. We need each other. And when we extend grace and love to one another, when we pray for one, another, man, things can happen and we can go sideways. But man, God God's, grace is sufficient. We can come back together. 4 (1h 2m 10s): We endure 2 (1h 2m 10s): Hardship better when we are in it with others. Let's talk about friendship for a minute. If you need a friend to do do these four things. If you need a friend, some of us are just lacking friendship where like, I don't have any friends in my life. Do you do four things? I started out with two. I added two more. So we have four forgive people. If you need a friend, just start forgiving, be friendly. Number two, number three, love people. Number four, pray for a friend. Paul had many friends as is evidence in this final instruction. Verse 11, Jesus. The one they call justice also sends his greetings. 2 (1h 2m 52s): These are the only Jewish believers among my coworkers. They are working with me here for the kingdom of God and what a comfort they have been. a member of your own fellowship, probably the guy who planted this church in Colossae and in Colossi at the first a member of your own fellowship and a servant of Christ. Jesus send you his greetings. He always prays earnestly for you. I love it. When people tell me that, Hey, I'm praying for your church. I'm praying earnestly for your church, asking God to make you strong and perfect, fully confident that you are following the will of God. God responds to prayer. Prayer will make you strong and perfect, fully confident that you are doing the will of God. 2 (1h 3m 33s): The word perfect means to complete and mature. This is God's desire that we'd be complete and mature, confident that we're doing the will of God, that we know the will of God. As we pray for people are we're making them strong. As we pray for people, we're making them strong in Jesus name, perfect, fully confident that they are doing the will of God. Verse 13. I can assure you that he prays hard for you and also for the believers in Laodicea and higher opera. Hieropolis Luke, the beloved doctor sends his greetings. And so does Demas. Please give my greetings to our brothers and sisters at Laodicea and to Nympha and the church that meets in her house. 2 (1h 4m 17s): After you've read this letter, pass it on to the church at Laodicea so they can read it too. And you should read the letter I wrote to them. That's why we teach through these letters because they're meant to be read and understood and say to R-CHOP is to be sure to carry out the ministry. The Lord gave you a little bit of challenge there. Say to R-CHOP is to be sure to carry out the ministry of the Lord gave you. As I read that, I thought that's for somebody here 4 (1h 4m 39s): Today, 2 (1h 4m 42s): Maybe the Lord's given you a ministry to carry out. Okay? 4 (1h 4m 45s): And you've been unresponsive, unwilling, maybe even disobedient. I'll just say this. 2 (1h 4m 59s): Be sure to carry out the ministry. 4 (1h 5m 2s): The Lord gave you. 2 (1h 5m 6s): Here's my greeting in my own handwriting. Paul, remember my chains. May God's grace 4 (1h 5m 11s): Be with you 2 (1h 5m 14s): Don't ever get away from the basics. Pray with an alert mind with a thankful heart and pray for other people. And remember your assignments live wisely among those who are not believers, make the most of every opportunity and let your conversations be gracious and attractive so that you will have the right response for everyone with that. Let's go ahead and Pray let's invite the worship team forward and we're going to continue with Church Lord. Thank you for Church. Thank you for the opportunity to gather, to sing, to pray, to hear a message, to open our hearts and to avail ourselves to you. Lord, we just need you to continue to speak to us as we worship, God, help us to worship in spirit, being present with you. 2 (1h 5m 58s): And in truth, being honest with you, with you and honest with you, help us to be with you and honest with you, Lord, thank you Jesus. For that. God, we love you. And we, we know that you're going to continue to minister. As we open up our hearts and saying, and give ourselves as we make an offer a sacrificial offering of our singing to you, or thank you. Thank you for taking care of Harvest Church we love you Lord in Jesus name. Amen. Let's sing 0 (1h 6m 33s): To, to do it. here is where I lay it down is where lay it down. 0 (1h 7m 28s): Every burden, every crown. This is my silver and this is my . This is my servant. I'll make room. 0 (1h 7m 50s): crown. 0 (1h 8m 30s): This is my son. This is my son. He is where every lie and every doubt, this is my son. 0 (1h 8m 50s): I'm going to say shake up to the ground of our tradition. 0 (1h 9m 44s): Break down the laws of our religion. Here we go. 0 (1h 9m 46s): you want your will to be done in our lives. 0 (1h 11m 20s): Would you lead us? Would you guide us? 0 (1h 11m 47s): you are close. 0 (1h 13m 2s): I've known you as a all my life who have been, who have been. 0 (1h 15m 2s): So would you stir our hearts? 0 (1h 16m 12s): Help us to hear you speak as we need to guide us. Pray pray for others. Speak with hearts seasoned with salt. Thank you for being in our midst here today. We love you and we look forward to worshiping, speak to you in there again next week in Jesus name. Amen. Amen. Thank you so much for being with us both online and here on campus. We can't wait to see you next Sunday. Have a wonderful day. If anyone would like prayer, feel free to come forward. We would love to pray with you. There'll be some staff or others available to meet with you. Thanks so much.

Zagrevanje Bullet Journal (https://bulletjournal.com/) Cal Newport: time blocking (https://www.calnewport.com/blog/2020/03/16/text-file-time-blocking/) Yuval Noah Harari (https://www.ynharari.com/): Sapiens (https://en.wikipedia.org/wiki/Sapiens:_A_Brief_History_of_Humankind) TED Talk (https://www.ted.com/speakers/yuval_noah_harari) Twitter (https://mobile.twitter.com/harari_yuval) Davos i ostala predavanja (https://ncfacanada.org/how-to-survive-the-21st-century-davos2020-yuval-noah-harari/) Jared Diamond (http://jareddiamond.org/Jared_Diamond/Welcome.html): Guns, Germs, and Steel (https://www.amazon.com/Guns-Germs-Steel-Fates-Societies/dp/0393317552) Collapse (https://www.goodreads.com/book/show/475.Collapse) Upheaval (https://en.wikipedia.org/wiki/Upheaval:_How_Nations_Cope_with_Crisis_and_Change) Loši medicinski primeri: IBM Watson - uspon i pad (https://www.forbes.com/sites/matthewherper/2017/02/19/md-anderson-benches-ibm-watson-in-setback-for-artificial-intelligence-in-medicine/) Theranos (https://www.npr.org/2018/06/23/622795416/reporter-john-carreyrou-on-the-bad-blood-of-theranos) (nije bio spomenut!) Ko je Tyler Cowen (https://en.wikipedia.org/wiki/Tyler_Cowen)? Politika i politikanstvo (http://balkanist.net/serbian-elections-are-a-personality-show-but-we-can-take-it-off-the-air/) Šta sve nije u redu sa knjigom Ako nije bilo dovoljno jasno: prva polovina knjige je rekapitulacija Sapiensa David Chapman: Twitter (https://twitter.com/Meaningness) Meaningness (https://t.co/NiQpJXD3CO?amp=1) CGP Gray: Humans need not apply (https://www.youtube.com/watch?v=7Pq-S557XQU). Izgleda strašno dok ne shvatite da već živimo u tom svetu i da višak ljudi rade kao administratori Naše shvatanje o ljudskom mozgu samo prati tehnološki razvoj (https://www.theguardian.com/science/2020/feb/27/why-your-brain-is-not-a-computer-neuroscience-neural-networks-consciousness) Metaphors we live by (https://en.wikipedia.org/wiki/Metaphors_We_Live_By) (Lakeoff & Johnson) Sidarta Mukharji: Dobro: Emperor of all maladies (https://en.wikipedia.org/wiki/The_Emperor_of_All_Maladies) Loše: Gene (https://en.wikipedia.org/wiki/The_Gene:_An_Intimate_History) Zlo: The improvisational oncologist (https://www.nytimes.com/2016/05/15/magazine/oncologist-improvisation.html) Imunoterapija i ciljana terapija pomažu, ali ne toliko (https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2732329) GREŠKA: pre 100 godina nije bilo nikakvih phase III studija (https://www.sciencedirect.com/science/article/pii/S0889858805703099) Hararijev prikriveno neprikriveni budizam (https://www.vox.com/2017/2/28/14745596/yuval-harari-sapiens-interview-meditation-ezra-klein) Završne reči Kriza reproducibilnosti (https://www.nature.com/news/1-500-scientists-lift-the-lid-on-reproducibility-1.19970) Plazmidi u mišićima (https://www.theatlantic.com/science/archive/2018/02/biohacking-stunts-crispr/553511/) Microdosing with LSD (https://www.scientificamerican.com/article/do-microdoses-of-lsd-change-your-mind/) Apple watch EKG (https://www.apple.com/apple-watch-series-5/health/) Atrijalna Fibrilacija (https://www.nejm.org/doi/full/10.1056/NEJMoa1901183) Quantified self (https://en.wikipedia.org/wiki/Quantified_self) COPD (https://en.wikipedia.org/wiki/Chronic_obstructive_pulmonary_disease) Bedside rounds podcast (https://www.acponline.org/cme-moc/cme/internal-medicine-podcasts/bedside-rounds) R-CHOP za DLBCL (I koliko dugo postoji?) (https://link.springer.com/article/10.1007/s11899-019-00518-8) Shane Parish - Knowledge Project (https://fs.blog/knowledge-project/) Jeste CEO duckduckgo-a - Gabriel Weinberg (https://ye.gg) Number needed to treat (https://en.wikipedia.org/wiki/Number_needed_to_treat) Medikalizacija zdravlja (https://en.wikipedia.org/wiki/Medicalization) Opportunity cost (https://en.wikipedia.org/wiki/Opportunity_cost) 10 000 koraka ne znaci nista (https://www.theatlantic.com/health/archive/2019/05/10000-steps-rule/590785/) Sickle cell gene therapy (https://www.nejm.org/doi/full/10.1056/NEJMoa1609677)

In today's episode, we hear from Dr. Raghuveer Ranganathan, a clinical instructor in the Division of Hematology and Oncology at the UNC School of Medicine at Chapel Hill. His clinical focus is lymphomas and leukemias, with a specific focus on using cellular immunotherapy to treat patients with hematologic malignancies. Dr. Ranganathan discusses how the treatment landscape has changed with the introduction of CAR-T therapies and other advances in cellular immunotherapy techniques.   Transcript ASCO Daily News: Welcome to the ASCO Daily News Podcast. I'm Geraldine Carol, a reporter for the ASCO Daily News. Today I'm speaking with Dr. Raghuveer Ranganathan, a clinical instructor in the Division of Hematology and Oncology at the University of North Carolina's School of Medicine at Chapel Hill. His clinical focus is lymphomas and leukemias, with a specific emphasis in using cellular immunotherapy to treat patients with hematologic malignancies.   His research on cellular immunotherapy techniques, such as optimized TCR and CAR T-cells, has been published in peer-reviewed journals, and his work has been recognized by the Lymphoma Research Foundation and the American Society of Hematology. Dr. Ranganathan reports no conflicts of interest relevant to this podcast, and full disclosures relating to all Daily News podcasts can be found on our episode pages. Dr. Ranganathan, welcome to the podcast.   Dr. Raghuveer Ranganathan: Hi, Geraldine. Thank you for inviting me and having me on your podcast today.   ASCO Daily News: Dr. Ranganathan, how has the treatment landscape changed with the introduction of CAR T- cell therapies for hematologic diseases? Dr. Raghuveer Ranganathan: The CAR-T therapies have really revolutionized our treatment options in general. Currently, the main pillar of front-line treatment for hematologic malignancies is chemotherapy, with radiation sometimes playing a supportive role, and surgery being a rare adjunct. Now immunotherapy, and specifically cellular immunotherapy, has formed an additional and critical option for these diseases, especially in the relapsed refractory setting.   In particular, CAR T-cell therapy has provided hope in achieving long-term remissions, and maybe even a cure in patients, with these hematological cancers who are chemorefractory, or have exhausted all other treatment modalities due to the persistence of their disease. Interestingly, due to the success in multiple-relapse refractory disease, CAR T-cell therapy is being explored as an option earlier to patients with relapsed refractory disease.   As stated, chemotherapy is still the front-line option for hemotological malignancies. As an example, for diffuse large B-cell lymphoma that is not a double- or triple-hit variant, the standard of care is still R-CHOP as front-line therapy. And if the patient relapses systemically, then the goal is to give salvage chemotherapy, with the hope of proceeding to an autologous stem cell transplant, if they're in CR and transplant-eligible.   CAR-T is approved for a second relapsed disease and beyond in lymphomas. It's thought, though, that patients who have been exposed to high-dose chemotherapy or numerous salvage chemo regimens display less P-cell fitness overall, which subsequently reduces the cytotoxic efficacy of CAR T-cells derived from those patients' regular T-cells. As a result, there are ongoing clinical trials comparing the use of CD19 targeting CAR T-cell therapy with aggressive B-cell lymphoma in first relapsed, and comparing it prospectively against autologous hematopoietic stem cell transplants.   ASCO Daily News: So what are some of the recent FDA drug approvals for CAR T-cell therapy that you are now using when treating lymphoma patients, and what you expect to see approved in 2020?   Dr. Raghuveer Ranganathan: So there are two currently FDA-approved CAR-T products that are now available for commercial use. Both CAR-T products target a CD19 antigen present on B-cell derived hemotological malignancies. One of them is axicabtagene ciloleucel, otherwise known as Axi-Cel, or its trade name of YESCARTA. And it's FDA-approved for use in adult patients who have received two or more lines of therapy for relapsed refractory aggressive B-cell lymphomas, which includes diffuse large B-cell, including high-grade variants, primary mediastinal B-cell, and transform follicular lymphomas.   The other CAR-T product is also CD19-targeting, named tisagenlecleucel, which we will call as Tisa-Cel, its trade name being KYMRIAH. And it has two indications as part of its approval. One is for adults with relapsed refractory diffuse large B-cell lymphoma, including high-grade variants and transport and follicular lymphomas. So in other words, the indication's very similar to Axi-Cel, except with the exclusion of primary mediastinal B-cell lymphoma.   The second indication for Tisa-Cel is for use in children and young adults up to the age of 25 years with B-cell acute lymphoblastic leukemia, or B-cell ALL, that is either refractory to treatment or has relapsed twice or more. The main difference between the two CD19 CAR constructs molecularly is that Axi-Cel has a CD28 intracellular costimulatory domain, while Tisa-Cel uses a 4-1BB costimulatory domain. Axi-Cel had an initial overall response rate and a complete response rate of 82% and 58% respectively, with ongoing complete response rates of about 35% at six months in its ZUMA-1 phase 2 trial.   Tisa-Cel displayed an initial overall and complete response of 53% and 40%, respectively, with ongoing Complete Response, or CR rate, at six months of 30% in its Juliet phase 2 trial in its patients. In both trials, those patients who reached and remained in CR at eight to 10 months displayed a high chance of remaining in complete remission long-term. Several patients in both trials demonstrated conversion of a partial response to a complete response as much as 15 to 18 months after Cartesian infusion, though most of these conversions happened within the first six months.   It's difficult to compare the clinical trials for each of these CD19 CAR-T products with each other because each of the trials were conducted in critically different ways regarding patient selection, disease types, allowing bridging therapy or not, and different dosages of lymphodepletive chemotherapy. How these differences matter clinically is yet unknown and requires more research at this time. However, there were some interesting similarities and results between the two trials.   Patients both below age 65 and above 65 did equally well. Germinal center and non-germinal center lymphomas both responded equally to both CD19 CAR-T products. Both trials include a small number of patients with CD19 negative lymphomas, and some of them responded to CAR-T therapy. Also interestingly, the early use of tocilizumab, which is an aisle 6 receptor-blocking antibody used in cases of Cytokine Release Syndrome, or CRS, did not negatively impact response outcomes, and neither did the early use of corticosteroids for CRS and/or neurotoxicity.   Now, in addition to the Axi-Cel and Tisa-Cel, a third CD19-targeting CAR-T product, lisocabtagene maraleucel, or Liso-Cel cell for short, is supposedly nearing FDA approval for 2020 in relapsed refractory lymphoma. Its distinct feature, compared to the other two products, is that Liso-Cel is formulated as specified CD4, CD8 composition ratio administered at a flat dose. At the recent ASH meeting in December 2019 in Orlando, Liso-Cel showed promising response rates that were comparable to Axi-Cel and tisagenlecleucel in relatively short follow-up time. And the pure publication of the data from its clinical trials is still eagerly awaited.   ASCO Daily News: Right. And what about the use of CAR-T therapy in mantle cell lymphoma?   Dr. Raghuveer Ranganathan: So relapsed mantle cell lymphomas, especially with blastoid or pleomorphic morphologies, have a dismal prognosis with available salvage therapies. And this is where CAR-T can hopefully help. At the recent ASH meeting, the ZUMA-2 clinical trial with Axi-Cel in mantle cell lymphoma showed very promising response rates. An overall response rate of 93%, with 67% CR rate, was seen in 68 patients, with most of these patients having relapsed after autologous hematopoietic cell transplants. And the majority showing refractory disease to BTK inhibition, which is the standard therapy after a first relapse.   The CAR-T therapy results appeared to be agnostic towards the morphology of patients' mantle cell lymphoma. Meaning those with the more aggressive blastoid or premorphic variant morphologies responded as well as those with the classical morphologies. Grade 3 or higher CRS neurotoxicity were seen in 15% and 31% of patients, respectively. And we're waiting for the official publication of these results as well to gauge its full efficacy and safety profile in this disease sub-type for lymphoma.   ASCO Daily News: Let's focus on patients with multiple myeloma for a moment. How does CAR T-cell therapy differ for patients with multiple myeloma?   Dr. Raghuveer Ranganathan: So multiple myeloma tumor cells rarely express CD19. So CD19 is not really regarded as a dependable target for myeloma. B-cell Maturation Antigen, or BCMA for short, is a trans-membrane protein which is expressed on multiple myeloma cells. There have been a handful of phase 1 trials looking at BCMA-targeting CAR T-cells in multiple myeloma.   And the first phase I trial was out of the NCI published in 2015, looking at 12 patients who received anti-BCMA CAR at varying dose levels where they had one stringent CR and two very good partial responses, and one partial response, with response durations lasting between 16 and 30 weeks. But eventually all of the patients relapsed, unfortunately. A follow-up trial by the same group using a different anti-BCMA CAR, with a 4-1BB post-stimulatory domain, instead of the CD28 domain used in the first trial, was used in the multi-center phase I trial with 33 patients enrolled.   Similar to their first trial, the new trial had varying dose levels of the anti-BCMA CAR cells as well, and had slightly higher doses given than seen in CD19 CAR trials. An overall response rate of 85% was seen, with 45% CR or stringent CR. Very good partial response and better were only seen in the higher dose levels of at least 150 million CAR-positive T-cells or higher.   Four of these patients showed ongoing CR or stringent CR of 12-plus months at the time of study publication. In a subset analysis of patients whose myeloma tumor expression of BCMA was less than 50%, and comparing them to patients whose BCMA expression was greater than 50%, there was no difference in response. 16 out of 18 patients who were assessed for MRD negativity were negative at 10 to the minus 4 nucleated cells, and median progression-free survival was 11.8 months.   Another phase 1 trial out of University of Pennsylvania, using a fully-humanized anti-BCMA CAR, was administered to 25 patients, either with or without lymphodepletive conditions prior to CAR-T infusion. In the cohort of 11 patients receiving both lymphodepletion and a higher CAR-T infusion dose, an overall response rate of 64% was seen. Since publication of these studies, unfortunately though, the majority of the study patients have all relapsed with disease.   It is somewhat difficult to pinpoint the reason for this large amount of relapse, but it might have something to do with the nature of the BCMA antigen itself. BCMA is cleaved by an enzyme called gamma secretase and shed off of the surface of myeloma tumor cells normally. High levels of soluble BCMA circulating in the peripheral blood, incidentally, is associated with a poor clinical outcome in general.   While the study showed efficacy in a myeloma tumor whose BCMA expression was less than 50%, there is very likely an expression level below which the CAR T-cells will not be effective in identifying and eliminating a tumor. And since BCMA can be cleaved off the myeloma cell surface, it's basically an escape route for the tumor cells to evade detection from the BCMA-targeting CAR. Interesting data shown at the recent ASH Conference out of the Fred Hutchinson Cancer Center showed the addition of an inhibitor of gamma secretase keeps the BCMA from being cleaved and shed off of the myeloma tumor cell surface, thereby increasing its expression levels and keeping it on the tumor cell surface.   When the gamma secretase inhibitor is combined with anti-BCMA CAR-T cells in patients, it preliminarily showed promising long-standing results in a phase 1 trial with six patients. But further follow-up and additional clinical trials are necessary to validate these findings. Additionally, here at UNC Chapel Hill, we have a clinical trial open that uses CAR T-cells targeting CD138, which is another antigen also expressed on myeloma cells instead of BCMA. We're currently enrolling patients and hope to see an efficacy in myeloma, which would help advance the treatment paradigm from our studies as well.   ASCO Daily News: Excellent. Well, Dr. Ranganathan, I think it's important to address the issue of toxicities. So how are the toxicities unique to CAR-T being addressed? And do you foresee a time when biomarkers will be used to predict toxicity in patients?   Dr. Raghuveer Ranganathan: Sure. The two toxicities uniquely seen with CAR-T therapy are Cytokine Release Syndrome and Neurotoxicity, otherwise known as ICANS. The pathophysiology of these two toxicities is still somewhat unknown, and an area of concerted investigation currently. Cytokine Release Syndrome, or CRS, is a systemic inflammatory response produced by a superphysiologic elevation of cytokines. IL-6, in particular, seems to be a culprit.   Cytokine analyses have shown a relation between higher peak levels of IL-6 and higher grades of CRS in CAR-T patients. It's characterized by a constellation of symptoms, which include fever, malaise, headaches, myalgias, and arthalgias and rigors with fever usually being the first symptom observed with CRS onset. Though it's time of onset can vary from a few hours to more than weeks post CAR-T infusion.   In severe CRS, patients can have life-threatening hemodynamic instability, stemming from capillary leakage, hypoxia, coagulopathy, and organ dysfunction. Risk factors for severe CRS include high tumor burden, higher intensity of lymphodepletive chemotherapy prior to cell infusion, a higher level of administered CAR-T cell dose, and possibly also elevated inflammatory markers at baseline prior to infusion, such as abnormally high C-reactive protein and ferritin. Since high elevations of IL-6 were noted in the early CD19 CAR-T trial patients, administration of tocilizumab, a monoclonal antibody blocking the IL-6 receptor, was noted to demonstrate a rapid de-escalation of CRS symptoms. So now tocilizumab is actually a mainstay of treatment for CRS.   Corticosteroids are also used in the treatment of CRS, especially if tocilizumab is not enough to curtail the symptoms. As I had already mentioned, earlier intervention with tocilizumab and/or corticosteroids did not appear to negatively impact CAR-T efficacy in clinical trials. Now, the second unique toxicity is neurotoxicity, which is now termed as Immune Cell Associated Neural Toxicity Syndrome, or ICANS for short.   It can manifest as a tremor, impaired attention, difficulty writing, expressive aphasia, and confusion, but also can develop into more serious symptoms such as encephalopathy, delirium, stupor, and seizures. In rare cases, diffuse cerebral edema has developed, sometimes as a progressive crescendo, but occasionally also with very little preceding warning or clinical signs. ICANS can happen during CRS, but more commonly occurs after CRS, and can lag behind CRS by up to two weeks.   Expressive aphasia is the most common characteristic symptom that develops first in patients before other symptoms, with the symptom progression taking anywhere from hours to days. Though cytokines leaking through a disruptive blood brain barrier is theorized as a possible cause of ICANS, its pathophysiology really remains largely unknown, and is a hot area of study currently. Unlike with CRS, treatment with tocilizumab does not lead to symptom benefit because tocilizumab does not cross the blood-brain barrier. So corticosteroids are really the only option for treatment of ICANS at this time.   ASCO Daily News: So what's on the horizon for CAR T-cell therapies? Do you think they will be used to treat solid tumors in the future?   Dr. Raghuveer Ranganathan: So far as the horizon and future directions for CAR T-cell therapies, there are already several modifications and upgrades being attempted to improve the current science and technology. One such enhancement is adding additional co-stimulatory intracellular domains to the actual CAR construct, a so-called "third generation" CAR-T. The idea is that by increasing that matter of costimulatory domains in the CAR construct, such as adding a CD28 costimulatory domain to the 4-1BB costimulatory domain that might be already present, there can perhaps be either amplification of signals within the CAR-T cells, and also harnessing of the different properties inherent to each different costimulatory domain, with augmented proliferation tumor cytotoxicity as a result.   Currently, however, third-generation CAR-T constructs have yet to show better tumor cytotoxicity and better long-term remissions clinically, compared to second-generation constructs. Another enhancement is targeting two antigens simultaneously, or dual-targeting CAR0T. One of the purposes of this approach is to minimize tumor escape. Since the current second generation CAR T-cells target one cancer antigen at a time, if tumor cells were to down-regulate the expression of the targeted antigen, it would result in the tumor being able to evade recognition by the CAR T-cells. By targeting two antigens simultaneously, it's thought that the risk for tumor escape is lessened. A spinoff of dual-targeting CAR-T utilizes a sort of Boolean logic-gated approach where the CAR T-cells can be recalibrated to activate in an inducable fashion.   In these logic-gated CAR T-cells, sensing of antigen 1 by a synthetic notch receptor within a modified T-cell then induces transcription and subsequent expression of a CAR receptor, which is specific for antigen number 2. Meaning that without binding of the antigen number 1 by our genetically-modified T cell, there is no expression of the CAR receptor binding to antigen number 2, which could help minimize on-target off-tumor toxicity. Another approach is called T-cells Redirected for Universal Cytokine Killing, or termed somewhat tongue-in-cheek as TRUCK T-cells, a playoff of CAR- T cells. These cells, in addition to direct tumor killing, also produce a pro-inflammatory cytokine, like IL-15 or IL-18, on coming into contact with a tumor, which helps to recruit a second wave of immune cells in a locally-restricted fashion, hopefully, to initiate a secondary attack on cancer cells, and also help enhance its own proliferation, cytotoxicity, and longevity. Now, there are unique obstacles and challenges for CAR-T and solid tumors that make it more difficult when compared to hematologic malignancies. Some of the existing challenges include overcoming the hostile tumor microenvironment, nutrient depletion, hypoxia, and inhibitory checkpoint molecule expression on solid tumors. Now, any one of these impediments would be a strong stumbling block to try and overcome, but when all of these hurdles occur together all at once, it can be very difficult to combat.   In addition, on-target off-tumor toxicity is somewhat of a bigger challenge to overcome in solid tumors. And a likely cause for this is the overlapping antigen expression on epithelial tissues from which most solid tumor types originate. And also the spatial proximity and restriction of critical sites when targeting solid tumors. For example, a few years ago, a patient with metastatic colon cancer who had received CAR T-cell therapy as part of a trial died from acute respiratory distressive failure, with the cause thought to be low-levels of being expressed on lung epithelial cells. That said, I do believe CAR T can become a viable treatment modality in solid tumors with some modifications and improvements. One such method being tested in clinical trials is combining immune checkpoint therapy, such as PD-1 inhibitors, with CAR T-cells. Another possibility is to edit the native inhibitory receptor in CAR T-cells by switching out the inhibitory receptor's intracellular domain for an intercellular domain from a stimulatory receptor. For instance, we take the native PD-1 molecule from a CAR-T cell and edit or switch out the intracellular domain, and put in the intercellular domain from CD28. What you get now is a molecule which has the PD-1 receptor on the outside, but a CD28-signaling mechanism on the inside, so that the net result is actually positive for the CAR-T, which now gets added stimulus instead of inhibition.   Such switch receptors are being incorporated into CAR T-cells to augment their activity and proliferation potential. And as I mentioned before, TRUCK T-cells and logic-based CAR T-cells are also other possible methods to conquering some of these obstacles posed by solid tumors. So while there's still much more investigation to be done in overcoming solid tumors, I do hope that we can make some strong headway in the near future. ASCO Daily News: Well, thank you Dr. Ranganathan for sharing your insights on CAR T-cell therapies with us today. Dr. Raghuveer Ranganathan: My pleasure. Thank you, Geraldine. ASCO Daily News: And to our listeners, thank you for tuning into the ASCO Daily News Podcast. If you're enjoying the content, please rate and review us on Apple Podcasts.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Proceedings from Part 1 of a 2-part satellite symposia series during the 61st ASH Annual Meeting. Featuring perspectives from Dr Jeremy Abramson, Dr Bruce D Cheson, Prof John G Gribben, Dr Brad S Kahl, Dr Loretta Nastoupil and Dr Laurie H Sehn. Introduction Program Overview: Dr Love (00:00) Evolving Therapeutic Algorithms for Patients with Treatment-Naïve Chronic Lymphocytic Leukemia (CLL) Case (Dr Khan): A man in his late 40s with IGHV-mutated CLL who achieves a complete remission with first-line FCR but experiences multiple toxicities (01:26) Case (Dr Peswani): A man in his late 70s who presents with highly symptomatic CLL requiring an immediate response to treatment (10:36) Faculty Presentation: Dr Kahl (18:19) Management of Relapsed/Refractory (R/R) CLL and Novel Investigational Approaches Case (Dr Kale): A woman in her late 70s with small lymphocytic lymphoma who is hospitalized for the initial cycles of venetoclax/obinutuzumab because of poor renal function (31:50) Case (Dr Lamar): A man in his early 70s with CLL who receives ibrutinib and develops atrial fibrillation and hematuria requiring dose reduction (39:25) Faculty Presentation: Prof Gribben (46:38) Contemporary Management of Newly Diagnosed and R/R Follicular Lymphoma (FL) Case (Dr Kale): A man in his mid-70s with Stage III FL and multiple comorbidities who experiences a prolonged response to rituximab monotherapy (1:00:14) Additional questions from the community oncologist/hematologist panel regarding the management of FL (1:03:34) Faculty Presentation: Dr Cheson (1:12:05) Protocol and Off-Protocol Care for Patients with Mantle Cell Lymphoma (MCL) Case (Dr Peswani): A man in his early 70s who is diagnosed with MCL with gastrointestinal involvement (1:24:13) Additional questions from the community oncologist/hematologist panel regarding the management of MCL (1:28:31) Faculty Presentation: Dr Abramson (1:33:51) Recent Breakthroughs and Other Promising Approaches in the Treatment of Diffuse Large B-Cell Lymphoma (DLBCL) Case (Dr Brenner): A woman in her mid-80s with DLBCL and a performance status of 2 who receives R-mini-CHOP but experiences disease progression after 4 months (1:47:02) Case (Dr Morganstein): A man in his early 60s with triple-hit DLBCL (1:52:35) Faculty Presentation: Dr Sehn (1:55:18) Integration of CD19-Directed Chimeric Antigen Receptor (CAR) T-Cell Therapy into the Management of Lymphomas Questions from the community oncologist/hematologist panel regarding CAR T-cell therapy (2:08:34) Case (Dr Morganstein): A man in his early 40s with DLBCL who receives CAR T-cell therapy after no response to up-front R-CHOP and disease progression after salvage chemotherapy followed by ASCT (2:13:19) Faculty Presentation: Dr Nastoupil (2:16:08) CME information and select publications

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Michael Williams will discuss some of the new research in lymphoma that was presented at the 2019 American Society of Hematology Annual Meeting, held December seventh through tenth in Orlando, Florida. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center. He is also the Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. View Dr. Williams’ disclosures at Cancer.Net. ASCO would like to thank Dr. Williams for discussing this research. Dr. Williams: Hello, and thanks for joining us for this podcast. My name is Michael Williams. I'm Professor and Chief of Hematology/Oncology at the University of Virginia in Charlottesville. And I'm pleased to discuss some exciting advances in lymphoma that were presented at the American Society of Hematology meeting held in Orlando in December 2019. My disclosures are that my research group here at the university, through the university, has received research support from pharmaceutical companies AbbVie, Pharmacyclics, and Janssen, and I have received honoraria for speaking at conferences from Xian-Janssen in China. So what I'm going to talk about today are 2 reports about the management of localized diffuse large B-cell lymphoma, an update on a novel therapeutic approach for relapsed mantle cell lymphoma. And then, I'll finish with a brief introduction of an agent that is showing promise for treating highly resistant relapsed lymphoma that was presented in the plenary session during the ASH meeting. So let's start with localized diffuse large B-cell lymphoma. So DLBCL is the most common subtype among the many forms of non-Hodgkin lymphoma. Usually, people present with advanced stage disease. But as many as 25 to 30 percent may have a disease that's localized to just 1 site or a very localized area of lymph nodes, so these would be stage I or stage ll patients. And the first report that I'll comment upon was presented by Dr. Laurie Sehn at the BC Cancer Agency in Vancouver, British Columbia. So they did a retrospective review looking at 319 patients treated in British Columbia over the past 15 years. So these were patients who had a nonbulky mass, they were localized disease. And the treatment currently for this disease is that people get either 6 cycles of a regimen such as rituximab and CHOP chemotherapy or more limited chemotherapy. Typically, 3 cycles of R-CHOP followed by radiation therapy. The importance of this study is that it is exploring a mechanism to de-escalate therapy, if you will, by avoiding the use of the radiation therapy. So what they did, is patients with localized disease received 3 cycles of rituximab plus CHOP therapy and then underwent a PET scan. So PET scans, unlike CT scans, are nuclear-medicine imaging that shows the functional uptake of radioactive glucose by the sites involved by lymphoma. So if you become PET negative after the three cycles of rituximab, CHOP therapy, then it seems likely that you've got a very highly responsive disease, and you may be able to avoid radiation therapy. So they did the PET scan after 3 cycles, and for those who were PET negative, then those patients received 1 additional cycle of rituximab CHOP, and that was the end of their therapy. If they were still PET positive, then they moved on to radiation therapy to the involved area. So what they found was quite interesting that of the 319 patients, 254 were negative after their PET scan. And so went on, virtually all of them, to just getting 1 more cycle of rituximab CHOP as planned. The outcomes for those patients were that very few of them relapsed over the next several years. They followed patients now, for about four years or more, in most cases, and they found that the overall, 5-year progression-free survival was 88% for those who were PET negative. For the subset of patients who were still PET positive, and got the radiation therapy, their outcome was somewhat worse, in that there was only 74% who were still progression free. The overall survival for these patients was 90%, at 5 years, for those who were PET negative and 77% for PET positive. So what this study shows us, is that a PET scan after 3 cycles, can inform us about patients who are 90% likely to have good control of their disease, with just 4 treatments, and you can avoid the exposure to radiation therapy. Those who were still PET positive still did well: 3 out of 4 were still in remission beyond 5 years but not quite as good an outcome. So these are patients who may be candidates for an alternative approach to try to do better with their long-term cure rates. So that leads us to the second presentation that I want to discuss. This was presented by Dr. Daniel Persky on behalf of the Southwest Oncology Group, which is part of the National Clinical Trials Network, in the United States. So they had a very similar approach. They studied patients with localized Stage 1 or 11, nonbulky diffuse large B-cell lymphoma, and they got standard rituximab CHOP therapy, and then a PET scan after the third cycle. Just as in the paper I discussed from British Columbia. Those who had negative PET scans got one additional cycle of rituximab CHOP. Those who were still PET positive got involved-field radiation therapy and treatment with a radio-labeled monoclonal antibody. Essentially, a radioactive form of rituximab, which has given us a single dose about a month after they'd finished their involved-field radiation therapy and then they got a follow-up PET scan, thereafter. So this study went on for several years, at multiple sites around the country. They enrolled 132 patients, and of those patients, 110 were PET negative after their third cycle. So only 18 needed to go on to this additional radiation therapy and the systemic treatment with the radio immuno therapeutic called Ibritumomab tiuxetan. They followed these patients now for 4 and a half years, and only 5 patients have progressed, and only 2 have died of their lymphoma. So of those who progressed, 3 of them had gotten just the R-CHOP alone. There was another patient who was PET positive but declined getting the radiation therapy who progressed. And then, another patient who had only 1 treatment was rituximab CHOP but then went off treatment due to toxicity. So similar, and in fact, almost identical to the British Columbia report. Five-year freedom from progression of their disease was 87%, and the overall survival was 90%. So these patients can do quite well, since many times, the location for localized DLBCL is in the head neck. There can be significant late effects of radiation therapy. So I think these studies reassure us that patients with localized disease can have very durable outcomes and cure rates. It's important to note that there's a higher rate of late relapse beyond three years in patients with localized DLBCL compared to more diffuse extensive disease suggesting that there may be some differences in the biology of a localized disease. So very important data, and data that gives us the opportunity to de-escalate treatment in localized large cell lymphoma. So let's switch gears and talk about mantle cell lymphoma. There's been a lot of progress in this disease over the past decade. Much of it related to the use of nonchemotherapy targeted agents such as Bruton’s tyrosine kinase inhibitors including ibrutinib and the Bcl-2 inhibitor, venetoclax. There was a study reported last year by an Australian group led by Dr. Constantine Tam. This study was updated at the ASH meeting with a longer follow up. So these were patients with Relapsed/Refractory disease, heavily pretreated. Many of them, previously, having had intensive chemotherapy and a stem cell transplant. And half of them had mutations in a gene called TP53, which is correlated with frequent chemotherapy resistance and high relapse rate. And what they found by combining the targeted agents ibrutinib and venetoclax, that they got very high response rates. The majority of patients responded although, there were a few who were primarily resistant, and about a third of patients, actually, got very deep remissions. PET negative and negative for minimal residual disease detection. If you look at the subset, of the highest risk patients, with the TP53 mutation, half of them achieved a complete response rate, and some of these patients have had durable responses. There have been a few patients who've had deep responses, who've been able to come off treatment. And overall, the duration of response at 2 and a half years is 74%. But what this study shows us, is yet again, that these novel targeted drugs that are typically better tolerated than cytotoxic chemotherapy can have very good and indeed dramatic responses, and so is showing a lot of promise. It reminds us that in mantle cell, whether it's newly diagnosed or relapsed, that talking to your oncologist about clinical trial opportunities can often avail you of some of the most promising new approaches. And indeed, that's true for all forms of lymphoma, that clinical trial options should be part of the discussion with treatment planning. I'm going to finish by just mentioning another novel agent that is being applied to patients with highly resistant relapsed disease. This is a molecule called mosunetuzumab, and this is a bispecific antibody. So there are a number of these now that are in clinical development, and some are FDA approved for treating leukemias and certain lymphomas. This one is designed to basically connect a body's immune system, the T cells, with the B-cell lymphomas by using an antibody that can recognize each of those and bring them physically together. So this was presented by Dr. Steven Schuster; it was a multinational study of this bispecific antibody in patients with very aggressive relapsed/refractory lymphomas including, diffuse large B-cell and transformed follicular lymphoma. And what they found in this study, is that response rates were 64%, with 42% of patients achieving a complete remission. So it's still early, but quite promising because these are patients who had failed CAR T-cell therapy. They may have failed transplant, or they were patients who needed a treatment to bridge them over to get to a CAR T or another treatment such as an allogeneic stem cell transplant. The toxicities were generally manageable and similar to those seen with other bispecific antibodies. So it's early, but across subtypes of patients with aggressive and relapsed lymphoma, I think this is another promising molecule, that may well provide good therapeutic options via a clinical trial for patients who have very limited other options to manage their disease. So thanks again for joining this podcast. There was a lot of other exciting data that we didn't have time to go through, so I encourage you to continue learning about what's new in the field, discussing with your oncologist, or with a consulting specialist in lymphoma, to make sure you can avail yourself of the best in current diagnostics and therapeutics. Thanks very much. ASCO: Thank you, Dr. Williams. Learn more about lymphoma at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by the Conquer Cancer Foundation of ASCO, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.

This podcast summarizes the findings of the Lunenburg Lymphoma Biomarker Consortium systematic evaluation of MYC rearrangements in DLBCL, and discusses the prognostic impact of MYC, BCL2 and BCL6 rearrangements, and implications for FISH testing in newly diagnosed DLBCL.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma - A Study by the Lunenburg Lymphoma Biomarker Consortium” by Rosenwald et al. My name is Jeremy Abramson, and I am an attending physician at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. My oncologic specialty is lymphoma. MYC rearrangements occur in approximately 10% of diffuse large B-cell lymphomas and have been associated with a worse prognosis.  When the MYC translocation occurs in concert with translocations of BCL2, BCL6, or both, initial series have suggested particularly poor outcomes with few patients achieving long term survival with conventional therapies.  This entity has been classified in the current WHO classification as high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 and is more conventionally known as double (or triple) hit lymphoma.  Though initial series painted a grim prognosis for these patients, more recent larger series have suggested that approximately 40% of double hit lymphoma patients may be cured, and that outcomes may be improved with more intensive regimens such as dose-adjusted EPOCH-R.  Most of these published series to date, however, continue to be limited by significant selection bias whereby cases with the most aggressive clinical or histopathologic features are likelier to be tested for MYC translocations, thus potentially excluding more prognostically favorable patients.  The small size of series to date has also made it difficult to assess more granular questions in MYC translocated diffuse large B cell lymphoma, hereafter referred to as DLBCL, such as the prognostic impact of MYC translocations when occurring without other translocations, the impact of translocation partner with MYC (Ig or non-Ig gene locus) in double hit lymphoma, and the significance of MYC/BCL6 double hit lymphomas which are far less common than MYC and BCL2.  Another practical question is who should we be testing for MYC translocations in the first place? Do we need to test every new case of DLBCL?  Or should we routinely test only an enriched population, such as those with MYC protein expression by immunohistochemistry, or GCB-like DLBCLs, which include the majority of double hit lymphomas? In the article that accompanies this podcast, the Lunenberg Lymphoma Biomarker Consortium  presents the single largest and most systematic analysis to date of MYC translocations in DLBCL, and sheds significant light on many of the most outstanding questions in this population. The Consortium studied over 2000 cases of DLBCL with available tissue and clinical data, drawn from large prospective cooperative group studies as well as population-based registries in Canada, the United Kingdom and the United States. The median age of the cohort was 66 years, and the median follow up was mature at greater than 6 years. All patients were treated with R-CHOP or R-CHOP-like therapy.  MYC rearrangements were found in 11% of patients. One third of these occurred as a sole rearrangement, 39% in concert with a BCL2 rearrangement, 15% with a BCL6 rearrangement, and 12% with both (i.e. triple hit lymphoma). Patients with MYC rearrangements had higher risk features by the IPI score than the entire DLBCL population, and patients with double/triple hit lymphoma had higher clinical risk factors than patients with MYC rearrangements alone. Patients with double or triple hit lymphoma had a significantly inferior outcome in terms of both progression free and overall survival compared to the overall DLBCL cohort, while no negative prognostic impact was conferred by a MYC translocation alone. Notably, the prognostic impact was only observed in the first 2 years from diagnosis.  They also compared the 31 MYC/BCL6 double hit patients with 82 MYC/BCL2 double hits, and found similar outcomes in the groups, validating that MYC/BCL6 double hit lymphomas should be considered high risk along with their BCL2 translocated counterparts. Prognosis for triple hit lymphoma was no worse than double hit lymphoma.  Perhaps most striking, however, was how well double and triple hit lymphoma patients did when compared to previously published retrospective studies. In this comprehensive evaluation by the Consortium, approximately 60% of double and triple hit lymphoma patients remained progression free beyond 5 years, and two thirds remained alive.  These remarkable data suggest that the majority of double and triple hit lymphomas identified by broad screening of the DLBCL population may be cured with chemoimmunotherapy and should offer encouragement to patients and providers alike.  Importantly the Consortium's analysis includes only patients with DLBCL morphology, so excluded double/triple hit patients with Burkitt or Burkitt-like histology who may have an inferior outcome compared to the double hit lymphoma patients in this analysis. MYC and BCL2 protein expression (so called dual expressor lymphomas) was also analyzed in 1414 cases with available tissue. MYC (≥40%) and BCL2 (≥50%) co-expression was associated with an inferior outcome compared to he general DLBCL population, though better than double/triple hit lymphomas, and notably the majority of dual expressor patients remained free from progression and alive at greater than 2 years of follow up after treatment with R-CHOP-like therapy. On evaluation by cell of origin, patients with GCB-like DLBCL had a slightly more favorable outcome compared to non-GCB, as defined by immunohistochemistry.  GCB-like DLBLC more commonly had MYC rearrangements, and exclusively contained the MYC/BCL2 subset of double hit lymphoma, while MYC/BCL6 cases occurred within both cell of origin subgroups. These robust data from this large systematic analysis address several pressing questions regarding MYC-rearranged DLBCL.  First, they tell us that a MYC rearrangement in the absence of a rearrangement of BCL2 and/or BCL6 does not predict an adverse outcome in DLBCL and may be treated as a routine DLBCL with R-CHOP-like therapy. Second, we learn that MYC translocation partner in the setting of a double/triple hit lymphoma matters, with the negative prognosis driven by MYC/Ig translocations rather than MYC rearranged with a non-Ig partner which does not appear to confer negative prognostic influence. Third, while MYC/BCL6 double hit lymphomas are uncommon, they appear to predict similarly inferior outcomes as MYC/BCL2 double hit lymphomas and triple hit lymphomas.  And fourth, very importantly, the outcome of double/triple hit DLBCL, though inferior to the entire DLBCL population, appears much better than previously estimated with approximately two thirds of patients achieving long term progression free and overall survival when treated with standard chemoimmunotherapy.  It warrants emphasis that this applies to cases morphologically classified as DLBCL, not necessarily to cases with Burkitt-like or blastoid features which were not included in the LLBC study and likely have a less favorable outcome.  For this reason, it is essential that pathologists signing out cases as aggressive B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 also indicate the morphologic subtype as DLBCL versus a higher grade appearance as this information will be essential for clinicians in applying the LLBC findings to prognostication in the clinic. Finally, this study provides us critically needed guidance in determining which cases warrant evaluation with fluorescence in situ hybridization (FISH) to detect MYC, BCL2 and BCL6 rearrangements. Presently, practice patterns are mixed with some centers testing all cases for MYC, while others test only enriched populations such as GCB-like DLBCL or double expressor DLBCL, and still other centers not routinely evaluating MYC at all in DLBCL.  The Consortium data validate that MYC translocations in DLBCL affect a sufficient proportion of the population and confer sufficient prognostic importance as to warrant testing.  They also show us that conventional immunohistochemistry for either cell of origin or MYC/BCL2 double expression status are not sufficient to direct FISH testing. Testing only GCB-like DLBCL would indeed identify all cases of MYC/BCL2 double hit lymphomas but would fail to identify a significant proportion of MYC/BCL6 double hit cases.  Performing FISH only on cases meeting current immunohistochemical thresholds for MYC and BCL2 double expressor lymphomas would fail to identify more than one quarter of cytogenetically defined double hit lymphomas, which would also be unacceptable. These data therefore support testing all newly diagnosed cases of DLBCL and high-grade B-cell lymphoma with FISH for MYC.  A positive FISH assay for MYC should prompt reflexive testing for both BCL2 and BCL6, which would then differentiate cases of single hit cases with MYC translocations alone from the higher risk double and triple hit lymphoma patients. The fact that the prognostic impact of double and triple hit lymphoma is seen only within the first 2 years from diagnosis underscores the need to optimize upfront therapy in these diseases. The data from the Lunenburg Lymphoma Biomarker Consortium suggest that R-CHOP-like therapy remains an acceptable standard of care in double expressor lymphomas, DLBCL cases with isolated MYC rearrangements, and perhaps even double/triple hit lymphomas with DLBCL morphology, though these cases have increasingly been treated with more intensive regimens such as dose-adjusted EPOCH-R or Burkitt-like regimens based on prior series.  In the absence of data clearly supporting one approach versus the other, I would consider either intensive approaches or standard R-CHOP as reasonable considerations in cases of double hit lymphoma with DLBCL morphology and should be individualized to the patient. Ultimately, we would like to overcome biological liabilities with biologically directed therapies, and the US Intergroup is now conducting a randomized clinical trial evaluating chemoimmunotherapy with or without the BCL2 inhibitor venetoclax specifically in double hit and double expressor lymphomas, with the chemoimmunotherapy backbone being dose adjusted EPOCH-R for double hits, and R-CHOP for double expressors. Participation in this important study is encouraged. This concludes this JCO Podcast. Thank you for listening.

Meet The Professors: Key Questions and Emerging Research in the Management of Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma — Part 1: A special video supplement to a CME symposium held at the 2019 ASCO Annual Meeting featuring Dr Smith’s comments on the application of emerging research to patient care: Appropriate management of molecular subtypes of diffuse large B-cell lymphoma (DLBCL); challenges in improving outcomes with the addition of novel agents to front-line R-CHOP (0:00) Smart Start study: Final results with a rituximab/lenalidomide/ibrutinib lead-in before the combination with chemotherapy for patients with newly diagnosed DLBCL (3:25) Importance of the interval between diagnosis and treatment for newly diagnosed DLBCL and implications for bias in clinical trials (7:05) Risk of relapse with germinal center versus non-germinal center subtypes of DLBCL (8:19) Activity and tolerability of the recently FDA-approved anti-CD79b antibody-drug conjugate polatuzumab vedotin in combination with bendamustine/rituximab (BR) for relapsed/refractory (R/R) DLBCL (9:45) Activity of single-agent polatuzumab vedotin in patients with R/R DLBCL; integration of polatuzumab vedotin/BR into clinical practice (12:06) Therapeutic options and investigational approaches for R/R DLBCL (14:50) POLARIX: An ongoing Phase III trial comparing polatuzumab vedotin with R-CHP to R-CHOP for patients with previously untreated DLBCL (17:22) Variations in chimeric antigen receptor (CAR) T-cell constructs; activity and tolerability of different CAR T-cell therapy products for R/R DLBCL (19:37) Integration of CAR T-cell therapy into the treatment algorithm for R/R DLBCL (24:12) Neurologic toxicity and cytokine release syndrome associated with CAR T-cell therapy (27:01) Selection and sequencing of therapy for patients with R/R mantle cell lymphoma (MCL) (32:00) Drug activity and tolerability and patient quality of life with ibrutinib compared to acalabrutinib (34:42) Results of the Phase III ECOG-E1912 trial evaluating up-front ibrutinib/rituximab versus FCR (fludarabine/cyclophosphamide/rituximab) for younger patients with chronic lymphocytic leukemia (CLL) (38:05) Alliance A041202 trial: Efficacy and tolerability of ibrutinib alone or in combination with either rituximab or BR for older patients with untreated CLL (42:44) Response rates and duration of minimal residual disease (MRD) negativity with limited-duration nonchemotherapy combination regimens for previously untreated CLL (44:28) Risk assessment, prevention and management of venetoclax-associated tumor lysis syndrome (48:39) Activity and tolerability of acalabrutinib alone or in combination with obinutuzumab for CLL (54:44) Second- and third-line therapy options for patients with CLL (56:54) Perspective on the results of the Phase III RELEVANCE trial: Lenalidomide/rituximab (R2) versus rituximab/chemotherapy, each followed by maintenance rituximab, for patients with newly diagnosed follicular lymphoma (FL) (59:00) Available data with and current clinical role of R2 for patients with R/R FL (1:0m49) Comparison of the activity and side-effect profiles of approved and investigational PI3 kinase inhibitors for R/R FL (1:04:02) Approach to choosing among brentuximab vedotin with doxorubicin/vinblastine/dacarbazine (AVD), standard AVD/bleomycin (ABVD) and response-adapted ABVD as first-line therapy for advanced classical Hodgkin lymphoma (1:06:24) Activity of brentuximab vedotin alone or in combination with nivolumab in patients with R/R Hodgkin lymphoma (1:09:48) CME information and select publications  

Proceedings from a CME symposium held at the 2019 ASCO Annual Meeting. Featuring perspectives from Drs Jeremy Abramson, Bruce D Cheson, Ann S LaCasce, Noopur Raje, Paul G Richardson and Sonali M Smith. Introduction Program overview: Dr Love 0m0s Newly Diagnosed and Relapsed/Refractory Multiple Myeloma (MM) — Dr Raje and Dr Richardson Newly Diagnosed Disease (1:21) Case (Dr Raje): A man in his early 80s with smoldering MM who was observed for 4 years before requiring treatment (5:20) Case (Dr Richardson): A woman in her mid-70s with symptomatic high-risk MM who received RVD followed by bortezomib/dexamethasone maintenance (26:02) Relapsed/Refractory Disease (34:45) Chronic Lymphocytic Leukemia and Follicular Lymphoma — Dr Cheson and Dr LaCasce Chronic Lymphocytic Leukemia (CLL) (53:39) Case (Dr LaCasce): A man in his early 90s with progressive CLL who discontinued treatment with ibrutinib because of poor tolerability and was switched to venetoclax (1:05:17) Case (Dr Cheson): A man in his mid-60s with multiply relapsed CLL who attained a complete response to venetoclax/rituximab (1:07:52) Follicular Lymphoma (FL) (1:18:04) Case (Dr Cheson): A man in his early 60s with newly diagnosed FL who refused chemotherapy and received lenalidomide/rituximab (1:24:58) Case (Dr LaCasce): A man in his late 40s with relapsed FL who received bendamustine/obinutuzumab and attained a complete remission (1:25:40) Case (Dr LaCasce): A woman in her mid-70s with bulky Grade IIIA FL who received R-CHOP (1:34:52) Hodgkin and Other Lymphomas — Dr Abramson and Dr Smith Hodgkin Lymphoma (HL) (1:37:29) Case (Dr Smith): A man in his early 20s with Stage IVB classical HL who received brentuximab vedotin/AVD and remains in remission 1 year later (1:46:29) Mantle Cell Lymphoma (MCL) (1:57:48) Case (Dr Abramson): A man in his early 60s with MCL who has received multiple lines of therapy, including chemotherapy followed by transplant, acalabrutinib and venetoclax (2:02:17) Diffuse Large B-Cell Lymphoma (DLBCL) (2:14:34) Case (Dr Smith): A man in his early 50s with heavily pretreated DLBCL who received chimeric antigen receptor T-cell therapy on a clinical trial (2:14:42) CME information and select publications  

In this episode, The ASCO Post's Editor-in-Chief Dr. James Armitage talks about the International Conference on Malignant Lymphoma (ICML), which he attended recently in Lugano, Switzerland; in particular, Dr. Armitage shares insight from a workshop on bridging liquid biopsy into the management of patients with lymphoma. He also discusses two studies from the plenary session looking at the impact of adding lenalidomide to R-CHOP in the management of diffuse large B-cell lymphoma. Later in the podcast, we discuss findings from the PHARE trial on adjuvant trastuzumab dosing in HER2-positive breast cancer and we report two recent approvals by the FDA.Coverage of stories discussed this week on ascopost.com:Final Analysis of the PHARE Trial: 6 Months vs 12 Months of Adjuvant Trastuzumab in HER2-Positive Breast CancerFDA Approves Daratumumab in Combination With Lenalidomide and Dexamethasone for Newly Diagnosed, Transplant-Ineligible Patients With Multiple MyelomaFDA Approves Bevacizumab Biosimilar for Five Cancer Types

This JCO Podcast provides observations and commentary on the JCO article “Dose-Adjusted EPOCH-R Compared to R-CHOP as Frontline Therapy for Diffuse Large B Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial CALGB 50303 (Alliance)” by Bartlett et al. My name is Patrick Stiff, and I am Division Director of Hematology-Oncology at Loyola University Stritch School of Medicine in Maywood, Illinois. My oncologic specialty is hematologic malignancies and stem cell transplantation.     CHOP has remained the chemotherapy backbone of choice for the treatment of diffuse aggressive non-Hodgkin lymphoma since the 4 arm randomized SWOG study was performed 25 years ago1. Since then, only the addition of rituximab has improved patients' outcome2.   Investigators have tried to improve outcomes by employing other strategies like increasing drug intensity, shortening the interval between cycles, adding newer agents, changing the method of administration, and adding transplantation, but none clearly demonstrated a survival advantage. Among these strategies is an infusional one designed to increase apoptosis and inhibit BCL6 and p-glycoprotein in resistant cells.  While SWOG tested infusional CHOP in 2001 and found no difference in outcomes, compared to bolus CHOP3, the NCI group has explored a modified CHOP infusional regimen known as EPOCH consisting of etoposide, vincristine, and doxorubicin given simultaneously as a continuous 4 day infusion with a bolus dose of cyclophosphamide at the end of the 4 days along with daily oral prednisone Combined with aggressive dose escalations based on nadir myelosuppression, they tested this regimen with rituximab, EPOCH-R, reporting an impressive 5 year PFS of 79% in an unselected study of 72 patients from 3 centers4.  Based on this, 18 CALGB institutions treated 69 patients with dose adjusted EPOCH-R, demonstrating a similar 62 month TTP of 81%, with an impressive 100% TTP for the germinal center B cell subgroup as defined by the Hans algorithm, all seemingly superior to R-CHOP5.  Equally impressive was a Phase II study in mediastinal B cell NHL with a 5-yr EFS of 93% administered without consolidative radiotherapy, added frequently to R-CHOP6.  Therefore, a head-to-head comparison was the natural next step.   The trial that accompanies this podcast was designed to compare the PFS and OS at 3 years between patients treated with 6 cycles of dose adjusted EPOCH-R to the standard R-CHOP.  The trial opened in 2005 and enrolled 524 patients with either DLBCL, primary mediastinal BCL or intravascular large cell NHL over an 8+ year period to its close in 2013.  Seventy-four % had stage III/IV disease and 12% high IPI disease.   Eighty-eight percent of the R-CHOP and 82% of the dose adjusted EPOCH-R cycles were administered with 75% of the dose adjusted EPOCH-R patients receiving initial dose escalations per protocol. At a median follow-up of 5.2 years the 5 year PFS and OS were 66 and 85% for the R-CHOP treated patients no different from the 68 and 77.5% for the dose adjusted EPOCH-R  patients.  Prognostic factors for PFS were age > 60, IPI, and double expressers (15.6% of the 270 with complete data) for MYC, BCL-2 and BCl-6.  There were a number of post hoc subgroup analyses performed. Of these, the PFS for the combined High and High intermediate IPI group was higher for the dose adjusted EPOCH-R group (p = 0.041) but no difference in OS was noted.  In none of the other subgroups was a benefit seen for dose adjusted EPOCH-R including CNS relapses, mediastinal B cell NHL, double expressors or those with MYC positivity although percentages of these subgroups were small.  There were however significantly increased grade III-IV myelotoxic and non-myelotoxic complications for the infusional regimen. Should we take these results as the final word on the lack of a benefit of dose adjusted EPOCH-R in the treatment of DLBCL?  In other words is this a case of "déjà vu all over again"?.  This trial recruited slowly, 524 patients over more than 8 years, with < 5% of US eligible patient enrolled. The reasons seem obvious.  Encouraging enrollment on a trial comparing a familiar outpatient regimen administered over hours, versus a 4+ day in-patient regimen was at best difficult. Recall also that this trial took place during the Great Recession, with patients/families fearful of losing their jobs dealing with an in-pt regimen. Slow accrual in and of itself should not have been impacted outcome. But these were not a unselected group as the authors concluded. First by design, all who had an ECOG PS of > 2 (20% of the phase II study5) were excluded.  Second there was the requirement for submission of fresh/frozen material including a second biopsy if needed thereby likely eliminating mostly patients with rapidly progressing disease.  Together possibly with some investigator bias, given the promising Phase II data, there was a decrease in High IPI enrollment of only 12% versus the 20% in the Phase II study, which extended to other high risk patients including double expressors, C-Myc positive, and mediastinal B cell disease. Combined these led to the 3 year PFS for R-CHOP of 72%, 17% better than the planned outcome. However, considering the trial exclusions, and ultimately a PFS similar to that of other recent R-CHOP experiences7,8 one could argue that the 3-yr 55% PFS endpoint for this trial was far too conservative.  While the R-CHOP PFS was 17% better than planned, the dose adjusted EPOCH-R 5-yr PFS was 7% worse than the Phase II results, which is difficult to explain considering the earlier studies, in which the more favorable patients did better5. A lower administered dose intensity compared to prior studies4,5 was not apparent with the incidence of grade III/IV febrile neutropenia and neurotoxicity similar to the Phase II trial.  However 82%  vs 91% of those in the Phase II study completed all dose adjusted EPOCH-R cycles with the decrease mostly due to on treatment deaths and AEs, suggesting that when used in a more 'real world setting' this regimen is more toxic than initially seen.  Might those who completed therapy also have had dose reductions or delays that could also have impacted PFS?  Finally, this report does not include PFS based on cell of origin(COO), which for patients with  germinal center B cell of origin in the Phase II study was 100%.  Perhaps the germinal B cell percentage was lower than in the Phase II studies as well. So what can be concluded about these negative results?  The authors conclude that there was a "potential patient selection bias", at least partially explainable by trial design, and that this "may preclude generalizibility….to specific subgroups".  I would conclude that given the outcome and toxicity data, for the low and low intermediate IPI patient, R-CHOP remains the treatment of choice.  The post hoc PFS improvement for the high risk subgroup might argue for dose adjusted EPOCH-R, but the lack of an OS advantage in this subgroup needs to be acknowledged. However, other compelling phase II studies in high risk subsets, e.g double hit, underrepresented in this trial, still makes the efficacy of dose adjusted EPOCH-R in certain circumstances an open question.  This concludes this JCO Podcast. Thank you for listening.

Dr. Elly Lugtenburg (Erasmus MC, Rotterdam) presenteerde de gegevens van de tweede randomisatie van de HOVON-NORDIC fase 3-studie, waarin onderzocht is of een onderhoudsbehandeling met rituximab de uitkomsten van patiënten met diffuus grootcellig B-cellymfoom (DLBCL) kan verbeteren ten opzichte van observatie. Patiënten die een complete remissie hadden bereikt na R-CHOP werden gerandomiseerd naar een onderhoudsbehandeling met rituximab gedurende twee jaar of observatie. De ziektevrije overleving na vijf jaar was 79% voor onderhoud met rituximab en 74% voor observatie, een niet-significant verschil. Ook het verschil in algehele overleving was niet significant tussen beide groepen.

ASCO Daily News Editor-in-Chief, Dr. John Sweetenham on Hematologic Poster Presentations To See at #ASCO19   Welcome to the ASCO Daily News podcast. I'm Lauren Davis. And joining me today is Dr. John Sweetenham, the ASCO Daily News editor-in-chief. As attendees are getting ready for the annual meeting, Dr. Sweetenham will highlight some of the poster sessions and hematologic malignancies that will capture the attention of attendees. Dr. Sweetenham, welcome to the podcast. Thank you. It's good to have the opportunity to talk. We're glad you're here. For attendees who are interested in hematologic malignancies, what areas in this specialty are you most looking forward to? So I think at ASCO this year in heme malignancies, I would characterize a lot of the studies that are being presented in poster format as confirmatory, or long-term confirmation of some earlier results. But I think they're no less interesting because of that. And I think that there is some important follow-up data, particularly in CLL, and some important confirmatory data for CAR T-cell therapy and hematologic malignancies. Added to which, I think there are a lot of potentially exciting new agents for the treatment of acute myeloid leukemia, in particular. That's been an area of a lot of interest and a lot of new treatment developments over the last two to three years. And I think that the poster sessions at ASCO this year confirm that trend is still ongoing and that the outlook for this very challenging group of patients is improving. That's great. What else can attendees expect this year? Any surprising or practice-changing data? I think, in terms of practice-changing data, I would list some of the specific abstracts which I think, as I mentioned earlier, are really confirming the importance of some agents and certainly will confirm practice changes that have happened over the last couple of years. To give you a couple of examples of that, perhaps I'll start with chronic lymphocytic leukemia. The RESONATE study was a very important study for patients with relapsed and refractory CLL, which assessed the use of ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor against ofatumumab in this group of patients. The original study was published in The New England Journal, but at the meeting this year, there is mature follow up, a now six-year follow up of patients treated on this study. And the encouraging news is that the initial ibrutinib treatment, which was originally shown to produce improved overall survival, that has been confirmed. So the median duration of ibrutinib treatment on this study is now 41 months. So it really is quite extensive follow up at this point. And encouragingly, the overall survival and median progression-free survival benefits, which was 44.1 months for the ibrutinib arm versus 8.0 months for the ofatumumab arm, that has been maintained. And so it's clear that the long-term therapy with ibrutinib remains highly effective and that the number of patients who are required to discontinue ibrutinib because of adverse events is fortunately relatively low. So I think it confirms ibrutinib now across just about the entire spectrum for CLL as the important treatment, both in front line for those patients who are previously untreated, and in second and subsequent-line therapy for those who've had some other agents as the first-line treatment. I think that is very important. And along with that, there is a cautionary note from a study which explored the second cancer incidence in CLL patients receiving BTK inhibitors. Contextually, there's been quite a lot of data, over the years, exploring second malignancies in patients with CLL. In this particular study, they did actually suggest that there probably is a somewhat higher incidence of second primary neoplasms in patients who are taking ibrutinib for CLL. And those included cancers at the lung, melanoma, prostate, and bladder cancer. So I think, at this point, this is just an alert and something that we will need to watch closely as it does appear as if there is a slightly elevated risk of second cancers in these patients. And then one other follow-up study, which I think is of importance, is the fact that second-generation BTK inhibitors are now really starting to gain some traction in CLL. And there was a nice study presented in poster format which is going to explore the use of acalabrutinib, which is a second-generation BTK inhibitor, in patients who were intolerant of ibrutinib. So for those patients who need to discontinue ibrutinib because of adverse events, the second-generation acalabrutinib is effective with an overall response rate of 77% and well-tolerated so that if patients are in tolerance of ibrutinib, they certainly do have other options. I think, also, to complete the CLL field, there is a great deal of interest in the potential use of CAR T-cell therapies for CLL. And although it is very immature and the data to be presented at ASCO poster are very limited, it is just worth pointing out that there is an ongoing ZUMA-8 study for patients with relapsed and refractory CLL exploring the use of CAR T-cells. And I think that's going to be important. It will be very interesting to watch how that develops over the coming year or two. Another area which I think is very important is that we're starting to see now that there are some studies which are really exploring not only the disease-related benefits of some of these therapies, but are also starting to look at patient-reported outcomes. And there are two posters, in particular, which I think are interesting in this regard. There is one study which looked at patient-reported outcomes in patients with Waldenstrom's macroglobulinemia who were treated with ibrutinib as a single agent or in combination with rituximab. So in the iNNOVATE study, it was demonstrated that ibrutinib plus rituximab produced higher sustained hemoglobin improvements and meaningful improvements in other laboratory parameters when compared with placebo and rituximab. In this study, the investigators have gone a step further and have actually looked at patient-reported outcomes and shown that, in addition to the standard response improvements that are seen, there's a clear improvement in patient-reported outcomes associated with the use of this novel combination with ibrutinib and rituximab. And so along with the improvements in anemia, for example, there are marked improvements in fatigue-related symptoms, constitutional symptoms. And the clinical improvements are truly meaningful. And that's actually mirrored in a different context, but in patients with multiple myeloma who were previously undiagnosed and treated with a novel combination of daratumumab, lenalidomide, and dexamethasone versus the same regimen but without the daratumumab. And here, again, there is important patient-reported outcomes demonstrating that, essentially, with the novel combination, patients feel better more quickly. So the clinical responses that have been demonstrated on that trial are confirmed by patient-reported outcomes, which demonstrate that patients are truly feeling better. So, again, I think at the patient level, these are very important data. Some other things that I think are important to look out for at this year's meeting, there are a series of posters which explore novel therapies for acute myeloid leukemia and myelodysplastic syndrome. Without listing these in great detail because there are several of them, I would simply say that these studies add to the extraordinary expansion of available treatment options for patients with AML that we've seen developing over the last few years. And I think that the treatment landscape for these patients is really changing now. Sequencing prior to therapy is becoming important as more novel targets are identified, but consistent with the trend we've seen in the last two or three years, more important emerging therapies for patients with acute myeloid leukemia. Shifting gears for just one moment and looking at patients with B-cell lymphoma, and specifically aggressive non-Hodgkin lymphomas, I think that there are a couple of studies here which show promise, although certainly I wouldn't categorize them right now as being practice changing, but the findings are interesting. One of those is, again, in the context of CAR T-cell therapy. So it's difficult to talk about heme malignancies at the moment and not talk about CAR T-cells because there's such a lot of buzz and excitement around those. And one of the areas where this intervention is now FDA approved is in the treatment of patients with relapsed, aggressive non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma. And that was the subject of the so-called ZUMA-1 study, which was a phase 1/2 study of axicabtagene ciloleucel in patients with refractory large B-cell lymphoma. The study reported out some months ago now, but one of the concerns that some of us have had is that this may be a very reasonable treatment for the young patients with a good performance status who typically don't represent the bulk of patients with large B-cell lymphoma. But what about those patients who are older? And how do they tolerate this therapy? And what's the outcome? And in a study that's going to be reported at ASCO this year, the investigators of the ZUMA-1 study conducted a specific subset analysis on that group of patients who were aged 65 years or older. It's a small group. But I think the take-home message from the study is that the outcomes in this group, in terms of the overall response, complete response, and overall survival rates are very comparable to the younger age group. And the toxicities are very comparable to the younger age group, as well. So I think this is important that age, in itself, may not be a barrier to the applicability of CAR T-cell therapy. And that's a very important message. The flip side of that is that these one, it seems a pretty highly selected group of patients aged 65 years or older. And certainly, that's reflected in the performance status and the IPI scores of these patients as reported in the abstract. So they may be a highly selected group of patients aged 65 or over with this disease, but nevertheless, I think they're quite compelling results. And I think it speaks to the broader applicability of this therapy in patients with relapsed, aggressive lymphoma. The big remaining question being, how are patients and perhaps, more importantly, how is the health system, as a whole, going to cope with the cost and the financial toxicity associated with this very important new treatment? Again, on the subject of aggressive B-cell lymphoma, there is one more study which caught my eye. And it's interesting for a couple of reasons. This is a study which explores the use of a PD-L1 inhibitor, durvalumab, alongside either the R-CHOP regimen or the R2-CHOP regimen in patients with newly diagnosed high-risk diffuse large B-cell lymphoma. And this includes patients with double-hit lymphoma where we know the prognosis is particularly bad. These are very preliminary data in which a standard therapy with R-CHOP or R2-CHOP is being modified by the addition of this anti-PD-L1 monoclonal antibody. At the moment, the data are very largely related to adverse events. And there are some very preliminary outcome data, but probably difficult to read anything very much into those. The interest, to my mind, is that some recently-published data have suggested that checkpoint inhibitors in aggressive B-cell lymphoma may not be a particularly effective treatment modality. But I think it will be very interesting to see whether the combination of checkpoint inhibitors plus regular chemotherapy have the opportunity to improve outcome. So I think this is a study in progress. It's way too early to draw any conclusions at the moment. But I do think it's important not to write-off the role of checkpoint inhibitors in aggressive lymphomas without conducting important studies like this one which look at combination therapies rather than just the single-agent therapy. And then, in conclusion, one other study which I think is quite important, again, presented in poster form, and this was a study that looked at survival disparities of diffuse large B-cell lymphoma in a community-based cancer center. And essentially, this was a retrospective study which looked at 381 patients who had aggressive lymphomas and looked at outcome according to race and showed very highly significant disparity in survival for those patients who were African American where their overall survival was markedly inferior to other patients with a hazard ratio of 2.19. So it was a really very marked difference in outcome. The explanation for this is not entirely clear from the abstracts. But I think it's something which is very important for us to take note of. So that is just a quick run-through some of the poster presentations that caught my eye at the meeting this year. I think that there will be some important practice-changing studies presented during the oral presentations. And I would certainly strongly encourage folks to be at those. But I think that, as always, there are some important highlights in the poster presentations. And I could go on with many more, but I think that those probably be the highlights from my perspective. Sounds like some promising studies to look forward to. Again, today my guest has been Dr. John Sweetenham. Thank you for being on our podcast today. Thank you. Great to have the opportunity to talk. And to our listeners, thank you for tuning into the ASCO Daily News podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple podcast.

We begin this episode with a discussion of two recent clinical trials in lymphoma: CALGB 50303 and REMoDL-B, respectively published in the Journal of Clinical Oncology and The Lancet Oncology. We include a primer on the history of lymphoma and the development of R-CHOP. We follow that with an in-depth interview with Dr. Ameet Sarpatwari of the Harvard Medical School on Risk Evaluation and Mitigation Strategies (REMS), the Orphan Drug Act, and, broadly, the purpose of the US FDA. CALGB 50303: doi.org/10.1200/JCO.18.01994 REMoDL-B: doi.org/10.1016/S1470-2045(18)30935-5 Dr. Sarpatwari's online course: https://www.edx.org/course/the-fda-and-prescription-drugs-current-controversies-in-context Back us on Patreon! www.patreon.com/plenarysession

Stefan K. Barta, MD, of the University of Pennsylvania, joins David Henry, MD, to discuss the treatment and diagnosis of lymphoma in patients with HIV.    In this week's Clinical Correlation, Ilana Yurkiewicz, MD, has Part 2 of her discussion on informed consent in cancer. Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford University and is also a columnist for Hematology News. More from Dr. Yurkiewicz here. Notes, Transcripts, Links  Show notes By Emily Bryer, DO Resident in the department of internal medicine, University of Pennsylvania.  Immunosuppression in patients with HIV, especially with low CD4 counts, is associated with the development of lymphomas.  Diffuse large B-cell lymphoma is the most common lymphoma in patients with HIV followed by Burkitt lymphoma and Hodgkin lymphoma.  Extra-nodal manifestations of lymphoma are more common in patients with HIV, especially with lower CD4 counts. Following pathologic diagnosis, staging of lymphoma should include: CT scan PET scan Evaluation of CNS (MRI brain and LP) Bone marrow biopsy Evaluation for hepatitis B and C co-infection. Fluorescence in situ hybridization (FISH) is a molecular technique that identifies portions of DNA and helps to identify translocations and rearrangements. cMYC, BCL2, and BCL6 are all pro-proliferative genes and commonly implicated in lymphoma. cMYC rearrangement pose higher risk of CNS involvement and CNS relapse.  cMYC rearrangement (as opposed to cMYC translocation) requires therapy that is more aggressive therapy than R-CHOP.  Treatment of high grade diffuse large B-cell lymphoma: R-EPOCH Ibrutinib plus R-EPOCH Resources/Links: AIDS Malignancy Consortium Blood. 2004;103:275-82. Blood. 2010 Apr 15; 115(15): 3008-16. Clinical Trial: NCT03220022  Ibrutinib, Rituximab, Etoposide, Prednisone, Vincristine Sulfate, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With HIV-Positive Stage II-IV Diffuse Large B-Cell Lymphomas  

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Michael Williams will discuss some of the new research in lymphoma that was presented at the 2018 American Society of Hematology Annual Meeting, held December first through fourth in San Diego, California. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center, and Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. ASCO would like to thank Dr. Williams for discussing this topic. Dr. Williams: Hello. This is Michael Williams. I'm a professor at the University of Virginia Health System in Charlottesville, Virginia, and I'm reporting today on some exciting advances in lymphoma that were presented at the Annual Meeting of the American Society of Hematology, which was held in San Diego, California in early December 2018. Well, there were a number of areas of lymphoma that had important reports, and I'm going to just give you a small sampling of these today. We'll start with a new treatment option for patients with follicular lymphoma. Traditionally, this type of lymphoma, when it's symptomatic and needs therapy, the treatment of choice has been chemotherapy combined with a monoclonal antibody such as rituximab or obinutuzumab. But investigators, in a multicentered trial, decided to test whether you could use a chemotherapy-free treatment approach for patients like this by using rituximab combined with lenalidomide, which is also known as Revlimid, as a substitute for chemotherapy. And this is based on the fact that Revlimid plus rituximab has synergistic activity in patients with relapsed disease, so maybe we could see acceptable, high responses when it would be compared directly with rituximab plus chemotherapy. So the way the trial worked is this. Patients who needed therapy, who had advanced-stage follicular lymphoma—they had never had any therapy before—were randomized to either the rituximab-lenalidomide combination or a rituximab-chemotherapy combination that could include the regimens CVP or cyclophosphamide, vincristine, prednisone, the same combination given with daunorubicin, or the CHOP regimen, or rituximab combined with bendamustine. So over 1,000 patients were treated in this multinational study and the goal of the treatment, of the study was to prove that, actually, the ritux-lenalidomide was superior to the chemotherapy regimens. So the results showed, not superiority, but comparability. The complete remission rate between rituximab-len and ritux-chemotherapy were really identical, 48 and 53 percent, and the 3-year likelihood that the patients were progression-free, so had had no recurrence of their disease, was identical as well: 77 to 78 percent. There was no difference in survival which was 94% at 3 years in both arms. The toxicities differed, however. There was more rash with the lenalidomide combination, whereas low blood counts and the need for growth factor support such as G-CSF was greater with chemotherapy. And it was also interesting that some of the traditional risk factors didn't seem to apply, as much, for lenalidomide. So what would be considered higher risk patients treated with chemotherapy, seemed to do somewhat better with the lenalidomide combination. The importance for a patient with untreated follicular lymphoma who needs therapy is that a chemotherapy-free approach with rituximab plus lenalidomide can be considered equivalent to rituximab-chemotherapy. It’s worth discussing this with your oncologist when you're considering what treatment to use initially. The next subtype of lymphoma that I want to discuss is diffuse large B-cell lymphoma, and there's 2 presentations that I'm going to summarize. One, in patients with advanced stage disease, meaning stage III or IV. This identifies patients who have disease both above and below the diaphragm, to make it stage III, or stage IV means they've got bone marrow or other sites of involvement such as liver or bone. And the question being asked in this trial, which was part of the International GOYA trial, will take just a moment to explain. So the original GOYA trial compared whether a newer form of anti-CD20 monoclonal, namely obinutuzumab, which is also called Gazyva, how that would compare with the standard established monoclonal antibody, rituximab. And the initial findings of this study found that there was no benefit for the newer antibodies. So rituximab and CHOP chemotherapy was equivalent to obinutuzumab and CHOP chemotherapy in overall outcomes. But there was an opportunity with this trial to answer a question that's been out there for many years, and that is how many cycles of treatment does one need? So the investigators took advantage of this large study which included 712 patients who were randomized to rituximab plus CHOP. Just over 500 of them received 6 cycles, and the remaining 186 received 8 cycles. Even the patients who got 6 cycles of CHOP chemotherapy also got an additional 2 doses of rituximab, so the immunotherapy monoclonal antibody was equivalent between the 2 arms. And the results of this showed that there was really no difference at all with a followup of about 3 years. Response rates were equivalent and there was no difference in the patients staying in remission. It didn't matter in terms of survival which was excellent in both arms. There was, however, more toxicity in patients who received 8 cycles, including cardiac problems, infections, etc. These results showed that, I think we can finally put to rest the use of 8 cycles of rituximab-CHOP chemotherapy for advanced-stage large cell lymphoma. It's been an unknown entity because we never had a direct comparison of these. So we can now say that 6 cycles plus the additional 2 doses of rituximab is a standard for advanced-stage diffuse large B-cell lymphoma. Now, what about patients who have limited-stage, so stage I or II diffuse large cell lymphoma? That means just a single lymph node area's involved or 2 adjacent lymph node areas. In the past, these were treated either with 6 cycles of rituximab-CHOP or sometimes cycles of R-CHOP plus local radiation therapy. And in this study, which took a long time to complete; it began in 2005, but it enrolled 592 patients who were then randomized to either 4 cycles or 6 cycles of treatment. Radiation therapy was not planned for any of these patients except for very specific locations of involvement such as testicular DLBCL where radiation therapy is a standard. So the take-home message after over 5 years of follow-up for patients on this study showed that 4 versus 6 were identical. So 89% of patients were still in remission at 3 years after completing treatment, and the overall survival was really impressive, 98 to 99 percent in the 2 arms. So there was no benefit with limited-stage favorable disease. Now, who are these patients? So younger than age 60, stage I or II disease, and normal LDH. They did not have bulky disease, meaning there was no nodal mass more than 7 and a half centimeters. So if you fit those criteria, then you can benefit from a de-escalation of treatment and be spared the additional 2 cycles of R-CHOP. Now, sticking with the topic of diffuse large B-cell lymphoma, a challenging problem in our field is for patients who relapse after their initial therapy, or in some cases, fail to respond to a treatment like rituximab-CHOP or an equivalent immuno-chemotherapy regimen. And a very exciting advance in the field, over the past few years, has been the development of chimeric antigen receptor T cells or CAR Ts. Traditionally, what we've done with patients who relapse or have resistant diffuse large cell lymphoma is to give them a second-line, high-dose chemotherapy regimen, and if they showed a good response to that, they could then go to a dose-intensive treatment with a follow-up consolidation by autologous stem cell transplantation. And with that, you can cure, overall, about 40% or so of patients. The CAR T-cell approach takes a very novel immunotherapy effort, and that is that a patient's own T-cells are removed from the peripheral blood, and then in the laboratory, they're modified and reprogrammed so they can attack the patient’s diffuse large B-cell lymphoma cells that are resistant to chemotherapy. So there were 2 important follow-up studies, each of them involved 1 of the agents, the CAR T-cell products, that are approved by the Food and Drug Administration for patients with relapsed or refractory diffuse large cell lymphoma. The first used the CAR T known as axicabtagene ciloleucel. It's quite a complex name, but it goes by the abbreviation of axi-cel or the trade name is Yescarta. So in this study, the investigators wanted to show that this is a treatment that can be extended to many centers with the product, the CAR T being made in a central facility by the pharmaceutical company. So it was a retrospective study of 295 patients at 17 international centers: a lot of patients across a broad spectrum of sites in North America and Europe. Virtually all the patients were able to develop and obtain a CAR T product. It included patients with some of the higher risk forms of the DLBCL such as double and triple-hit lymphoma. About 3% of patients died during the treatment, although only 1% of these were felt to be related to the treatment itself. The response rates were quite good, with about 80% of people responding. The complete remission rates at 30 days after the CAR T infusion were 47%. So it proved that you can use this centrally manufactured product. So the patients T-cells are collected at the local center, they're shipped to the manufacturing facility, the CAR Ts are generated, sent back to the home institution, and then infused. And I'll say a word in a moment, after I introduce the next paper, to explain some of the side effects of this treatment. So the second study was also presented at the ASH meeting and published simultaneously in the New England Journal of Medicine in early December 2018. So this used the second FDA approved CAR T known as tisagenlecleucel or Kymriah. In this study, there were 93 patients who were able to receive a CAR T-cell infusion, 40% of them achieved a complete remission, and another 12% had a partial response. And that a year after their documented response, two-thirds of these patients were maintaining the response, including 79% of those who achieved a complete remission. So this trial again confirmed across multiple centers that CAR T-cells can be an effective therapy. The side effects of both of these drugs can include something called cytokine release syndrome where the immunologic effects, essentially, release cytokines into the blood that can mediate a capillary leak, respiratory troubles, and low blood pressures, that can, in some cases, require intensive care unit support. This can be managed by other mediators that tamp down the cytokine effect such as an interleukin-6 antagonist. The other toxicity which is less well understood and problematic can be neurologic effects which can include confusion, speech alterations and even coma. But again, approaches and treatments to identify and manage this are being developed. So CAR Ts have become established. They're available at a number of centers, but it's important to consider this as a treatment option in the setting of relapsed or refractory diffuse large cell lymphoma. The long-term curability is still unknown, although it's encouraging that patients with very resistant disease who'd get a good response can maintain that response out to a year and more. So we're going to be very interested to see how the longer-term follow-up comes together. The final topic I wanted to mention today is Waldenstrom macroglobulinemia. So this is a unique form of indolent B-cell lymphoma where the lymphoma cells release a monoclonal immunoglobulin into the blood known as IGM. Now, IGM is a very large antibody, and because of that, when the levels are very high, patients can have problems with high viscosity or thickening of the blood, which can cause confusion, vision changes, sometimes respiratory problems. And these patients also can become anemic or develop enlarged lymph nodes or enlarged spleen. So one of the standard treatments for this disease is, again, the immunotherapy monoclonal antibody rituximab, but the responses are typically incomplete and somewhat short-lived. So it was exciting, a couple of years ago, when the targeted tyrosine kinase inhibitor, ibrutinib, which targets the bruton tyrosine kinase in malignant B-cells. This is an agent that's approved in chronic lymphocytic leukemia, and certain lymphomas such as mantle cell, marginal zone, as well as lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. So here's the study. Investigators had shown that if you combine rituximab with ibrutinib, that the response rates were improved as compared with rituximab by itself. And in a follow-up study that looked at this over a longer period of time, these benefits of the combined therapy were confirmed. These included patients without prior treatment or with prior treatment, with either chemotherapy or rituximab. And there was a confirmed benefit for the ibrutinib-rituximab combination in patients, whether they had had treatment before or not, and regardless of certain genetic markers that we use to assess risk in Waldenstrom. It was also shown that because these treatments continue indefinitely, as long as patients are responding and tolerating therapy, that the response rates improved over time. The side effects of treatment with ibrutinib are well-known, now, after several years of use across a variety of diseases, as mentioned, and include diarrhea, sometimes rash. You can see problems with easy bruising or bleeding, atrial fibrillation, and sometimes skin rash, or muscle and joint aches. But most patients are able to continue therapy and to benefit from it over an extended period of time. So the combination of ibrutinib plus rituximab was shown to add benefit compared with rituximab alone, and again, is a treatment approach and option that you could consider whether you have previously untreated or relapsed Waldenstrom macroglobulinemia. So overall, it was a very exciting meeting. We've had practice-changing data presented, and I've given you just a sampling of those. I think it's important for anyone dealing with lymphoma, or related malignancy, such as CLL or multiple myeloma to be very encouraged by the progress in the field, the opportunity to get much better responses with less toxicity and with minimal or no use of traditional chemotherapy. So we're pleased to be able to offer these treatment approaches for our patients. And I thank you for your taking part in the podcast and hope you found it useful. Thanks again. ASCO: Thank you, Dr. Williams. Learn more about lymphoma at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. Cancer.Net is supported by ASCO’s Conquer Cancer Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.

Toevoeging van lenalidomide aan R-CHOP aan de behandeling van MYC+ patiënten met een grootcellig B-cellymfoom resulteert in 62% complete remissies. Dit was een van de resultaten uit de fase 2 HOVON 130-studie gepresenteerd door dr. Martine Chamuleau, internist-hematoloog, Amsterdam UMC, locatie VUmc. Referentie1. Chamuleau M, et al. ASH 2018; abstr 786.

Dr Rummel speaks with ecancer at ASCO 2017 about 10 years of data gathered from across German clinics from patients with indolent lymphoma who were treated with bendamustine rituximab as a first line therapy. Compared to alternative R-CHOP regimens, the bendamustine data shows equivalent overall survival at 10 years, with less patients relapsing, later.

When diffuse large b-cell lymphoma returns after the cancer patient is initially treated, it is called relapsed diffuse large b-cell lymphoma (DLBCL). If this happens, other therapies besides the standard R-CHOP (chemotherapy drugs cyclophosphamide, doxorubicin, vincristine, and prednisone) may be successful in fighting the disease. Jason Westin, M.D., assistant professor in Lymphoma/Myeloma at MD Anderson Cancer Center, discusses these therapies, including high dose chemotherapy combined with stem cell transplantation, as well as clinical trials for relapsed diffuse large b-cell lymphoma.

This podcast evaluates the context and reviews results of a randomized phase III trial comparing R-CHOP given at conventional 21 day intervals with R-CHOP given at 14 day intervals in patients with newly diagnosed follicular lymphoma.

ASHTB11 - A 76-year-old woman with altered mentation, hypercalcemia, anemia and abdominal bloating with ascites, omental caking and elevated CA125 is diagnosed with DLBCL and achieves a complete response after three courses of R-CHOP but has a decreased cardiac ejection fraction. Case discussion moderated by Neil Love, MD. Produced by Research To Practice.

Prof Giuseppe Saglio of the University of Turin and San Luigi Gonzaga Hospital in Italy on nilotinib as a new standard of care for chronic myeloid leukaemia. ASH President Nancy Berliner of Brigham & Women's Hospital adds her thoughts. Jorge Cortes of M. D. Anderson Cancer Center on three different ASH papers by his group looking at alternatives to standard imatinib in CML. Jane Apperley of Hammersmith Hospital and Imperial College London, reflects on these, and discusses strategies for dealing with imatinib resistance. OT Broadcast News Scientific Editor George Canellos of Dana-Farber Cancer Institute on what some were jokingly calling a re-run of World War II that took place in the Non-Hodgkin’s Lymphoma session: R-CHOP 14 vs R-CHOP 21 in elderly patients with diffuse large B-cell lymphoma. Andrzej Jakubowiak of the University of Michigan discusses a 4-drug regimen to treat newly diagnosed multiple myeloma....Ruben Niesvizky of Weill Cornell Medical College in New York City on the novel proteasome inhibitor carfilzomib, used in combination with lenalidomide and dexamethasone to treat relapsed or refractory multiple myeloma. OT interviewers: Peter Goodwin and Sarah Maxwell.

ResearchToPractice.com/HOUJC109 – Case 3: 75yo woman initially treated with R-CHOP for Stage IV diffuse large B-cell lymphoma and then with R-EPOCH for recurrent disease. Interviews conducted by Neil Love, MD. Produced by Research To Practice.

ResearchToPractice.com/MTPH109 – Case 3 from the practice of Isaac Levy, MD presented to Drs Gregory and Orlowski, moderated by Neil Love, MD. An 83-year-old woman with mantle-cell lymphoma experienced a complete response to R-CHOP. Produced by Research To Practice.