Podcasts about bcl2

Drs. Brander and Cohen discuss an ongoing debate in the management of CLL about BTK and BCL2 inhibitor combinations in the frontline treatment of CLL. Is it better to combine BTK and BCL2 inhibitors, or to start with one or the other as monotherapy?

BUFFALO, NY- October 9, 2024 – A new #review was #published in Oncotarget's Volume 15 on September 30, 2024, entitled, “Zika virus and brain cancer: Can Zika be an effective treatment for brain cancer? A systematic review.” As highlighted in the introduction of this review, many studies have identified oncolytic viruses as a promising new class of therapeutic agents for central nervous system (CNS) tumors, particularly glioblastomas (GBM). Zika virus (ZIKV) proteins, specifically targeting certain stem cells, have shown promising results in both in vitro and animal model studies. In their review, researchers Mateus Gonçalves de Sena Barbosa, Beatriz Rodrigues Messias, Rafael Trindade Tatit, Maycon Cristian Gomes de Paula, Valdecir Boeno Spenazato Júnior, Maria Gabriella Borges Braga, Caio Vinícius Marcolino Santos, Luiza D'Ottaviano Cobos, Vinícius Otávio da Silva, Eberval Gadelha Figueiredo, Nicollas Nunes Rabelo, and Bipin Chaurasia from Atenas University Center, Passos; University of Israelita de Ciências da Saúde Albert Einstein; University of Sapucaí Valley; Atenas University Center, Sete Lagoas; Nove de Julho University, Campus Vergueiro; José do Rosário Vellano University, Alfenas; School of Medicine-University of São Paulo (FMUSP), Hospital das Clínicas/FMUSP; and Neurosurgery Clinic in Birgunj, evaluated the efficacy and safety of using ZIKV for treating CNS tumors. Data from in vivo studies were extracted and assessed for bias using the Robins-I tool, evaluating factors such as selection, performance, detection, attrition, and reporting bias. The 14 studies demonstrated that ZIKV reduced cell viability, inhibited the growth and proliferation of glioma stem cells (GSCs), and decreased Bcl2 expression, potentially enhancing chemotherapy and radiotherapy effects. ZIKV caused cytopathic effects, induced tumor cell damage, showed oncolytic properties, and selectively killed GSCs safely. This ultimately led to significant tumor remission and improved long-term survival through an enhanced T-cell response. “Although current evidence suggests ZIKV as a promising treatment for CNS tumors and may improve survival when combined with surgery and radiotherapy.” DOI - https://doi.org/10.18632/oncotarget.28647 Correspondence to - Bipin Chaurasia - trozexa@gmail.com Video short - https://www.youtube.com/watch?v=JINORGdqAO4 Sign up for free Altmetric alerts about this article: https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28647 Subscribe for free publication alerts from Oncotarget: https://www.oncotarget.com/subscribe/ Keywords - cancer, Zika, neurotropism, glioblastoma, glioma, brain tumor About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

In today's VJHemOnc podcast, we will be sharing key updates in the treatment of chronic lymphocytic leukemia (CLL) and Richter's... The post Updates in the treatment of CLL from EHA 2024: BTK and BCL2 inhibitor combinations, BTK degraders, and more appeared first on VJHemOnc.

Drs. John Sweetenham and Marc Braunstein discuss practice-changing studies in hematologic malignancies that were featured at the 2024 ASCO Annual Meeting, including the ASC4FIRST trial in chronic myeloid leukemia and IMROZ and CARTITUDE-4 in multiple myeloma.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham from UT Southwestern's Harold C. Simmons Comprehensive Cancer Center and host of the ASCO Daily News Podcast. On today's episode, we'll be discussing practice-changing abstracts and other key advances in hematological malignancies that were featured at the 2024 ASCO Annual Meeting. Joining me for this discussion is an old friend, Dr. Marc Braunstein, a hematologist and oncologist from the NYU Langone Perlmutter Cancer Center.  Our full disclosures are available in the transcript of this episode. Marc, it's great to have you back on the podcast again. There were some important studies in the heme space at the Annual Meeting this year, and we're very pleased that you're able to share your takeaways.  Dr. Marc Braunstein: Thank you, John. It's great to be back again. Dr. John Sweetenham: Let's start out, Marc, with LBA6500. This abstract reports the primary results of the ASC4FIRST trial, and this was a trial comparing asciminib with investigator selected tyrosine kinase inhibitors in newly diagnosed patients with chronic myeloid leukemia. Could you tell us a little about the trial and how you think it's going to impact clinical practice? Dr. Marc Braunstein: Absolutely. So, asciminib is an oral tyrosine kinase of the ABL kinase domain. As we know in CML, the BCR-ABL translocation is characteristic of the disease, and asciminib is approved for chronic phase CML with a T315I resistance mutation or for patients who have received 2 or more prior lines of therapy. So the ASC4FIRST trial was a randomized trial of 405 patients with newly diagnosed chronic phase CML who are randomized one to one to receive either asciminib at 80 milligrams once daily, or investigator's choice of a first generation TKI imatinib or one of three second generation TKIs nilotinib, dasatinib, or bosutinib. The primary endpoint of the study was the major molecular response, or MMR, at 48 weeks. Pretty much, the study met its primary endpoint with a 67% rate of MMR at 48 weeks, with asciminib versus 49% in patients treated with the investigator's choice of TKI. And in addition, the major molecular remission or MMR of 4.5, which is a deep remission, those rates were higher as well, with asciminib versus investigator's choice at a rate of 39% versus 21% when comparing the groups. Furthermore, when we looked at toxicity, there were fewer grade 3 or higher adverse events, with the asciminib at 38% versus either 44% with the first generation, or 55% with the second generation TKI, and fewer discontinuations as well with asciminib.  So I think this abstract is practice-changing. I think it offers compelling data to use asciminib upfront for chronic phase CML. Those who don't agree with that sentiment might argue that we want to see longer term follow up. There's a planned follow-up at 96 weeks. We would want to see the rate of progression to acute myeloid leukemia and of course overall survival as well. But I think the abstract certainly shows an improvement in outcomes with asciminib versus our current array of TKIs. Dr. John Sweetenham: Yeah, I think it certainly is, at least at minimum, potentially practice changing. I agree with you. Just one question, and this may be a little bit speculative, but do you have any thoughts about treatment free survival with asciminib and how that might line up against some of the other TKIs? Dr. Marc Braunstein: Yeah, that's a great question. The abstract did not necessarily address that, patients were treated until progression, but we know that with the current landscape of TKIs, that in patients who have achieved a deep MR of 4 or 4.5 for at least 2 years who discontinue their TKI, the rate of relapse is about 50%. The current study, the ASC4FIRST, doesn't address that, but I think it's a really good question about whether, for those patients who have achieved a deep remission, whether they can eventually stop asciminib down the line. Dr. John Sweetenham: Yeah, I guess it's one of those ‘watch this space' things.  So we'll see how the data mature out. And let's move on to what I think is another potentially practice-changing study, at least in certain parts of the world. And that's [the] LBA7000 study in classical Hodgkin lymphoma. As you remember, this was a German Hodgkin lymphoma study group trial which looked at the tolerability and efficacy of a novel regimen, BrECADD versus eBEACOPP for patients with advanced stage classical Hodgkin lymphoma in their study, which is known as GHSG HD21. Can you give us your thoughts and take home messages from this trial? Dr. Marc Braunstein: Yeah, John, absolutely. So the German HD21 study is a phase 3 study of 1,500 patients with classical Hodgkin lymphoma. The majority were stage 3 or 4, 84%, that compared two regimens BEACOPP to BrECADD. The major difference between these 2 groups being that the newer BrECADD regimen swaps out bleomycin for brentuximab vedotin, which is an anti-CD30 antibody drug conjugate. Also, in the BrECADD regimen they eliminate vincristine that's incorporated into BEACOPP. Those are kind of the global differences between these 2 regimens. And when comparing these, they looked at the primary endpoint of progression-free survival. Of note, in this study there was a PET adjusted approach where if patients achieved interim PET negativity after 2 cycles, that was followed by an additional 2 cycles of their treatment as opposed to 4 cycles if they were PET positive after the initial 2 cycles of their respective treatment. And of note, there were similar rates of PET2 negativity between both arms, about 58% in both arms.  So at a median follow-up of 48 months, the 4-year progression-free survival was significantly better with the brentuximab containing BrECADD regimen at 94% versus 91% with a hazard ratio of 0.66. And the overall survival of the BrECADD arm was 98.6%, which is very high and impressive. The 4-year overall survival was similar between the arms at around 98%, but of note, there were fewer severe adverse events with BrECADD, the brentuximab containing arm versus BEACOPP at about 42% versus 59% and interestingly less peripheral neuropathy with the brentuximab containing BrECADD. So we're doing extremely well in treating advanced stage classical Hodgkin lymphoma. So the bar is set very high. But in this study, the rates of progression-free survival and overall survival are very impressive.  While these intensive regimens tend to be used outside of the U.S., there are several notable benefits of the study, including greater than 50% PET2 negativity and high rates of progression-free survival at 4 years. In discussing this abstract, it's worth noting that there are other competing regimens, if you want to call it that, that are more commonly used in the U.S. So the ECHELON-1 study looked at brentuximab AVD compared with ABVD with bleomycin and it was a 94% versus 89% 6-year overall survival rate favoring the brentuximab containing A+AVD regimen. And lastly, more recently, the SWOG S1826 study that hasn't been published but was presented in abstract form looked at nivolumab AVD versus brentuximab AVD at a median follow up of 12 months showed a progression-free survival of 94% versus 86%. And that study still has yet to be published and needs to mature. But both of those regimens are in the NCCN guidelines. So, we're definitely pushing the bar higher in terms of improving responses in treating advanced classical Hodgkin lymphoma. Dr. John Sweetenham: I think that there's no question that these results from BrECADD are very impressive. But I'm taken back to what I think has been a kind of philosophic discussion in Hodgkin lymphoma now for a number of years about balancing disease control and efficacy against the potential short-term and long-term toxicity of the regimens, particularly when you have very effective salvage therapies for those patients who may suffer a relapse. So I think that this is a discussion over whether you take a very intensive, upfront approach to Hodgkin lymphoma versus something that may be less and slightly less intensive. I suspect that's a discussion that's going to continue for a long time. I don't know what you feel, but my own feeling about this is that this study will likely have a major influence over treatment of Hodgkin lymphoma, particularly in western Europe. Less likely in the US.., I would think. I don't know what your thoughts about that are. Dr. Marc Braunstein: Well, it's a great question. In SWOG S1826, that study did include pediatric patients. In HD21, the median age was 31 and did not include pediatric patients. So I think we have to be selective in terms of fitness and which patients may be better suited for different regimens. But I think what all these studies show is certainly when we incorporate novel immunotherapies, whether it's brentuximab vedotin, nivolumab, we improve progression-free survival and even overall survival. Dr. John Sweetenham: Absolutely.  So let's shift gears now and take a look at Abstract 7500, the IMROZ study. This was the study of isatuximab, bortezomib, lenalidomide and dexamethasone versus VRD alone for transplant ineligible patients with newly diagnosed multiple myeloma. I know we discussed this in our preview podcast a few weeks back, Marc, but I just wonder now, having seen the data in more detail, what do you think of the important takeaways? And again, are we looking at a new standard of care? Dr. Marc Braunstein: You know, there are many standards of care in multiple myeloma, but we're always looking to make improvements on the regimens we have at our disposal. So, just to recap, IMROZ is a phase 3 randomized study of the anti-CD38 monoclonal antibody isatuximab with the backbone of bortezomib, lenalidomide, dexamethasone or VRD versus VRD alone, specifically, in transplant ineligible newly diagnosed multiple myeloma patients age less than 80. They studied 446 patients in this study, randomized 3 to 2 to Isa-VRD versus VRD alone, with the primary endpoint of progression free survival. Now, similar to other studies where they included a monoclonal antibody up front, the study met its primary endpoint of improving progression-free survival with the quad regimen containing the monoclonal antibody isatuximab versus VRD alone.  So what was interesting about the study, it's really the first of its kind to be presented that specifically looked at transplant ineligible patients, which is presumably a less fit or perhaps more frail population that wouldn't go on to consolidation with stem cell transplant. And in this study, the progression-free survival at 5 years was 63% versus 45%, clearly superior when you included isatuximab. And the rates of complete remission and MRD negativity were all significantly improved, too. However, that was also met with slightly more grade 3 or higher treatment emergent adverse events, 92% versus 84% in the control arm. There are also 11% grade 5 treatment emergent adverse events with the isatuximab group versus 5.5% with VRD alone. Although there was no major difference in treatment discontinuation. One small caveat worth noting, too, is that high-risk patients in this study, when presented at ASCO, did not necessarily show a difference in benefit, although there wasn't necessarily a detriment either.  So, John, I think that clearly quadruplet regimens are superior in outcomes of efficacy to triplets, even in transplant-ineligible patients. But I think we have to tailor these treatments to individual patients because I think when it comes to transplant-ineligible patients, it's a spectrum of patients who may be more or less fit for quad regimens versus triplet regimens. It's also worth noting, though, that in this study, the patients are really only getting a quad regimen for 4 cycles. They get their Isa-VRD, and then you drop the bortezomib.  So when we think about quads, it's not that they're getting the quad regimen indefinitely, it's really for the induction cycles. But still, I think we have to be aware of potential safety issues. Dr. John Sweetenham: Okay, great. And let's stay on the theme of multiple myeloma, Marc, and talk a little bit about Abstract 7504, which was a subgroup analysis of the CARTITUDE-4 study. This is a report on the use of ciltacabtagene autoleucel versus standard of care in patients with functional high risk multiple myeloma. Can you give us your thoughts on this and maybe put it into a bit of context for us?  Dr. Marc Braunstein: Absolutely, John. It's really a great time to be in the field of multiple myeloma. We're making tremendous progress, but when we think about one of the unmet needs, it's just consistently the high-risk patients who have shorter responses and are at higher risk for poorer outcomes. Just to review, cilta-cel is one of the 2 available anti-BCMA CAR T-cell products available for the treatment of relapsed or refractory multiple myeloma. Very recently, the FDA approved cilta-cel for lenalidomide refractory patients after 2 or more prior lines of therapy based on the CARTITUDE-4 study, which was published by San-Miguel and colleagues in New England Journal of Medicine in July 2023. And that study randomized 419 patients with multiple myeloma with 1 to 3 prior lines of therapy to receive either cilta-cel or physician's choice of standard of care, which was either 1 of 2 triplet regimens, a pomalidomide, bortezomib, dexamethasone or daratumumab, pomalidomide and dexamethasone. It's worth noting that about 25% of the patients in the CARTITUDE-4 study had prior anti-CD38 antibody treatment previously and the carfilzomib was not included in one of the standard-of-care arms, and we know that those regimens containing carfilzomib do increase survival in relapsed myeloma.  Nevertheless, the primary outcome of progression-free survival was not reached in the CAR T-cell arm versus 11.8 months in the standard-of-care arm, with a significant reduction in progression of 74%. So clearly a positive study and CAR T-cell therapy is included in the NCCN guidelines for patients who have an early relapse from their myeloma. The current abstract by Costa et al focused specifically on a subgroup of 79 patients from CARTITUDE-4 in second line of treatment and looked at what they called functional high-risk myeloma, defined as progression of disease within 18 months of initial treatment or after stem cell transplant. Again, the study showed a retained benefit of cilta-cel with significant improvement in progression-free survival either not reached or 12 months with the control standard of care arm, as well as complete remission rate and rates of MRD negativity of 65% versus 10% in the control.  The overall survival outcome was still immature and not presented. Nevertheless, cilta-cel is clearly superior to standard-of-care triplet regimens. I think that for patients with high risk, they clearly derive a benefit from CAR T-cell therapy if they have short progression-free survival after initial therapy.  Dr. John Sweetenham: Thanks, Marc. So let's round this out by talking about another area of unmet need, I guess in a way in a difficult to treat patient group. And that's Abstract 7007, the SYMPATICO study. This is a study which looks at the efficacy and safety of ibrutinib and venetoclax in patients with mantle cell lymphoma who had a mutated TP53. Can you just briefly review this for us and tell us what you think we should be taking away from this studys? Dr. Marc Braunstein: So, mantle cell lymphoma typically has an aggressive behavior, but the subgroup of patients with a P53 mutation tend to have the poorest outcomes and do represent an area of unmet need. Although BTK inhibitors are making important improvements in mantle cell lymphoma, they have yet to be approved in newly diagnosed mantle cell lymphoma. Acalibutinib and zanubrutinib are FDA-approved BTK inhibitors for previously treated mantle cell lymphoma. Ibrutinib was withdrawn from the market in the U.S. for mantle cell lymphoma. Dr. Michael Wang's group presented late-breaking data from the phase 3 SYMPATICO trial at ASH 2023, in which 267 patients with relapsed refractory mantle cell lymphoma were randomized to receive either ibrutinib plus the BCL2 inhibitor venetoclax or ibrutinib plus placebo after 1 to 5 prior lines of therapy. And that study showed a 32 versus 22 months progression-free survival at a median follow up of 51 months. The current abstract, also by Dr. Wang and colleagues, looked at the subgroup of patients who had a P53 mutation and included an open label cohort of 44 patients in the first line of treatment and a relapse refractory cohort of 75 patients, and compared this subgroup of patients with P53 mutation to those without. When we look at the outcomes, the patients who did not have a P53 mutation clearly did better in terms of progression-free survival being not reached in first-line treatment compared to 22 months progression-free survival in those patients with first-line [treatment] with a P53 mutation. As well as in the relapsed refractory setting, the PFS without the P53 mutation was 47 months versus 21 months with the mutation. However, when you look at these patients treated with ibrutinib and venetoclax comparing whether they got treated in first line or the relapse refractory setting, the overall response rates are very similar at about 80% to 90% and the CR rates were very similar at about 55% to 58%, which to me suggests that although patients with P53 mutation do worse than those without it, whether they're treated in the first-line or the relapse setting with this combination of venetoclax, they tend to do somewhat similar, suggesting that you can overcome resistance to prior therapy in the relapse setting. So I think further data are certainly warranted to explore the role of combination therapies that include novel agents such as BTK inhibitors in the first line setting.  It's worth noting that the TRIANGLE study was recently published, and this study looked at including ibrutinib at various phases, including at induction in combination with intensive chemotherapy and during the maintenance phase. And that study showed encouraging outcomes in patients who received ibrutinib even without stem cell transplant compared to those who received stem cell transplant. So the role of BTKIs in mantle cell lymphoma is certainly evolving, and I think it offers a very effective intervention without the same kind of toxicities we see with cytotoxic chemotherapy that's traditionally used in mantle cell lymphoma. But I think the subgroup of patients with P53 mutation in this disease still represent an area of unmet need that unfortunately have worse outcomes. But novel agents may be able to overcome some of those adverse outcomes. Dr. John Sweetenham: Yeah, I agree. I think these are intriguing data, and obviously it needs more follow-up and probably more prospective studies. But nevertheless, I think there are some signals there for sure that need to be followed up on.  Marc, as always, it's great to have your insights on key advances in the heme space from ASCO. An important year this year, and we really appreciate your time and effort in sharing with us your thoughts on what we've learned this year. So thank you as always. Dr. Marc Braunstein: My pleasure. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today in the transcript of this episode. 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 guest:  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 Oncology  Research Funding (Institution): Janssen, Celgene/BMS   

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Anti-CD19 Chimeric Antigen Receptor T-cell therapy for Richter's Transformation: An International, Multicenter, Retrospective Study by Kittai, et al published in the Journal of Clinical Oncology March 29th, 2024.  TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing an original report published in the June 10th issue of JCO titled, “Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study,” by Kittai et al. This report addresses the real world efficacy of CAR T-cell therapy for patients with Richter transformation of CLL to large B cell lymphoma, which represents a high risk group of patients with an unmet need for novel and more effective therapeutic agents than are currently available. Richter's represents the transformation of chronic lymphocytic leukemia, or CLL, to an aggressive lymphoma, most often a large B cell lymphoma, most similar to diffuse large B cell lymphoma or DLBCL. Treatment for Richters is often modeled after treatment practices for DLBCL. However, there's no clear standard of care and outcomes for these patients lag behind those of large B cell lymphoma patients otherwise. An important advance in recent years in the DLBCL field is the approval of anti CD19 CAR T-cell therapy in the second and third line settings. However, patients with Richter transformation were largely excluded from these pivotal trials. This study in JCO thus set out to address what the real world outcomes were for patients with Richters who were treated with CAR T-cell therapy across 12 centers internationally. The study included 69 patients across these twelve sites, with a median age of 63 years at diagnosis of Richters and a median of six years after initial CLL diagnosis. Included patients received a median of four prior lines of therapy for either CLL or Richters, with a median of two prior lines of therapy for Richters, although two patients had not received any prior therapy for their Richter transformation. The most recent prior treatments included chemoimmunotherapy in 29% of patients, followed by BTK inhibitors in 19%, as well as combinations of BTK inhibitors and BCL2 inhibitors in 12%. 17% of patients had not received prior therapy for their CLL before their diagnosis with Richters, 58% of cases had known TP53 mutations at time of transformation, and 41% exhibited deletion 17p by FISH. Prior to receiving CAR T-cell therapy, 86% of patients required additional bridging therapy, most commonly with a BTK inhibitor or chemoimmunotherapy. A diverse set of commercial CAR T-cell products were represented in this study, with the majority of patients at 64% receiving axi-cel, 25% receiving tisa-cel, 10% receiving liso-cel, and one patient received brexu-cel in an investigational setting. Median time from apheresis to CAR T infusion was 34 days, and 59% of patients continued on a BTK inhibitor throughout CAR T-cell therapy. When we move on to look at responses, 66 out of 69 patients were available for response. Three patients died related to adverse events after infusion and before response assessment, with the best overall response of complete response or CR in 46% of patients and partial response or PR in 17% for an overall response rate of 63%. With a median follow up time of 24 months, the median PFS in the study was 4.7 months and the median OS was 8.5 months. For those who achieved a CR, the median duration of response was an impressive 27 months, and for those achieving PR, the median duration of response was only two months. The two year PFS rate was thus 28%, and the two year OS rate was 38%. Four patients who achieved a CR went on to receive an allogeneic stem cell transplant. Among those whose disease progressed, 8% had relapse involving the CNS, compared to 10% of patients having CNS involvement prior to CAR T in this study population. The authors were also able to look at minimal residual disease, or MRD testing for CLL in a subset of 27 patients in this study. MRD was undetectable by PCR or flow in either blood or bone marrow in 81% of these 27 patients. However, not all of these patients had paired pre and post CAR T samples available for comparison, thus limiting more detailed interpretation. In an analysis of risk factors linked to adverse outcomes, the study authors found in a multivariable analysis for overall survival that a greater number of prior lines of therapy for Richters, a higher Ki-67 proliferation index, and a higher baseline LDH and CRP were all associated with shorter OS. They did not find an association between patterns of BTK inhibitor use, whether prior to apheresis, as a part of bridging, or concurrent with CAR T-cell therapy, to be associated with either PFS or OS. In evaluating rates of toxicities for patients with Richters treated with CAR T, the authors find that grade 3 or higher cytokine release syndrome or CRS occurred in 16% of patients and grade 3 or higher neurotoxicity or ICANS occurred in 37%. They did not find any baseline features associated with higher risk of severe CRS, however, did find that prior venetoclax exposure was associated with severe ICANS. Overall, the authors find that CAR T-cell therapy is a feasible and effective therapy for Richter transformation of CLL to large B cell lymphoma, thus contributing data to support this additional therapeutic option in a high risk patient population with unmet therapeutic needs. While the PFS and OS rates are lower than those of their large B cell lymphoma counterparts, overall response rate of 63% and particularly the CR rate of 46% with a duration of response of 27 months for this group is quite promising. Those who achieved less than a CR had a much shorter duration of response and progressed quickly, and overall, the median overall survival of the whole study population is only over eight months, which reflects the high risk and poor outcome nature of treatment for Richters with currently available therapies. As the authors discuss, it is likely that the efficacy of CAR T-cell therapy is somewhat overstated in their results by virtue of not being able to include patients who were intended for CAR T-cell therapy but could not receive it in this retrospective study. This represents one of the many real world challenges patients and clinicians treating Richters face. However, the promising results for those who were able to receive CAR T-cell therapy represent a path forward for future investigations for Richters patients. One of the avenues of future pursuit is the addition of BTK inhibitors to CAR T-cell therapy. A subset of patients included in this study received BTK inhibitors for CLL before, during, and after CAR T-cell therapy, and although limited by subgroup analysis and statistical power constraints, this study's authors did not find a difference in outcomes for those who received BTK inhibitors in these settings. Toxicities with severe CRS and ICANS were higher than rates reported in large B cell lymphoma CAR T trials. However, as the authors note, these were comparable to the study of liso-cel toxicity in CLL patients. Higher rates of infection related deaths were also noted compared to large B cell lymphoma patient counterparts, however, in line with comparable CLL patient studies and thus likely related to the unique biology of Richters arising from CLL rather than de novo large B cell lymphoma. In summary, this important work evaluating the outcomes of patients with Richter's transformation treated with anti CD19 CAR T-cell therapy in the commercial setting provides important evidence as to the efficacy of this therapy among patients with an unmet need for efficacious and novel therapies to improve outcomes. As this group of patients is often excluded from clinical trials, this data is particularly important and should drive forward future studies focusing on and or including patients with Richters, given the benefits seen for a subset of patients who achieve a response in the study. While the antecedent CLL distinguishes Richters from de novo large B cell lymphoma biologically along with differences in prior treatment regimens, this study in JCO suggests that future strategies targeting improving baseline disease factors prior to CAR T-cell therapy, including successfully bridging patients to CAR T, reducing risk of CRS and ICANS with treatment, and improving long term efficacy after CAR T with novel constructs, and CAR design, may all be promising next steps in the advancement of CAR T-cell therapy for patients with Richter transformation. This is Alexandra Rojek. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/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. 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.  

In this week's epside we'll learn about ADAMTS recovery after caplacizumab therapy in patients with immune thrombotic thrombocytopenic purpura. Then, we'll hear about preclinical characterization of sonrotoclax, a potential second-generation BCL2 inhibitor. Finally we'll hear about new insights into the etiology of Castleman disease where researchers describe the unusual occurrence of idiopathic multicentric Castleman disease in identical twins. Featured Articles: ADAMTS13 recovery in acute thrombotic thrombocytopenic purpura after caplacizumab therapySonrotoclax overcomes BCL2 G101V mutation–induced venetoclax resistance in preclinical models ofhematologic malignancySingle-cell landscape of idiopathic multicentric Castleman disease in identical twins

It wasn't even two weeks into the new year when the Food and Drug Administration made their first FDA approval. In this case, it was a Keytruda regimen for certain patients with gynecologic cancers. We at CURE® spoke with an the primary investigator on the study leading to the approval about what patients need to know about the latest new indication.  Also last week, we highlighted the Lymphedema Treatment Act and spoke to an expert about the new law.  Another story in the regulatory space: the FDA granted a Fast Track designation to speed up the review of a novel drug used to treat patients with relapsed or refractory CLL or SLL.  Finally, research from the American Cancer Society showed that Medicaid expansion states tended to have improved post-surgical outcomes in patients with non-small cell lung cancer.   Keytruda Plus CRT Offers ‘Better Chance of Cure' in Advanced Cervical Cancer The Food and Drug Administration has granted approval for Keytruda (pembrolizumab) in combination with chemoradiotherapy for the treatment of stages 3 to 4A cervical cancer, marking the first approval of an anti-PD-1 therapy with chemotherapy for this patient population and the third FDA approval for treating cervical cancer with Keytruda.  This week, I spoke with Dr. Linda R. Duska, a gynecologic oncologist and principal investigator on the study leading to the approval, who discussed the KEYNOTE-A18 trial, which enrolled 1,060 patients and demonstrated a 30% decrease in progression for those receiving the combination of Keytruda and chemotherapy. The overall survival data is not yet mature, but the treatment showed a 41% reduction in the risk of disease progression or death. While Dr. Duska emphasized that cervical cancer is preventable thanks to a safe and effective vaccine, she said that for patients with the disease, this new regimen is particularly exciting.  January is also Cervical Cancer Awareness month, so definitely stay tuned to curetoday.com for more of our coverage on the disease.  Medicare Must Now Cover Lymphedema Treatment Garments The Lymphedema Treatment Act, signed into federal law on Dec. 23, 2022, is now in effect as of Jan. 1, 2024, allowing Medicare coverage for doctor-prescribed compression supplies for patients experiencing. The bill encompasses standard and custom-fitted gradient compression garments and other approved items prescribed by healthcare professionals to treat lymphedema. Now basically what that means is that patients insured by Medicare Part B can now have their lymphedema garments covered by insurance.  This coverage is expected to ease financial burdens on patients, especially as these garments can be expensive.  I spoke with Joanna Fawzy Doran, CEO of Triage Cancer, who emphasized the importance of patient and provider awareness about coverage rights, appealing denials and navigating the process. Although the law does not mandate private insurers to cover compression sleeves for lymphedema patients, Doran noted that Medicare's coverage sets a precedent for broader access in the future. FDA Grants NX-5948 Fast Track Designation for R/R CLL, SLL The FDA has granted Fast Track designation to NX-5948, a novel drug, for adults with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma who have previously undergone two lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.  Fast Track designation aims to expedite the development and review of drugs addressing serious conditions with unmet medical needs.  NX-5948 is currently in a Phase 1a/1b clinical trial, with initial findings presented at the 2023 American Society of Hematology (ASH) annual meeting indicating safety, tolerance, and clinical activity. The drug showed no dose-limiting toxicities or treatment-related side effects leading to discontinuation, and the most common side effects were purpura/contusion, nausea, and thrombocytopenia.  Medicaid Expansion May Decrease Early Mortality in Some With NSCLC States with Medicaid expansion tended to have a significant decrease in early, postoperative mortality from non-small cell lung cancer, according to recent research.  The research focused on nearly 15,000 patients undergoing surgery for NSCLC, with 62.1% residing in states supporting Medicaid expansion. The study found notable reductions in 30-day and 90-day postoperative mortality in patients with stages 1, 2, or 3 NSCLC in expansion states. Patients in non-expansion states were found to be younger, non-Hispanic Black, uninsured, and with comorbidities.  The study also evaluated changes in early mortality before and after the Affordable Care Act (ACA) implementation, showing a decrease in the 30-day mortality rate in expansion states from 0.97% to 0.26% after the ACA. Now, advocates, including the American Cancer Society, continue to emphasize the importance of expanding Medicaid eligibility to improve health outcomes.  For more news on cancer updates, research and education, don't forget to subscribe to CURE®'s newsletters here.

Go online to PeerView.com/KBW860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative therapeutics have transformed the management of chronic lymphocytic leukemia (CLL) and allowed patients a greater range of treatment options. Covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i) have demonstrated efficacy in a wide variety of treatment settings, and newer, non-covalent BTKi are poised to overcome long-standing therapeutic standards. Do you have the tools needed to “level up” your practice? Find out in this “Clinical Consults” activity based on a symposium that was recorded at the Society of Hematologic Oncology's 11th Annual Meeting. Throughout this program, a panel of leading CLL experts use conversational, case-based dialogue to provide guidance on integrating modern therapeutics anchored by BTKi and BCL2i regimens, along with rapidly emerging non-covalent BTKi and BTKi-BCL2i combinations. Join the leading lights of CLL, sharpen your therapeutic skills, and reach the next level of CLL care today! Upon completion of this activity, participants should be better able to: Cite current evidence and updated practice guidelines supporting the use of targeted agents and emerging treatment options in CLL, such as BTK and BCL2 inhibitors, CAR-T, and bispecifics; Develop personalized management protocols that include established and emerging targeted strategies as single-agent and combination platforms for patients with treatment-naïve CLL based on prognostic information, the presence of comorbidities, and safety considerations; Implement sequential treatment plans with targeted options for patients with therapeutic intolerance and/or relapsed/refractory CLL; and Manage safety and care delivery considerations associated with the use of targeted agents and other newer therapeutics in the CLL setting

Go online to PeerView.com/BXU860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelodysplastic syndromes (MDS) encompass a diverse group of myeloid malignancies, and new data are changing what can be considered “optimal” care. In this “Seminar and Workshop” activity, two hematology-oncology experts employ case-centric discussions to provide experienced instruction on the changing nature of individualized care for patients with MDS. This activity includes updated evidence supporting the use of innovative therapies for first-line management of MDS anemia, how to treat patients with ESA-refractory MDS, and treatment strategies for individuals presenting with high-risk mutations or cytogenetics. Watch now and take your treatment plans for patients with MDS to new heights! Upon completion of this activity, participants should be better able to: Cite clinical, cytogenetic, and molecular features that can inform timely, accurate diagnosis and prognosis in the MDS setting; Describe the evidence that supports the use of innovative therapeutics, including erythroid maturation agents, telomerase inhibitors, hypomethylating agent platforms, BCL2 inhibitors, and immunotherapy, in the management of patients with low-risk or high-risk MDS; Develop personalized MDS treatment protocols for the first-line management of anemia, in the ESA-refractory setting, and for patients presenting with high-risk MDS subtypes; and Address practical aspects of modern MDS therapy, including appropriate dose selection, response monitoring, and therapy-related adverse events management

Go online to PeerView.com/BXU860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelodysplastic syndromes (MDS) encompass a diverse group of myeloid malignancies, and new data are changing what can be considered “optimal” care. In this “Seminar and Workshop” activity, two hematology-oncology experts employ case-centric discussions to provide experienced instruction on the changing nature of individualized care for patients with MDS. This activity includes updated evidence supporting the use of innovative therapies for first-line management of MDS anemia, how to treat patients with ESA-refractory MDS, and treatment strategies for individuals presenting with high-risk mutations or cytogenetics. Watch now and take your treatment plans for patients with MDS to new heights! Upon completion of this activity, participants should be better able to: Cite clinical, cytogenetic, and molecular features that can inform timely, accurate diagnosis and prognosis in the MDS setting; Describe the evidence that supports the use of innovative therapeutics, including erythroid maturation agents, telomerase inhibitors, hypomethylating agent platforms, BCL2 inhibitors, and immunotherapy, in the management of patients with low-risk or high-risk MDS; Develop personalized MDS treatment protocols for the first-line management of anemia, in the ESA-refractory setting, and for patients presenting with high-risk MDS subtypes; and Address practical aspects of modern MDS therapy, including appropriate dose selection, response monitoring, and therapy-related adverse events management

Go online to PeerView.com/KBW860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative therapeutics have transformed the management of chronic lymphocytic leukemia (CLL) and allowed patients a greater range of treatment options. Covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i) have demonstrated efficacy in a wide variety of treatment settings, and newer, non-covalent BTKi are poised to overcome long-standing therapeutic standards. Do you have the tools needed to “level up” your practice? Find out in this “Clinical Consults” activity based on a symposium that was recorded at the Society of Hematologic Oncology's 11th Annual Meeting. Throughout this program, a panel of leading CLL experts use conversational, case-based dialogue to provide guidance on integrating modern therapeutics anchored by BTKi and BCL2i regimens, along with rapidly emerging non-covalent BTKi and BTKi-BCL2i combinations. Join the leading lights of CLL, sharpen your therapeutic skills, and reach the next level of CLL care today! Upon completion of this activity, participants should be better able to: Cite current evidence and updated practice guidelines supporting the use of targeted agents and emerging treatment options in CLL, such as BTK and BCL2 inhibitors, CAR-T, and bispecifics; Develop personalized management protocols that include established and emerging targeted strategies as single-agent and combination platforms for patients with treatment-naïve CLL based on prognostic information, the presence of comorbidities, and safety considerations; Implement sequential treatment plans with targeted options for patients with therapeutic intolerance and/or relapsed/refractory CLL; and Manage safety and care delivery considerations associated with the use of targeted agents and other newer therapeutics in the CLL setting

Go online to PeerView.com/BXU860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelodysplastic syndromes (MDS) encompass a diverse group of myeloid malignancies, and new data are changing what can be considered “optimal” care. In this “Seminar and Workshop” activity, two hematology-oncology experts employ case-centric discussions to provide experienced instruction on the changing nature of individualized care for patients with MDS. This activity includes updated evidence supporting the use of innovative therapies for first-line management of MDS anemia, how to treat patients with ESA-refractory MDS, and treatment strategies for individuals presenting with high-risk mutations or cytogenetics. Watch now and take your treatment plans for patients with MDS to new heights! Upon completion of this activity, participants should be better able to: Cite clinical, cytogenetic, and molecular features that can inform timely, accurate diagnosis and prognosis in the MDS setting; Describe the evidence that supports the use of innovative therapeutics, including erythroid maturation agents, telomerase inhibitors, hypomethylating agent platforms, BCL2 inhibitors, and immunotherapy, in the management of patients with low-risk or high-risk MDS; Develop personalized MDS treatment protocols for the first-line management of anemia, in the ESA-refractory setting, and for patients presenting with high-risk MDS subtypes; and Address practical aspects of modern MDS therapy, including appropriate dose selection, response monitoring, and therapy-related adverse events management

Go online to PeerView.com/KBW860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative therapeutics have transformed the management of chronic lymphocytic leukemia (CLL) and allowed patients a greater range of treatment options. Covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i) have demonstrated efficacy in a wide variety of treatment settings, and newer, non-covalent BTKi are poised to overcome long-standing therapeutic standards. Do you have the tools needed to “level up” your practice? Find out in this “Clinical Consults” activity based on a symposium that was recorded at the Society of Hematologic Oncology's 11th Annual Meeting. Throughout this program, a panel of leading CLL experts use conversational, case-based dialogue to provide guidance on integrating modern therapeutics anchored by BTKi and BCL2i regimens, along with rapidly emerging non-covalent BTKi and BTKi-BCL2i combinations. Join the leading lights of CLL, sharpen your therapeutic skills, and reach the next level of CLL care today! Upon completion of this activity, participants should be better able to: Cite current evidence and updated practice guidelines supporting the use of targeted agents and emerging treatment options in CLL, such as BTK and BCL2 inhibitors, CAR-T, and bispecifics; Develop personalized management protocols that include established and emerging targeted strategies as single-agent and combination platforms for patients with treatment-naïve CLL based on prognostic information, the presence of comorbidities, and safety considerations; Implement sequential treatment plans with targeted options for patients with therapeutic intolerance and/or relapsed/refractory CLL; and Manage safety and care delivery considerations associated with the use of targeted agents and other newer therapeutics in the CLL setting

Go online to PeerView.com/KBW860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative therapeutics have transformed the management of chronic lymphocytic leukemia (CLL) and allowed patients a greater range of treatment options. Covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i) have demonstrated efficacy in a wide variety of treatment settings, and newer, non-covalent BTKi are poised to overcome long-standing therapeutic standards. Do you have the tools needed to “level up” your practice? Find out in this “Clinical Consults” activity based on a symposium that was recorded at the Society of Hematologic Oncology's 11th Annual Meeting. Throughout this program, a panel of leading CLL experts use conversational, case-based dialogue to provide guidance on integrating modern therapeutics anchored by BTKi and BCL2i regimens, along with rapidly emerging non-covalent BTKi and BTKi-BCL2i combinations. Join the leading lights of CLL, sharpen your therapeutic skills, and reach the next level of CLL care today! Upon completion of this activity, participants should be better able to: Cite current evidence and updated practice guidelines supporting the use of targeted agents and emerging treatment options in CLL, such as BTK and BCL2 inhibitors, CAR-T, and bispecifics; Develop personalized management protocols that include established and emerging targeted strategies as single-agent and combination platforms for patients with treatment-naïve CLL based on prognostic information, the presence of comorbidities, and safety considerations; Implement sequential treatment plans with targeted options for patients with therapeutic intolerance and/or relapsed/refractory CLL; and Manage safety and care delivery considerations associated with the use of targeted agents and other newer therapeutics in the CLL setting

Go online to PeerView.com/BXU860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelodysplastic syndromes (MDS) encompass a diverse group of myeloid malignancies, and new data are changing what can be considered “optimal” care. In this “Seminar and Workshop” activity, two hematology-oncology experts employ case-centric discussions to provide experienced instruction on the changing nature of individualized care for patients with MDS. This activity includes updated evidence supporting the use of innovative therapies for first-line management of MDS anemia, how to treat patients with ESA-refractory MDS, and treatment strategies for individuals presenting with high-risk mutations or cytogenetics. Watch now and take your treatment plans for patients with MDS to new heights! Upon completion of this activity, participants should be better able to: Cite clinical, cytogenetic, and molecular features that can inform timely, accurate diagnosis and prognosis in the MDS setting; Describe the evidence that supports the use of innovative therapeutics, including erythroid maturation agents, telomerase inhibitors, hypomethylating agent platforms, BCL2 inhibitors, and immunotherapy, in the management of patients with low-risk or high-risk MDS; Develop personalized MDS treatment protocols for the first-line management of anemia, in the ESA-refractory setting, and for patients presenting with high-risk MDS subtypes; and Address practical aspects of modern MDS therapy, including appropriate dose selection, response monitoring, and therapy-related adverse events management

Go online to PeerView.com/KBW860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative therapeutics have transformed the management of chronic lymphocytic leukemia (CLL) and allowed patients a greater range of treatment options. Covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i) have demonstrated efficacy in a wide variety of treatment settings, and newer, non-covalent BTKi are poised to overcome long-standing therapeutic standards. Do you have the tools needed to “level up” your practice? Find out in this “Clinical Consults” activity based on a symposium that was recorded at the Society of Hematologic Oncology's 11th Annual Meeting. Throughout this program, a panel of leading CLL experts use conversational, case-based dialogue to provide guidance on integrating modern therapeutics anchored by BTKi and BCL2i regimens, along with rapidly emerging non-covalent BTKi and BTKi-BCL2i combinations. Join the leading lights of CLL, sharpen your therapeutic skills, and reach the next level of CLL care today! Upon completion of this activity, participants should be better able to: Cite current evidence and updated practice guidelines supporting the use of targeted agents and emerging treatment options in CLL, such as BTK and BCL2 inhibitors, CAR-T, and bispecifics; Develop personalized management protocols that include established and emerging targeted strategies as single-agent and combination platforms for patients with treatment-naïve CLL based on prognostic information, the presence of comorbidities, and safety considerations; Implement sequential treatment plans with targeted options for patients with therapeutic intolerance and/or relapsed/refractory CLL; and Manage safety and care delivery considerations associated with the use of targeted agents and other newer therapeutics in the CLL setting

Go online to PeerView.com/BXU860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelodysplastic syndromes (MDS) encompass a diverse group of myeloid malignancies, and new data are changing what can be considered “optimal” care. In this “Seminar and Workshop” activity, two hematology-oncology experts employ case-centric discussions to provide experienced instruction on the changing nature of individualized care for patients with MDS. This activity includes updated evidence supporting the use of innovative therapies for first-line management of MDS anemia, how to treat patients with ESA-refractory MDS, and treatment strategies for individuals presenting with high-risk mutations or cytogenetics. Watch now and take your treatment plans for patients with MDS to new heights! Upon completion of this activity, participants should be better able to: Cite clinical, cytogenetic, and molecular features that can inform timely, accurate diagnosis and prognosis in the MDS setting; Describe the evidence that supports the use of innovative therapeutics, including erythroid maturation agents, telomerase inhibitors, hypomethylating agent platforms, BCL2 inhibitors, and immunotherapy, in the management of patients with low-risk or high-risk MDS; Develop personalized MDS treatment protocols for the first-line management of anemia, in the ESA-refractory setting, and for patients presenting with high-risk MDS subtypes; and Address practical aspects of modern MDS therapy, including appropriate dose selection, response monitoring, and therapy-related adverse events management

Go online to PeerView.com/BXU860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Myelodysplastic syndromes (MDS) encompass a diverse group of myeloid malignancies, and new data are changing what can be considered “optimal” care. In this “Seminar and Workshop” activity, two hematology-oncology experts employ case-centric discussions to provide experienced instruction on the changing nature of individualized care for patients with MDS. This activity includes updated evidence supporting the use of innovative therapies for first-line management of MDS anemia, how to treat patients with ESA-refractory MDS, and treatment strategies for individuals presenting with high-risk mutations or cytogenetics. Watch now and take your treatment plans for patients with MDS to new heights! Upon completion of this activity, participants should be better able to: Cite clinical, cytogenetic, and molecular features that can inform timely, accurate diagnosis and prognosis in the MDS setting; Describe the evidence that supports the use of innovative therapeutics, including erythroid maturation agents, telomerase inhibitors, hypomethylating agent platforms, BCL2 inhibitors, and immunotherapy, in the management of patients with low-risk or high-risk MDS; Develop personalized MDS treatment protocols for the first-line management of anemia, in the ESA-refractory setting, and for patients presenting with high-risk MDS subtypes; and Address practical aspects of modern MDS therapy, including appropriate dose selection, response monitoring, and therapy-related adverse events management

Go online to PeerView.com/KBW860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Innovative therapeutics have transformed the management of chronic lymphocytic leukemia (CLL) and allowed patients a greater range of treatment options. Covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i) have demonstrated efficacy in a wide variety of treatment settings, and newer, non-covalent BTKi are poised to overcome long-standing therapeutic standards. Do you have the tools needed to “level up” your practice? Find out in this “Clinical Consults” activity based on a symposium that was recorded at the Society of Hematologic Oncology's 11th Annual Meeting. Throughout this program, a panel of leading CLL experts use conversational, case-based dialogue to provide guidance on integrating modern therapeutics anchored by BTKi and BCL2i regimens, along with rapidly emerging non-covalent BTKi and BTKi-BCL2i combinations. Join the leading lights of CLL, sharpen your therapeutic skills, and reach the next level of CLL care today! Upon completion of this activity, participants should be better able to: Cite current evidence and updated practice guidelines supporting the use of targeted agents and emerging treatment options in CLL, such as BTK and BCL2 inhibitors, CAR-T, and bispecifics; Develop personalized management protocols that include established and emerging targeted strategies as single-agent and combination platforms for patients with treatment-naïve CLL based on prognostic information, the presence of comorbidities, and safety considerations; Implement sequential treatment plans with targeted options for patients with therapeutic intolerance and/or relapsed/refractory CLL; and Manage safety and care delivery considerations associated with the use of targeted agents and other newer therapeutics in the CLL setting

Go online to PeerView.com/UTY860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how CLL expert Jennifer Woyach, MD, employs patient treatment history, prognostic information, and other clinically relevant factors to develop comprehensive treatment plans for her patients and get up to date on the latest evidence with BTK inhibitors for CLL by participating in this video activity. Dr. Woyach will focus on enhancing your understanding of the mechanistic, selectivity, and safety differences between covalent and non-covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), the mechanisms of intolerance and BTK resistance, and how BTKi fit into personalized treatment plans informed by the use of validated techniques such as next-generation sequencing, FISH, and karyotype testing. Learners will also be exposed to resources from the CLL Society that can be used to help educate patients on the latest therapeutic advances in customized CLL care. Upon completion of this activity, participants should be better able to: Summarize the mechanistic, selectivity, and safety differences among covalent and non-covalent BTKi, including off-target effects, therapeutic intolerance, and mechanisms of BTK resistance; Cite validated techniques, including next-generation sequencing, to identify prognostic and predictive markers such as del(17p)/TP53, BTK mutations, and minimal residual disease status to inform treatment decisions; Develop team-based management strategies that include patient treatment history, prognostic information, and other clinically relevant factors; and Implement team-based strategies to educate patients on their prognosis, facilitate clinical trial enrollment, and address dosing and safety considerations when using BTKi strategies.

Go online to PeerView.com/UTY860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how CLL expert Jennifer Woyach, MD, employs patient treatment history, prognostic information, and other clinically relevant factors to develop comprehensive treatment plans for her patients and get up to date on the latest evidence with BTK inhibitors for CLL by participating in this video activity. Dr. Woyach will focus on enhancing your understanding of the mechanistic, selectivity, and safety differences between covalent and non-covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), the mechanisms of intolerance and BTK resistance, and how BTKi fit into personalized treatment plans informed by the use of validated techniques such as next-generation sequencing, FISH, and karyotype testing. Learners will also be exposed to resources from the CLL Society that can be used to help educate patients on the latest therapeutic advances in customized CLL care. Upon completion of this activity, participants should be better able to: Summarize the mechanistic, selectivity, and safety differences among covalent and non-covalent BTKi, including off-target effects, therapeutic intolerance, and mechanisms of BTK resistance; Cite validated techniques, including next-generation sequencing, to identify prognostic and predictive markers such as del(17p)/TP53, BTK mutations, and minimal residual disease status to inform treatment decisions; Develop team-based management strategies that include patient treatment history, prognostic information, and other clinically relevant factors; and Implement team-based strategies to educate patients on their prognosis, facilitate clinical trial enrollment, and address dosing and safety considerations when using BTKi strategies.

Go online to PeerView.com/UTY860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how CLL expert Jennifer Woyach, MD, employs patient treatment history, prognostic information, and other clinically relevant factors to develop comprehensive treatment plans for her patients and get up to date on the latest evidence with BTK inhibitors for CLL by participating in this video activity. Dr. Woyach will focus on enhancing your understanding of the mechanistic, selectivity, and safety differences between covalent and non-covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), the mechanisms of intolerance and BTK resistance, and how BTKi fit into personalized treatment plans informed by the use of validated techniques such as next-generation sequencing, FISH, and karyotype testing. Learners will also be exposed to resources from the CLL Society that can be used to help educate patients on the latest therapeutic advances in customized CLL care. Upon completion of this activity, participants should be better able to: Summarize the mechanistic, selectivity, and safety differences among covalent and non-covalent BTKi, including off-target effects, therapeutic intolerance, and mechanisms of BTK resistance; Cite validated techniques, including next-generation sequencing, to identify prognostic and predictive markers such as del(17p)/TP53, BTK mutations, and minimal residual disease status to inform treatment decisions; Develop team-based management strategies that include patient treatment history, prognostic information, and other clinically relevant factors; and Implement team-based strategies to educate patients on their prognosis, facilitate clinical trial enrollment, and address dosing and safety considerations when using BTKi strategies.

Go online to PeerView.com/UTY860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how CLL expert Jennifer Woyach, MD, employs patient treatment history, prognostic information, and other clinically relevant factors to develop comprehensive treatment plans for her patients and get up to date on the latest evidence with BTK inhibitors for CLL by participating in this video activity. Dr. Woyach will focus on enhancing your understanding of the mechanistic, selectivity, and safety differences between covalent and non-covalent BTK inhibitors (BTKi) and BCL2 inhibitors (BCL2i), the mechanisms of intolerance and BTK resistance, and how BTKi fit into personalized treatment plans informed by the use of validated techniques such as next-generation sequencing, FISH, and karyotype testing. Learners will also be exposed to resources from the CLL Society that can be used to help educate patients on the latest therapeutic advances in customized CLL care. Upon completion of this activity, participants should be better able to: Summarize the mechanistic, selectivity, and safety differences among covalent and non-covalent BTKi, including off-target effects, therapeutic intolerance, and mechanisms of BTK resistance; Cite validated techniques, including next-generation sequencing, to identify prognostic and predictive markers such as del(17p)/TP53, BTK mutations, and minimal residual disease status to inform treatment decisions; Develop team-based management strategies that include patient treatment history, prognostic information, and other clinically relevant factors; and Implement team-based strategies to educate patients on their prognosis, facilitate clinical trial enrollment, and address dosing and safety considerations when using BTKi strategies.

A new research perspective was published in Oncotarget's Volume 14 on August 7, 2023, entitled, “CDK9 INHIBITORS: a promising combination partner in the treatment of hematological malignancies.” In their new perspective, researchers Daniel Morillo, Gala Vega and Victor Moreno from Hospital Fundación Jiménez Díaz discuss Cyclin-dependent kinases (CDK) in hematological malignancies. CDKs belong to a family of serine/threonine kinases that need to form heterodimeric complexes with cyclins to perform their functions. These kinases are involved in multiple processes within cells, including cell cycle, apoptosis, transcription and differentiation. These kinases are often overexpressed in different malignancies, making them potential targets for new drugs. Most hematological malignancies are characterized by overexpression of certain cancer promoting genes, such as MYC, MCL1 and cyclin D1. Preclinical studies in animal models have shown that CDK9 inhibitors suppress the transcription of these anti-apoptotic and pro-survival proteins, and suggest their potential synergism with other drugs. In its first in-human trial, enitociclib demonstrated clinical activity in a small cohort of patients with high grade B lymphoma with MYC and BCL2 and/or BCL6 rearrangements, inducing complete responses in 2 of 7 subjects (29%) in monotherapy. “In summary, most hematological malignancies are characterized by overexpression of certain cancer promoting genes, such as MYC and MCL1. CDK9 inhibitors are relatively new drugs that inhibit transcription of these anti-apoptotic and pro-survival proteins.” DOI - https://doi.org/10.18632/oncotarget.28473 Correspondence to - Victor Moreno - victor.moreno@startmadrid.com Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28473 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, cyclin-dependent kinases (CDK), CDK9, hematological malignancies About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.12.548688v1?rss=1 Authors: Wang, S., Cheng, H., Li, M., Wu, H., Zhang, S., Gao, D., Huang, Y., Guo, K. Abstract: Although increasing studies has demonstrated that cell competition widely involved in the growth and homeostasis of multicellular organisms is closely linked to tumorigenesis and development, the mechanistic contributions to the association between tumor cell competition-driven heterogeneity and drug resistance remains ill-defined. In our study, lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obviously competitive growth dominance against sensitive cells through reprogramming energy metabolism. Mechanistically, when BCL2 interacting protein3 (BNIP3) overexpression activates mitophagy activity in lenvatinib-resistant HCC cells, energy imbalance signal caused by reduced mitochondrial oxidative phosphorylation levels provokes the phosphorylation of AMP-activated protein kinase (AMPK) sensor; subsequently, enabled AMPK specifically targets enolase 2 (ENO2) to enhance glycolysis and eventually promots the competitive capacity and dominant growth. Of note, BNIP3 deficiency shows certain inhibition of cell competition outcome. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism; meanwhile this work recognaizes BNIP3 as a promising target to overcome HCC drug resistance. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/PYA860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Newer treatment modalities for acute myeloid leukemia (AML) have rapidly eclipsed the decades-long cytarabine-based standard of care and helped clinicians adopt more personalized management using innovative cytotoxic platforms, targeted agents (including FLT3, BCL2, and IDH inhibitors), and other unique management strategies. Clinicians can now improve patient outcomes across all AML treatment settings, while at the same time selecting the most potent, personalized option that can be designed to address a given patient's needs. This “Seminars and Tumor Board” activity, adapted from our recent live event held at the 2023 ASCO Annual Meeting and developed in collaboration with the HealthTree Foundation for Acute Myeloid Leukemia, reveals how modern baseline assessment paired with cutting-edge prognostication has pushed patient management to new heights of innovation and changed the management of patients with AML with therapeutically relevant features (such as FLT3 or IDH mutations), patients presenting without driver mutations, or individuals with comorbid illnesses or higher-risk features. Join the AML experts for a real-world “Tumor Board”–style discussion of how the latest evidence can inform your practice. Upon completion of this activity, participants should be better able to: Summarize baseline patient-related and disease-related factors, including age, comorbidities, functional status, and cytogenetic/mutational findings, that can influence prognostication and treatment selection in AML; Cite current evidence supporting the personalized use of novel treatment modalities, including new cytotoxic platforms, targeted agents, immunotherapy, and epigenetic strategies, for the management of newly diagnosed or relapsed/refractory AML; Integrate novel therapeutics into the personalized team-based management of AML according to the results of baseline assessment, presence or absence of targetable mutations, functional status, or AML subtype; and Address care delivery considerations, including optimized dosing and safety management, when caring for patients with AML

Go online to PeerView.com/KYR860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how the experts “defy the odds” every day by exposing patients with chronic lymphocytic leukemia (CLL) to the clinical benefits of innovative therapy! Novel therapeutics based on BTK and BCL2 inhibitor platforms have radically transformed the management of CLL and allowed for a greater range of treatment options in a range of CLL settings. This MasterClass & Case Forum activity, adapted from a recent live event and developed in collaboration with the CLL Society, offers learners expert guidance on how to select and sequence agents over several lines of therapy while proactively integrating newer BTKi strategies, targeted combination platforms, and cellular immunotherapy into safe, personalized treatment plans. Throughout, learn about offerings from the CLL Society that will help you engage with patients and offer them the resources they need to contribute to care decisions. Upon completion of this activity, participants should be better able to: Summarize safety/efficacy evidence and practice guidelines that support the use of novel targeted and emerging immunotherapy agents in CLL, such as BTK and BCL2 inhibitors, CAR-T cells, and bispecifics; Integrate novel and emerging targeted strategies into personalized single-agent and combination regimens for patients with TN CLL based on prognostic information, the presence of comorbidities, and safety considerations; Develop appropriate sequential treatment plans with targeted agents and emerging immunotherapy options for patients with therapeutic intolerance and/or R/R CLL; and Implement evidence-based protocols to address the unique safety considerations associated with the use of targeted agents and emerging immunotherapy options in the CLL setting.

Go online to PeerView.com/KYR860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how the experts “defy the odds” every day by exposing patients with chronic lymphocytic leukemia (CLL) to the clinical benefits of innovative therapy! Novel therapeutics based on BTK and BCL2 inhibitor platforms have radically transformed the management of CLL and allowed for a greater range of treatment options in a range of CLL settings. This MasterClass & Case Forum activity, adapted from a recent live event and developed in collaboration with the CLL Society, offers learners expert guidance on how to select and sequence agents over several lines of therapy while proactively integrating newer BTKi strategies, targeted combination platforms, and cellular immunotherapy into safe, personalized treatment plans. Throughout, learn about offerings from the CLL Society that will help you engage with patients and offer them the resources they need to contribute to care decisions. Upon completion of this activity, participants should be better able to: Summarize safety/efficacy evidence and practice guidelines that support the use of novel targeted and emerging immunotherapy agents in CLL, such as BTK and BCL2 inhibitors, CAR-T cells, and bispecifics; Integrate novel and emerging targeted strategies into personalized single-agent and combination regimens for patients with TN CLL based on prognostic information, the presence of comorbidities, and safety considerations; Develop appropriate sequential treatment plans with targeted agents and emerging immunotherapy options for patients with therapeutic intolerance and/or R/R CLL; and Implement evidence-based protocols to address the unique safety considerations associated with the use of targeted agents and emerging immunotherapy options in the CLL setting.

Go online to PeerView.com/KYR860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how the experts “defy the odds” every day by exposing patients with chronic lymphocytic leukemia (CLL) to the clinical benefits of innovative therapy! Novel therapeutics based on BTK and BCL2 inhibitor platforms have radically transformed the management of CLL and allowed for a greater range of treatment options in a range of CLL settings. This MasterClass & Case Forum activity, adapted from a recent live event and developed in collaboration with the CLL Society, offers learners expert guidance on how to select and sequence agents over several lines of therapy while proactively integrating newer BTKi strategies, targeted combination platforms, and cellular immunotherapy into safe, personalized treatment plans. Throughout, learn about offerings from the CLL Society that will help you engage with patients and offer them the resources they need to contribute to care decisions. Upon completion of this activity, participants should be better able to: Summarize safety/efficacy evidence and practice guidelines that support the use of novel targeted and emerging immunotherapy agents in CLL, such as BTK and BCL2 inhibitors, CAR-T cells, and bispecifics; Integrate novel and emerging targeted strategies into personalized single-agent and combination regimens for patients with TN CLL based on prognostic information, the presence of comorbidities, and safety considerations; Develop appropriate sequential treatment plans with targeted agents and emerging immunotherapy options for patients with therapeutic intolerance and/or R/R CLL; and Implement evidence-based protocols to address the unique safety considerations associated with the use of targeted agents and emerging immunotherapy options in the CLL setting.

Go online to PeerView.com/KYR860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how the experts “defy the odds” every day by exposing patients with chronic lymphocytic leukemia (CLL) to the clinical benefits of innovative therapy! Novel therapeutics based on BTK and BCL2 inhibitor platforms have radically transformed the management of CLL and allowed for a greater range of treatment options in a range of CLL settings. This MasterClass & Case Forum activity, adapted from a recent live event and developed in collaboration with the CLL Society, offers learners expert guidance on how to select and sequence agents over several lines of therapy while proactively integrating newer BTKi strategies, targeted combination platforms, and cellular immunotherapy into safe, personalized treatment plans. Throughout, learn about offerings from the CLL Society that will help you engage with patients and offer them the resources they need to contribute to care decisions. Upon completion of this activity, participants should be better able to: Summarize safety/efficacy evidence and practice guidelines that support the use of novel targeted and emerging immunotherapy agents in CLL, such as BTK and BCL2 inhibitors, CAR-T cells, and bispecifics; Integrate novel and emerging targeted strategies into personalized single-agent and combination regimens for patients with TN CLL based on prognostic information, the presence of comorbidities, and safety considerations; Develop appropriate sequential treatment plans with targeted agents and emerging immunotherapy options for patients with therapeutic intolerance and/or R/R CLL; and Implement evidence-based protocols to address the unique safety considerations associated with the use of targeted agents and emerging immunotherapy options in the CLL setting.

Go online to PeerView.com/KYR860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how the experts “defy the odds” every day by exposing patients with chronic lymphocytic leukemia (CLL) to the clinical benefits of innovative therapy! Novel therapeutics based on BTK and BCL2 inhibitor platforms have radically transformed the management of CLL and allowed for a greater range of treatment options in a range of CLL settings. This MasterClass & Case Forum activity, adapted from a recent live event and developed in collaboration with the CLL Society, offers learners expert guidance on how to select and sequence agents over several lines of therapy while proactively integrating newer BTKi strategies, targeted combination platforms, and cellular immunotherapy into safe, personalized treatment plans. Throughout, learn about offerings from the CLL Society that will help you engage with patients and offer them the resources they need to contribute to care decisions. Upon completion of this activity, participants should be better able to: Summarize safety/efficacy evidence and practice guidelines that support the use of novel targeted and emerging immunotherapy agents in CLL, such as BTK and BCL2 inhibitors, CAR-T cells, and bispecifics; Integrate novel and emerging targeted strategies into personalized single-agent and combination regimens for patients with TN CLL based on prognostic information, the presence of comorbidities, and safety considerations; Develop appropriate sequential treatment plans with targeted agents and emerging immunotherapy options for patients with therapeutic intolerance and/or R/R CLL; and Implement evidence-based protocols to address the unique safety considerations associated with the use of targeted agents and emerging immunotherapy options in the CLL setting.

Go online to PeerView.com/KYR860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Learn how the experts “defy the odds” every day by exposing patients with chronic lymphocytic leukemia (CLL) to the clinical benefits of innovative therapy! Novel therapeutics based on BTK and BCL2 inhibitor platforms have radically transformed the management of CLL and allowed for a greater range of treatment options in a range of CLL settings. This MasterClass & Case Forum activity, adapted from a recent live event and developed in collaboration with the CLL Society, offers learners expert guidance on how to select and sequence agents over several lines of therapy while proactively integrating newer BTKi strategies, targeted combination platforms, and cellular immunotherapy into safe, personalized treatment plans. Throughout, learn about offerings from the CLL Society that will help you engage with patients and offer them the resources they need to contribute to care decisions. Upon completion of this activity, participants should be better able to: Summarize safety/efficacy evidence and practice guidelines that support the use of novel targeted and emerging immunotherapy agents in CLL, such as BTK and BCL2 inhibitors, CAR-T cells, and bispecifics; Integrate novel and emerging targeted strategies into personalized single-agent and combination regimens for patients with TN CLL based on prognostic information, the presence of comorbidities, and safety considerations; Develop appropriate sequential treatment plans with targeted agents and emerging immunotherapy options for patients with therapeutic intolerance and/or R/R CLL; and Implement evidence-based protocols to address the unique safety considerations associated with the use of targeted agents and emerging immunotherapy options in the CLL setting.

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

Go online to PeerView.com/XPM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to implement advances with targeted agents in CLL in your pharmacy practice? Find out by viewing this “Pharmacy MasterClass & Case Forum” program, recorded during the 2023 Hematology/Oncology Pharmacy Association (HOPA) 19th Annual Conference. Throughout, expert pharmacists will present state-of-the-art evidence supporting the use of highly efficacious targeted strategies in CLL, including covalent and non-covalent BTK inhibitors, BCL2 inhibitors, and chemo-sparing combinations, and give insights on how to apply the evidence supporting these strategies to real-world practice. The experts will also prepare you to anticipate and manage adverse events; proactively address drug interaction and dosing complexities; and provide staff and patient education on single-agent and combination strategies. Don't miss this opportunity to get the latest on the new treatment mix in CLL! Upon completion of this activity, participants should be better able to: Summarize the mechanistic and pharmacokinetic profiles, and safety/efficacy evidence supporting the treatment roles of novel BTK and BCL-2 inhibitor approaches in CLL; Develop pharmacy-guided plans to optimize the integration of novel and emerging BTK and BCL-2 inhibitor strategies into personalized management plans for patients with TN and RR CLL; and Work collaboratively to address practical aspects of team-based care with targeted therapies in CLL, including care coordination, drug-drug interactions, patient counseling, staff education, and safety and dosing considerations.

Go online to PeerView.com/XPM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to implement advances with targeted agents in CLL in your pharmacy practice? Find out by viewing this “Pharmacy MasterClass & Case Forum” program, recorded during the 2023 Hematology/Oncology Pharmacy Association (HOPA) 19th Annual Conference. Throughout, expert pharmacists will present state-of-the-art evidence supporting the use of highly efficacious targeted strategies in CLL, including covalent and non-covalent BTK inhibitors, BCL2 inhibitors, and chemo-sparing combinations, and give insights on how to apply the evidence supporting these strategies to real-world practice. The experts will also prepare you to anticipate and manage adverse events; proactively address drug interaction and dosing complexities; and provide staff and patient education on single-agent and combination strategies. Don't miss this opportunity to get the latest on the new treatment mix in CLL! Upon completion of this activity, participants should be better able to: Summarize the mechanistic and pharmacokinetic profiles, and safety/efficacy evidence supporting the treatment roles of novel BTK and BCL-2 inhibitor approaches in CLL; Develop pharmacy-guided plans to optimize the integration of novel and emerging BTK and BCL-2 inhibitor strategies into personalized management plans for patients with TN and RR CLL; and Work collaboratively to address practical aspects of team-based care with targeted therapies in CLL, including care coordination, drug-drug interactions, patient counseling, staff education, and safety and dosing considerations.

Go online to PeerView.com/XPM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to implement advances with targeted agents in CLL in your pharmacy practice? Find out by viewing this “Pharmacy MasterClass & Case Forum” program, recorded during the 2023 Hematology/Oncology Pharmacy Association (HOPA) 19th Annual Conference. Throughout, expert pharmacists will present state-of-the-art evidence supporting the use of highly efficacious targeted strategies in CLL, including covalent and non-covalent BTK inhibitors, BCL2 inhibitors, and chemo-sparing combinations, and give insights on how to apply the evidence supporting these strategies to real-world practice. The experts will also prepare you to anticipate and manage adverse events; proactively address drug interaction and dosing complexities; and provide staff and patient education on single-agent and combination strategies. Don't miss this opportunity to get the latest on the new treatment mix in CLL! Upon completion of this activity, participants should be better able to: Summarize the mechanistic and pharmacokinetic profiles, and safety/efficacy evidence supporting the treatment roles of novel BTK and BCL-2 inhibitor approaches in CLL; Develop pharmacy-guided plans to optimize the integration of novel and emerging BTK and BCL-2 inhibitor strategies into personalized management plans for patients with TN and RR CLL; and Work collaboratively to address practical aspects of team-based care with targeted therapies in CLL, including care coordination, drug-drug interactions, patient counseling, staff education, and safety and dosing considerations.

Go online to PeerView.com/XPM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to implement advances with targeted agents in CLL in your pharmacy practice? Find out by viewing this “Pharmacy MasterClass & Case Forum” program, recorded during the 2023 Hematology/Oncology Pharmacy Association (HOPA) 19th Annual Conference. Throughout, expert pharmacists will present state-of-the-art evidence supporting the use of highly efficacious targeted strategies in CLL, including covalent and non-covalent BTK inhibitors, BCL2 inhibitors, and chemo-sparing combinations, and give insights on how to apply the evidence supporting these strategies to real-world practice. The experts will also prepare you to anticipate and manage adverse events; proactively address drug interaction and dosing complexities; and provide staff and patient education on single-agent and combination strategies. Don't miss this opportunity to get the latest on the new treatment mix in CLL! Upon completion of this activity, participants should be better able to: Summarize the mechanistic and pharmacokinetic profiles, and safety/efficacy evidence supporting the treatment roles of novel BTK and BCL-2 inhibitor approaches in CLL; Develop pharmacy-guided plans to optimize the integration of novel and emerging BTK and BCL-2 inhibitor strategies into personalized management plans for patients with TN and RR CLL; and Work collaboratively to address practical aspects of team-based care with targeted therapies in CLL, including care coordination, drug-drug interactions, patient counseling, staff education, and safety and dosing considerations.

Go online to PeerView.com/XPM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to implement advances with targeted agents in CLL in your pharmacy practice? Find out by viewing this “Pharmacy MasterClass & Case Forum” program, recorded during the 2023 Hematology/Oncology Pharmacy Association (HOPA) 19th Annual Conference. Throughout, expert pharmacists will present state-of-the-art evidence supporting the use of highly efficacious targeted strategies in CLL, including covalent and non-covalent BTK inhibitors, BCL2 inhibitors, and chemo-sparing combinations, and give insights on how to apply the evidence supporting these strategies to real-world practice. The experts will also prepare you to anticipate and manage adverse events; proactively address drug interaction and dosing complexities; and provide staff and patient education on single-agent and combination strategies. Don't miss this opportunity to get the latest on the new treatment mix in CLL! Upon completion of this activity, participants should be better able to: Summarize the mechanistic and pharmacokinetic profiles, and safety/efficacy evidence supporting the treatment roles of novel BTK and BCL-2 inhibitor approaches in CLL; Develop pharmacy-guided plans to optimize the integration of novel and emerging BTK and BCL-2 inhibitor strategies into personalized management plans for patients with TN and RR CLL; and Work collaboratively to address practical aspects of team-based care with targeted therapies in CLL, including care coordination, drug-drug interactions, patient counseling, staff education, and safety and dosing considerations.

Go online to PeerView.com/XPM860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Are you prepared to implement advances with targeted agents in CLL in your pharmacy practice? Find out by viewing this “Pharmacy MasterClass & Case Forum” program, recorded during the 2023 Hematology/Oncology Pharmacy Association (HOPA) 19th Annual Conference. Throughout, expert pharmacists will present state-of-the-art evidence supporting the use of highly efficacious targeted strategies in CLL, including covalent and non-covalent BTK inhibitors, BCL2 inhibitors, and chemo-sparing combinations, and give insights on how to apply the evidence supporting these strategies to real-world practice. The experts will also prepare you to anticipate and manage adverse events; proactively address drug interaction and dosing complexities; and provide staff and patient education on single-agent and combination strategies. Don't miss this opportunity to get the latest on the new treatment mix in CLL! Upon completion of this activity, participants should be better able to: Summarize the mechanistic and pharmacokinetic profiles, and safety/efficacy evidence supporting the treatment roles of novel BTK and BCL-2 inhibitor approaches in CLL; Develop pharmacy-guided plans to optimize the integration of novel and emerging BTK and BCL-2 inhibitor strategies into personalized management plans for patients with TN and RR CLL; and Work collaboratively to address practical aspects of team-based care with targeted therapies in CLL, including care coordination, drug-drug interactions, patient counseling, staff education, and safety and dosing considerations.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.09.536069v1?rss=1 Authors: Ferreira, A. F., Raposo, M., Shaw, E. D., Ashraf, N. S., Medeiros, F., Brilhante, M. d. F., Perkins, M., Vasconcelos, J., Kay, T., Costa, M. d. C., Lima, M. Abstract: Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD, and to evaluate if expression alterations of specific apoptosis genes/proteins could be used as transcriptional biomarkers of disease, the levels of BCL2, BAX and TP53 and the BCL2/BAX ratio, an indicator of susceptibility to apoptosis, were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue dependent behavior is partially replicated in a MJD mouse model. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this week's episode, we'll discuss the dynamics of measurable residual disease, or MRD, over time in myeloma patients undergoing ixazomib maintenance. Serial measurements were feasible and provided more detailed risk stratification than single timepoint measurements—findings that could have implications for the use of MRD to guide treatment duration. Up next, a research article exploring the relationships between poverty, and lack of neighborhood opportunity, with outcomes of CAR T -cell therapy in children with acute lymphoblastic leukemia. The findings suggest opportunities for interventions to improve access for less socioeconomically advantaged children. Finally, we'll review a report demonstrating that acquired mutations in the pro-apoptotic effector protein BAX are common in patients with AML treated with venetoclax. These and other research observations reveal BAX variants as a hurdle to the long-term success of BCL2-targeted therapy in this disease.

A new research paper was published on the cover of Aging (listed as "Aging (Albany NY)" by Medline/PubMed and "Aging-US" by Web of Science) Volume 15, Issue 1, entitled, “Single-cell transcriptomics of peripheral blood in the aging mouse.” Compositional and transcriptional changes in the hematopoietic system have been used as biomarkers of immunosenescence and aging. In this new study, researchers Yee Voan Teo, Samuel J. Hinthorn, Ashley E. Webb, and Nicola Neretti from Brown University used single-cell RNA-sequencing to study the aging peripheral blood in mice and characterize the changes in cell-type composition and transcriptional profiles associated with age. “Here, we applied scRNA-seq on young and old mice to dissect the transcriptional and cell composition changes of all cell types in the peripheral blood with age.” The team identified 17 clusters from a total of 14,588 single cells. They detected a general upregulation of antigen processing and presentation and chemokine signaling pathways and a downregulation of genes involved in ribosome pathways with age. In old peripheral blood, the researchers also observed an increased percentage of cells expressing senescence markers (Cdkn1a, and Cdkn2a). In addition, a cluster of activated T cells exclusively found in old blood was detected, with lower expression of Cd28 and higher expression of Bcl2 and Cdkn2a, suggesting that the cells are senescent and resistant to apoptosis. “Finally, targeting senescent cells using genetic approaches has been shown to ameliorate the aging phenotype [34, 35]. More recently, senolytics drugs are being identified or developed to target apoptotic pathways because senescent cells are known to be apoptosis-resistant [34]. Therefore, the Bcl2+ old T cells that we identified in old mice can potentially be targeted pharmacologically to ameliorate the phenotypes associated with the aging of the immune system.” DOI: https://doi.org/10.18632/aging.204471 Corresponding Author: Nicola Neretti - nicola_neretti@brown.edu Keywords: aging, single-cell transcriptomics, senescence, peripheral blood Sign up for free Altmetric alerts about this article: https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204471 About Aging-US: Launched in 2009, Aging (Aging-US) publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at www.Aging-US.com​​ and connect with us: SoundCloud – https://soundcloud.com/Aging-Us Facebook – https://www.facebook.com/AgingUS/ Twitter – https://twitter.com/AgingJrnl Instagram – https://www.instagram.com/agingjrnl/ YouTube – https://www.youtube.com/agingus​ LinkedIn – https://www.linkedin.com/company/aging/ Reddit – https://www.reddit.com/user/AgingUS Pinterest – https://www.pinterest.com/AgingUS/ For media inquiries, please contact media@impactjournals.com.

This week, please join author Trisha Singh as she discusses her article "Manganese-Enhanced Magnetic Resonance Imaging in Takotsubo Syndrome." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass for the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Carolyn, very interesting feature discussion this week. Many times we hear in magnetic resonance imaging the use of gadolinium contrast. And remember, gadolinium is an extracellular agent. And when we apply it in the heart, we look for infarcts, or areas of the heart that are perhaps dead, or scarred over. This week's feature discusses manganese as a contrast agent and it is an intracellular contrast agent. And very interestingly, it identifies calcium handling, so it's a marker of viability. And these authors are going to apply manganese as well as gadolinium in trying to understand mechanisms behind Takotsubo cardiomyopathy. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Dr. Carolyn Lam: Oh, I'd love to tell you about the other articles. But just have to first say, I loved your description of the feature paper. It's right up your alley and I can't wait to learn more. But my first paper today I want to talk about pulse field ablation. Now, what is that? Pulse field ablation, or PFA, is a unique and novel technique to treat atrial fibrillation. It has a unique safety profile largely related to its preferentially for myocardial tissue ablation. And thus, sparing the esophagus and thus, deemed to have a unique safety profile. Now, a pentaspline catheter was the first such PFA system studied for AF ablation. And in the initial trials the catheter was used for pulmonary vein isolation and left atrial posterior wall ablation. However, following its regulatory approval in Europe, in clinical practice, physicians have ablated both these locations and expanded lesions that could be in closer proximity to the coronary arteries. Now, this is an unstudied important issue since preclinical and maybe some clinical data have raised the potential for coronary arterial spasm. Hence, the investigators led by Dr. Vivek Reddy from Icahn School of Medicine at Mount Sinai and colleagues studied the vasal spastic potential of PFA lesion sets, both remote from and adjacent to coronary arteries. Dr. Greg Hundley: Wow, Carolyn, this is a really interesting question. So what did they find? Dr. Carolyn Lam: In this retrospective analysis of a series of 25 patients undergoing PFA for atrial fibrillation in whom coronary angiography was performed pre, during and post ablation, they found that during pulmonary vein isolation and left atrial posterior wall ablation, coronary spasm did not occur. However, cavotricuspid isthmus ablation provoked severe subtotal vasospasm in five out of five consecutive patients. And this was relieved by in coronary nitroglycerin. ST elevation was not observed. No patient had severe spasm if first pretreated with parenteral nitroglycerin, either intracoronary or intravenous. And so in summary, coronary vasospasm was not provoked during PFA at locations remote from the coronary arteries. But when the energy is delivered adjacent to a coronary artery, like in cavotricuspid isthmus ablation, PFA did provoke subclinical vasospasm. And the phenomenon was attenuated by nitroglycerine administered either post hoc to treat spasm or as prophylaxis. And this is discussed in accompanying editorial, I like it, “Coronary Vasospasm in PFA Primum Non Nocere” by Drs. Estes and Sundeep and Saba. Dr. Greg Hundley: Very nice Carolyn. Very important research in this area using that particular methodology. Well Carolyn, my next study comes to us again from preclinical science. And Carolyn, this study evaluated mechanisms responsible for pulmonary hypertension. So as background, pulmonary hypertension is associated with increased expression of VEGFA and it's receptor VEGFR-2. But whether and how activation of VEGFA signal participates in the pathogenesis of pulmonary hypertension, that's unclear. And so these authors led by Dr. Yangxin Chen from Sun Yat-Sen Memorial Hospital and Sun Yat-Sen University evaluated VEGFA, VEGFR-2 signal activation and VEGFR-2 Y949 dependent vascular leak in lung samples from patients with pulmonary hypertension as well as in mice exposed to hypoxia. Dr. Carolyn Lam: Another one of those excellent translational pieces, isn't it Greg? So what did they find? Dr. Greg Hundley: Right Carolyn. So these authors found that pulmonary hypertension led to excessive pulmonary vascular leak in both patients and hypoxic mice. And this was owing to over activated VEGFA and VEGFR-2 Y949 signaling axis. Abolishing VEGFR-2 Y949 signaling via a specific point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure. This, in turn, led to alleviation of pulmonary hypertension manifestations including muscularization of distal pulmonary arterials, elevation of right ventricular systolic pressure and right ventricular hypertrophy. And so Carolyn, in summary, these results suggest that VEGFA, VEGFR-2 Y949 dependent vascular permeability is an important determinant in the pathogenesis of pulmonary hypertension and might serve as an attractive therapeutic target pathway for this disease. Dr. Carolyn Lam: Aw, thanks Greg for explaining that so well. The next paper talks about transcatheter aortic valve replacement of TAVR, recognizing that it is a well established treatment now for high and intermediate risk patients with severe symptomatic aortic stenosis. However, the question asked here is what makes some, but not all patients improve their left ventricular ejection fraction following TAVR associated after load reduction? Now, hypothesizing that circulating microRNAs may play a role here, the authors led by corresponding authors, Dr. Hosen and Jansen from University of Bonn and their colleagues profiled the differential expression of microRNAs in circulating extracellular vesicles in patients after TAVR. And in particular, the novel role of circulating microRNA 1225p in cardiomyocytes. Dr. Greg Hundley: Oh wow. So Carolyn, important study. So what did they find? Dr. Carolyn Lam: Well, first aortic stenosis increases circulating microRNA 1225p, which correlated with a lack of improvement of the EF in patients after TAVR. Extracellular vesicles harbored microRNA 1225p and facilitated its startling into the cardiomyocytes. Vesicular shuttling of this particular microRNA was regulated by a direct interaction with a multifunctional RNA binding protein called heterogeneous nuclear ribonucleoprotein U in a sequence specific manner. Extracellular vesicles containing the specific microRNA post transcriptionally repressed BCL2 an anti-apoptotic gene, which is central to cell viability and apoptosis. So in summary, Greg, an increase in extracellular vesicle microRNA 1225p in patients with aortic stenosis represents a novel mechanism for the deterioration of cardiac function in patients following TAVR. And pharmacological manipulation of this axis may improve ejection fraction and cardiac function in patients with aortic stenosis by improving the viability of cardiomyocytes, which opens the door to a potential therapeutic approach in patients with limited EF improvement following TAVR. Dr. Greg Hundley: Oh Carolyn, beautiful, beautiful description of that wonderful preclinical science. Well, let's reach into the mail bag and see what else is in the issue. And first, there's a research letter by Professor van Raalte entitled “Kidney Hemodynamic Effects of Angiotensin Receptor Blockades Sodium Glucose Co-transporter 2 Inhibition Alone and in Their Combination: A Crossover Randomized Trial in People with Type 2 Diabetes.” And Carolyn, there's also an In Depth piece from Dr. Marx entitled “GLP1 Receptor Agonist for the Reduction of Atherosclerotic Cardiovascular Risk in Patients with Type 2 Diabetes.” Dr. Carolyn Lam: Very, very nice papers, those two. There's also an exchange of letters between Drs. Hou and Sedej regarding the article, “Fine Tuning Cardiac Insulin Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity.” As well as a Perspective by Dr. Eagle, “Comments on the 2022 Aortic Guidelines: Seeking More Precision in Aortic Care.” Now, let's go onto the feature discussion of all things MRI, shall we? Dr. Greg Hundley: You bet. More on manganese. Welcome listeners to this very interesting feature discussion on December 13th. And we have with us Dr. Trisha Singh from the University of Edinburgh in Edinburgh, Scotland. Welcome, Trisha. This is a fascinating study incorporating manganese cardiovascular magnetic resonance to study some of the mechanistic underpinnings of hypokinesis left ventricular hypokinesis in patients with Takotsubo syndrome. So maybe just describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address? Dr. Trisha Singh: Yes, of course. So we know with patients with Takotsubo syndrome, it predominantly affects middle aged women, patients present with a degree of left ventricular dysfunction, which is transient. And, unfortunately, it can be quite difficult to diagnose because it can phenotypically present very similar to an acute coronary syndrome. We know from previous studies that these patients do have ongoing symptoms despite normalization of their LV function. And actually their outcomes are not as benign as previously thought. In terms of manganese enhanced MRI imaging, we at Edinburgh University have imaged patients with other cardiac conditions such as hypertrophic cardiomyopathy, and dilated cardiomyopathy. And have established that it can be used as a surrogate marker of myocardial calcium uptake and handling. So we were very interested to see whether or not patients with acute Takotsubo syndrome have got a myocardial calcium dysfunction and more importantly whether or not this translates into long-term dysfunction and perhaps could explain their symptoms and worse prognosis in long-term. Dr. Greg Hundley: Trisha, manganese MRI. Now, we hear about gadolinium MRI, how is manganese different? You mentioned it's a nice marker for calcium handling. Is this widely used clinically? What kind of contrast does it provide? Dr. Trisha Singh: So manganese was actually one of the first contrast agents to be used with magnetic resonance imaging. It kind of came about in the 1970s and 1980s. And previous animal models have looked at how it is essentially an intracellular contrast agent. And what I mean by that is manganese is a calcium analog and therefore, in cells where they are viable and there's intact cell function, they will be taken up through a voltage gated calcium channels. So, for example, in the heart. So the theory is that manganese, when you've got normal viability, manganese is taken up into the myocardium via voltage gate calcium channels. And several studies have shown that if you then have disease myocardium, these tissues do not take up the manganese as normal tissue would. And the main difference between manganese and gadolinium is they are both paramagnetic, which is why they're helpful and useful in MRI. But gadolinium, as a compound, is too big and it cannot cross an intact cell membrane and therefore, gadolinium is more extracellular. And as, we know, accumulates in tissues where there is increased edema, or water content. So gadolinium, for all intents and purposes, is incredibly useful contrast agent, certainly what we use predominantly at the moment in clinical practice, but it is extracellular. So the theory behind manganese is that it is an intracellular contrast agent as opposed to gadolinium. And where gadolinium accumulates in disease tissue, manganese accumulates in viable tissue. So they behave almost kind of in contrast to each other. And currently, manganese is not used in clinical practice. I think the only clinical compound contrast agent utilizing manganese was mangafodipir, otherwise known as Teslascan, which I believe came off the market in 2012 and that was predominantly used for imaging liver metastasis. Dr. Greg Hundley: Well Trisha, thank you for clarifying for us the difference between manganese, the intracellular contrast agent, and gadolinium, the extracellular contrast agent, that's so widely used clinically. Well, with that description, can you describe for us now, your study population and your study design? Dr. Trisha Singh: Perfect. So the study population was we aimed to recruit 20 patients with acute Takotsubo syndrome. The diagnosis of Takotsubo syndrome was based on a clinical diagnosis, so all our patients underwent a baseline echocardiography and invasive coronary angiography. Now, for us, the coronary angiography was quite important because we wanted to ensure we ruled out anyone with an acute myocardial infarction, which can often be tricky in this cohort of patients. So after recruiting 20 patients during the acute phase of Takotsubo, they all underwent a baseline gadolinium enhanced MRI scan followed by a manganese enhanced MRI scan. And these were done at least 48 hours a part. And then about three months roughly after the acute index, they were all invited to participate in a second manganese enhanced MRI scan. Dr. Greg Hundley: Very good. So two exams separated longitudinally over time. What were your study results? Dr. Trisha Singh: Our results demonstrated that during the acute phase as one would expect, patients had a degree of left ventricular dysfunction. The majority of our patients had afibrillar Takotsubo, so had afibrillar ballooning with preservation of the basal segments. With this, we also noted that in the areas that were affected by Takotsubo, so kind of the mid ventricular wall and the apex that all patients had significantly elevated native T1 and associated T2 as well. And as we expected there was reduced uptake of manganese and therefore kind of reduced calcium uptake in the myocardium in the area affected by Takotsubo syndrome. Interesting, what we also noticed was that all these patients had significantly elevated LV mass, which has been described in previous Takotsubo papers, certainly by Professor Dawson. And when you measured the left ventricular wall thickness, the LV wall thickness is elevated in the affected and actually not even in the non-affected areas, which I suspect explains why in the acute phase people almost doubles up which kind I guess fit with kind of acute myocardial edema and intense water content. And then, three months later when these patients returned for their follow-up scan, a lot of the acute changes had resolved. So native T2 values had improved and gone back to baseline. Native T1 and post contrast T1 values had remained elevated compared to the control population. And what we found was that manganese uptake, though it had improved, it still remained abnormal and reduced compared to the control population, which is a finding that we weren't expecting to find. Dr. Greg Hundley: Very interesting. So acutely we've got extracellular water there, elevation of myocardial T2, and also impaired manganese uptake. So intracellular abnormalities with calcium handling. Then later, so three months later, we have restoration of myocardial T2 so the extra water content is absent, but we have impaired manganese uptake indicating an abnormality with calcium handling. So how do we put this all together mechanistically? What does this tell us about the pathophysiology of Takotsubo syndrome? Dr. Trisha Singh: For one thing, I think we can say that there is, as described before, there is obviously intense myocardial edema present in patients with acute Takotsubo. And I think the significant elevation in T2 and LV mass kind of all fits together. Actually interestingly, as native T2 improves in their follow-up scans, the LV mass actually all return back to normal baseline. So I think the acute edema does resolve. And as you said, interestingly, despite all of these patients, their LV function completely recover. And despite that their myocardial calcium uptake, or handling remain normal. And I think that's not been demonstrated before. And I think it just points to that there is obviously, still something going on in the myocardium and it's not behaving completely normally despite completely normal kind of gross LV function. And potentially, this might point in the direction of why these patients have ongoing symptoms. So, certainly, from our observational cohort group, about 70% of patients had ongoing symptoms and this was predominantly breathlessness and palpitations. And potentially, might be related to why patients have worse outcomes compared to the general population. Dr. Greg Hundley: Very nice. And Trisha, can you describe, was there a therapeutic intervention between the acute and then the three month later measurements? Were these patients administered any type of medical therapy and were there differences in what those therapies may have been between different patients in your study? Dr. Trisha Singh: So predominantly, most of the patient population that were started on some combination of heart treatment due to the baseline LV dysfunction. And this kind of was a combination of most of them were on Ramipril, a few of them were also on spironolactone or eplerenone. And then, every single one was on furosemide. And interestingly, I mean I appreciate, I think the population group was quite small, so it's very difficult to compare those that were on kind of full heart failure treatment versus those who were just on beta blocker and ramipril therapy. But even in that cohort there was a split of about, I think predominantly, I think 17, 16 patients were on kind just beta blockers and ramipril as opposed to beta blocker, ramipril, spironolactone. And there was no difference kind of in the recovery in manganese uptake in that cohort. But, again, the numbers are quite small, so I think it's difficult to extrapolate any kind of true meaning in that. Of course, we know there's a lack of randomized control trial data looking at how to best treat patients with acute Takotsubo syndrome and certainly, what treatment may prevent these patients from having a recurrence of Takotsubo. And I know some of the TACA registry data has looked at actually despite the fact patients of being on beta blocker, or ramipril therapy, they still go having recurrence of Takotsubo and certainly of our cohort, one of our patients went on having a recurrent episode of Takotsubo within a year of her index event and she was on aspirin, beta blocker, spironolactone as well. Dr. Greg Hundley: Very nice. And then lastly, when you made these measurements looking at the manganese uptake or lack thereof, were these in the regions of myocardium where you mentioned many had apical LV wall motion abnormalities, were they in those regions or did you also measure regions remote to where the wall motion abnormality occurred? Dr. Trisha Singh: Of course. So we took measurements in the affected regions of the heart that kind of demonstrated spironolactone syndrome. And we also took measurements in kind of, so to speak, the remote segments of the heart. Now, for the remote segments of the heart, we could only measure native T1 and post contrast T1 at 30 minutes and to measure manganese uptake well, unfortunately, what we have to do is take a measurement over time, so we'd do every two and a half minutes for 30 minutes after the manganese contrast. So we weren't able to calculate manganese uptake in the remote regions. But what we could do was measure the native T1 in the remote region, and then the post contrast T1 and see how it differed with the region of interest in the affected portion of the heart, so to speak. Dr. Greg Hundley: Very good. Well, Trisha, with this really exciting research and very nice methodology, what do you see as the next study to be performed in patients with Takotsubo? Dr. Trisha Singh: So I think, in terms of manganese enhanced imaging, I think it'd be really interesting to re-scan these patients at one year or at two years. And the question there is whether or not their manganese uptake ever recovers really. I know we previously talked about this and thought about whether or not these patients who go onto developing Takotsubo syndrome might actually have a kind of an underlying cardiomyopathy that puts them at risk of developing Takotsubo with stress. So it'd be interesting to see whether or not actually their calcium uptake ever recovers in the long-term, or whether actually they have more of a chronic heart failure type like picture. And I think another area of interest would be to see potentially using manganese imaging as a noninvasive measure of kind of myocardial calcium activity and to see whether or there's any changes with therapy over the course of months to years or so. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Trisha Singh from University of Edinburgh in Edinburgh, Scotland for bringing us this really interesting article in patients with Takotsubo syndrome demonstrating that there is a marked perturbation of myocardial manganese uptake, which is most evident in the acute phase of Takotsubo presentation, but also persists for at least three months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema. All of this suggesting that abnormal myocardial calcium handling may be implicated in the pathophysiology of Takotsubo syndrome. Well, on behalf of Carolyn and myself, we want to wish you a great week. And we will catch you next week on the run. This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, please visit ajjournals.org.

Featuring an interview with Dr Brady Stein, including the following topics: Case: A man in his late 70s with myelofibrosis (MF) presenting with fatigue and night sweats (0:00) Incidence and severity of fatigue and other symptoms; use of symptom scales to measure severity (3:43) Rapidity of symptom response to ruxolitinib; emerging data with momelotinib (7:34) Novel therapeutic targets for MF: BET, PI3K and BCL2 (13:25) Available data on JAK inhibitors for essential thrombocytosis and polycythemia vera; pathogenesis of pruritus and optimal management (20:31) Clinical pearls on managing splenomegaly, weight loss and other MF symptoms (26:34) Risks of localized therapy for splenomegaly; splenic progression among patients receiving ruxolitinib (30:14) Prevention and management of withdrawal rebound from ruxolitinib; factors to consider in choosing JAK inhibitors for different risk groups (34:17) Myths and misperceptions about MF among community general oncologists (38:26) Management algorithms for transplant-eligible and transplant-ineligible patients (44:32) Current understanding of MF pathophysiology; end-of-life care for patients with MF (50:13) CME information and select publications

Dr. Ya-Jen Chiu from the Department of Life Science at National Taiwan Normal University in Taipei, discusses a research paper she co-authored that was published by Aging (Aging-US) in Volume 14, Issue 18, entitled, “Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity.” DOI - https://doi.org/10.18632/aging.204306 Corresponding authors - Chiung-Mei Chen - cmchen@cgmh.org.tw, Ying-Chieh Sun - sun@ntnu.edu.tw, Guey-Jen Lee-Chen - t43019@ntnu.edu.tw Video - https://www.youtube.com/watch?v=1rT96K9VeZw Transcript - https://aging-us.net/2022/11/01/behind-the-study-novel-trkb-agonists-activate-trkb-and-downstream-erk-and-akt-signaling/ Abstract Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer's disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood-brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204306 Keywords - aging, Alzheimer's disease, TRKB agonists, Aβ, neuroprotection, therapeutics About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus​ LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

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.

Dr. Sullivan is co-founder and CEO of Vanqua. In addition, he has been a Venture Partner with Orbimed since January 2019. Previously, he was the Vice President of Research at Abbvie where he was responsible for the company's research efforts in a variety of therapeutic/disease areas including oncology, immunology, neurology, hepatitis C and cystic fibrosis. Jim has advanced more than 100 compounds into clinical development across a number of disease states and technology platforms. These include products on the market for HCV (Mavyret and Viekira), the first-in-class Bcl2 selective inhibitor, Venclexta, for hematological cancers, a new oral agent for patients with rheumatoid arthritis, RINVOQ, and multiple compounds currently in Phase II or III clinical trials. He has authored/co-authored more than 130 scientific publications and is an inventor on 11 patents. Jim is an adjunct faculty member at Northwestern University and serves on the board of several companies and foundations including Regis Technologies, Genomics Medicine Ireland, Genuity Science, MATTER Healthcare Incubator, Chicago Biotechnology Accelerator and the Pistoia Alliance. He earned his bachelor's degree and Ph.D. in biochemistry from Trinity College Dublin and conducted post-doctoral research in neurobiology at Northwestern University.

Acute myeloid leukemia (AML) is a cancer of the blood that begins in the bone marrow and progresses quickly if left untreated. AML can occur both in adults and children and is often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT is a procedure that replaces stem cells that were damaged or destroyed after radiation and/or chemotherapy treatment with stem cells from healthy donors. While allo-HSCT provides a high rate of curability in AML patients, the success of this procedure is partially dependent on the efficacy of pre-transplant treatment regimens. Researchers have identified an urgent need to determine new therapeutic approaches that provide better cytotoxicity in AML cells, without jeopardizing patient safety. To improve AML patient outcomes after allo-HSCT, researchers from the University of Texas MD Anderson Cancer Center and the University of Alberta's Cross Cancer Institute conducted a new study investigating the combinations of the BCL-inhibitor ABT199/venetoclax with two alkylating agents and a nucleoside analog. Their trending research paper was published by Oncotarget on February 10, 2022, and entitled, “ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.” “One such candidate drug is ABT199/venetoclax, a BH3-mimetic small molecule that binds to and inhibits the anti-apoptotic B-cell lymphoma 2 (BCL2) protein, preferentially causing malignant cells to undergo apoptosis.” Full blog - https://www.oncotarget.org/2022/02/17/trending-with-impact-new-pre-transplant-aml-treatment-combinations/ DOI - https://doi.org/10.18632/oncotarget.28193 Correspondence to - Benigno C. Valdez - bvaldez@mdanderson.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28193 Keywords - ABT199/venetoclax, busulfan, cyclophosphamide, fludarabine, acute myeloid leukemia About Oncotarget Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC: https://www.ImpactJournals.com Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

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.

RotoWire's Chris Liss and Yahoo Sports' Dalton Del Don talk easy Week 4 survivor, Urban Meyer, Danny Bitcoin, Saquon Barkley, Derrick Henry, BCL1, BCL2, Kyle Pitts, Cordarrelle Patterson, Liss' wine trip, Week 5 Supercontest, trip to the US via private jet, airport police state, Jalen Hurts, Joe Burrow, Kyle Shanahan, Trey Lance, Jimmy G, DDD's huge MLB season, DDD's bets, Phil Dussault overshadowing DDD, Chloe's running, Andrew Wiggins and increasing violations of civil liberties. Learn more about your ad choices. Visit podcastchoices.com/adchoices

Venetoclax in combination with FLAG-IDA chemotherapy shows safety and promising efficacy in both untreated and relapsed/refractory AML in this phase 1b/2 study, providing a strong rationale for phase 3 trials incorporating this agent in patients fit for intensive therapy.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia” by DiNardo et al. My name is Richard Dillon, and I am a Clinical Senior Lecturer in Cancer Genetics at King's College London and Consultant Hematologist at Guy's Hospital, London, UK. My oncologic specialty is Adult Acute Myeloid Leukaemia. I'd like to note that my institution receives research funding support from Abbvie.   The recently published VIALE-A and VIALE-C trials demonstrated significant efficacy of venetoclax when added to low dose chemotherapy in patients with newly diagnosed AML who cannot receive intensive chemotherapy due to their age or comorbidities. Venetoclax has now become the standard of care for these patients, and there is growing interest in investigating how the potent anti-leukemic efficacy of this agent can be exploited in younger patients, who are fit to receive intensive treatment with curative intent. To date, only a small number of studies have addressed this important question.   In the front-line setting, a phase 1b study performed in Australia by Chua and colleagues tested the addition of 14 days of venetoclax to a regimen consisting of 7 days of infusional cytarabine and two doses of idarubicin for patients aged over 65 with previously untreated AML. This was well tolerated, and the overall response rate was 72%: 97% in patients with de-novo and 43% in patients with secondary AML.   Karol and colleagues from St. Jude's Children's Hospital performed a phase 1 study testing the combination of 28 days of venetoclax with varying doses of cytarabine and idarubicin in children with relapsed or refractory AML. At the recommended phase 2 dose, which was 600mg of venetoclax and eight doses of 1000mg per square meter cytarabine, with or without idarubicin, the overall response rate was 70%. Importantly, for children who received a lower dose of cytarabine (20 doses of 100mg per meter square), the response rate was markedly lower at 33%.   In the study referred to in this podcast, DiNardo and colleagues combined venetoclax with the FLAG-IDA regimen. FLAG-IDA is an intensive chemotherapy schedule incorporating high-dose cytarabine, typically used for patients with refractory or relapsed AML. And in this setting, overall response rates between 50 and 60% have been reported. FLAG-IDA has also been used in patients with newly diagnosed AML—for example, in the UK NCRI AML15 study, where the overall response rate was 86% and 5-year overall survival was 44%.   The current study comprised a phase 1b dose escalation in patients with relapsed or refractory disease, followed by a phase 2 dose expansion in both newly diagnosed and relapsed or refractory patient cohorts. In total, 68 patients were treated with the venetoclax FLAG-IDA combination. As expected, this combination was severely myelosuppressive, and during the dose-escalation phase, a number of alterations were made to the schedule to mitigate this toxicity, including reductions in the cytarabine dose to 1.5g per meter square and the length of venetoclax treatment to two weeks in induction and one week in consolidation. With these modifications, hematological toxicity at the recommended phase 2 dose was manageable. The time to count recovery was 31 days for previously untreated patients and 37 days for patients with relapsed or refractory disease and was not prolonged in patients who had undergone previous allogeneic stem cell transplantation. Haematological toxicity was more severe in the second cycle of treatment with 59% of patients experiencing delayed count recovery beyond day 45. Nevertheless, day 60 mortality was low at 4.4%.   The response rates observed in this study were impressive. At the recommended phase 2 dose, 97% of newly diagnosed and 70% of relapsed or refractory patients had achieved a composite complete remission, which included CR, CRi and CR with partial hematological recovery, CRh. CR or CRi was achieved in 72% and 48%, and MRD negativity by flow cytometry was achieved in 89% and 48% of patients with newly diagnosed and relapsed or refractory disease, respectively.   Although the number of patients was too small to reliably identify molecular and cytogenetic groups with a differential response, patients with relapsed or refractory AML with genotypes previously reported to be particularly sensitive to venetoclax containing regimens, which are NPM1, IDH1 and IDH2, appeared to have a particularly high rate of response with a composite CR rate of 100% and 12-month overall survival rate of 83%. In addition, the 7 patients with MLL rearrangements appeared to do particularly well, with a composite CR rate of 100% and 80% of patients testing negative for MLL fusion transcripts by PCR. One-year overall survival in this group was 80%, possibly highlighting MLL-rearranged leukemias as an additional group with particular sensitivity to BCL2 inhibition. This signal was not apparent in earlier trials using low doses of chemotherapy, perhaps because MLL rearrangements are much less frequent in older adults, or alternatively perhaps because this lesion requires higher doses of chemotherapy to synergise with BCL2 inhibition to overcome the apoptotic threshold.   On the other hand, there appeared to be some groups with less favorable responses. Patients with core-binding factor leukemias appeared to do less well than expected, with a median overall survival time of 7.6 months. Patients with these leukemias were excluded from the earlier phase 2 and 3 studies of venetoclax, so there is no prior clinical data regarding their sensitivity to BCL2 inhibition; however, this finding does concur with in vitro data suggesting a lack of sensitivity.   The outcomes for patients with TP53 mutations were disappointing with a median overall survival time of 9 months for newly diagnosed and 7 months for relapsed patients. Interestingly, even in the four TP53-mutated patients who tested MRD negative by flow cytometry, the TP53 mutation was still detectable by next-generation sequencing after treatment. The number of patients in these groups were small and will require confirmation in larger studies; however, alternative treatment strategies might be required for these patients.   Overall, these results appear extremely promising and suggest that venetoclax may have significant activity when used with intensive induction or salvage chemotherapy schedules in younger adults. This now needs to be confirmed in randomized trials comparing intensive chemotherapy with and without venetoclax in both the front-line and salvage settings. If these trials are positive, further comparative studies will be needed to define the best chemotherapy schedule to combine with venetoclax. While limited data indicate that standard doses of cytarabine are likely inadequate, the optimal dose of cytarabine, and the additional value of fludarabine and anthracyclines remains to be defined. Nevertheless, the study by DiNardo and colleagues represents a significant step forward in the deployment of venetoclax in young fit adults, with the hope that this will increase the rate of long-term cures from this aggressive and frequently fatal hematological malignancy.   This concludes this JCO Podcast. Thank you for listening.

Listen to the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 9. View the complete issue: https://www.oncotarget.com/archive/v12/i9/ Oncotarget Volume 12, Issue 9 features: COVER PAPER: “Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore” https://doi.org/10.18632/oncotarget.27933 EDITORIAL: “Is there a role for CDK 4/6 inhibitors in breast cancer brain metastases?” https://doi.org/10.18632/oncotarget.27904 (PDF Download) EDITORIAL: “Epigenetic effects of pharmacologic ascorbate” https://doi.org/10.18632/oncotarget.27911 (PDF Download) RESEARCH PAPER: “Activation of plasmacytoid dendritic cells promotes AML-cell fratricide” https://doi.org/10.18632/oncotarget.27949 RESEARCH PAPER: “Piperlongumine promotes death of retinoblastoma cancer cells” https://doi.org/10.18632/oncotarget.27947 RESEARCH PAPER: “A higher De Ritis ratio (AST/ALT) is a risk factor for progression in high-risk non-muscle invasive bladder cancer” https://doi.org/10.18632/oncotarget.27944 RESEARCH PAPER: “Down regulation of lactate dehydrogenase initiates apoptosis in HeLa and MCF-7 cancer cells through increased voltage-dependent anion channel protein and inhibition of BCL2” https://doi.org/10.18632/oncotarget.27950 REVIEW: “Multigene tests for breast cancer: the physician’s perspective” https://doi.org/10.18632/oncotarget.27948 Keywords - breast cancer, bladder cancer, glioblastoma, plasmacytoid dendritic cells, pharmacologic ascorbate, retinoblastoma, cancer cells, cancer, science, research, oncology About Oncotarget Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com/ or connect with: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget LinkedIn - https://www.linkedin.com/company/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/oncotargetyoutube Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget Oncotarget is published by Impact Journals, LLC. Please visit https://www.impactjournals.com/ or connect with @ImpactJrnls Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

In this week’s episode, we consider the role of MYC and BCL2 copy number variants in double-hit diffuse large B-cell lymphoma, explore megakaryocyte-biased stem cells in JAK2-mutated myeloproliferative neoplasms, and finally, we look at long-term outcomes with emicizumab prophylaxis in patients with hemophilia, which are even better than in the first reports.

Treatments for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) have advanced in recent years, with more new developments on the horizon. James Gerson, MD, of the University of Pennsylvania, Philadelphia, reviewed some of these advances and future directions while describing how he would treat three patients. Host David H. Henry, MD, posed the following cases for consideration. Case 1 In a 75-year-old male with no comorbid illness, routine blood work revealed a WBC count of 15,000/mcL. The manual differential showed mature lymphocytes and smudge cells. The patient has no constitutional symptoms, but there is suspicion of CLL. What to do? An incidental finding of elevated WBC is the most common presentation for CLL, Dr. Gerson noted. Flow cytometry is how most diagnoses are made. If the patient’s blood sample is CD5+ and CD20+, in the vast majority of cases, the patient has CLL. The main alternative diagnosis is MCL, so Dr. Gerson recommends checking for cyclin-D1 overexpression and translocation (11;14), which would be present in MCL. Dr. Gerson also recommends fluorescence in situ hybridization (FISH), cytogenetics, and next-generation sequencing to assist with prognostication. When the exam is normal and the patient is asymptomatic, no imaging is required. For this patient, treatment should be deferred until disease progression. Case 2 A 75-year-old, fit male has a WBC of 25,000/mcL, noted after the patient reported not feeling well, having a distended abdomen, night sweats, and weight loss. Blood work shows a hemoglobin level of 10.5 g/dL and a platelet count of 130 x 103/mcL. What to do? Because this patient is symptomatic, treatment is indicated, Dr. Gerson said. However, because of the pandemic, Dr. Gerson would likely delay therapy, perhaps until after COVID-19 vaccination. To assess risk, Dr. Gerson would perform immunohistochemistry, FISH, and next-generation sequencing in this patient. Patients with 17p deletion have high-risk disease, those with TP53 missense or nonsense mutations have even higher-risk disease, and patients with both a deletion and a mutation are “at excessively high risk,” Dr. Gerson said. He favors giving a BTK inhibitor to patients with TP53 mutation/17p deletion because of results from the CLL14 trial (N Engl J Med 2019; 380:2225-36. https://bit.ly/38pVHbf). However, because of the “small signal” in the trial, Dr. Gerson said plenty of his colleagues use a BTK inhibitor interchangeably with a BCL2 inhibitor and anti-CD20 therapy (e.g., venetoclax and obinutuzumab). Dr. Gerson said ibrutinib and acalabrutinib have similar efficacy, according to unpublished results of the ELEVATE-RR trial (https://bit.ly/38onIjy). Both drugs inhibit platelets, and there appears to be a higher risk of atrial fibrillation with ibrutinib. Case 3 A 75-year-old, fit male has an elevated WBC, noted after complaints of bone pain, weight loss, night sweats, and enlarged lymph nodes. There is suspicion of MCL. What to do? MCL is a complicated disease and “incredibly” heterogeneous in clinical and pathological behavior, Dr. Gerson noted. The classic finding in MCL is cyclin-D1 overexpression caused by (11;14) translocation, but there are atypical translocations as well. The approach to first-line treatment of MCL varies and may include cytarabine-based induction, bendamustine plus rituximab, or rituximab alone. Brexucabtagene autoleucel, a chimeric antigen receptor T-cell therapy, is changing the landscape of treatment for relapsed/refractory MCL, Dr. Gerson said, as this treatment may offer a cure. Investigational therapies for MCL include the BTK inhibitor pirtobrutinib (LOXO-305) and hematopoietic stem cell transplant. Pirtobrutinib is under investigation in patients with MCL, CLL, and other indolent lymphomas that have progressed on or are intolerant to first-line therapy (Lancet. 2021 Mar 6;397[10277]:892-901. https://bit.ly/3rvRv1h). Show notes written by Ronak Mistry, DO, a resident at Pennsylvania Hospital, Philadelphia. Disclosures Dr. Gerson disclosed relationships with Loxo Oncology, Genentech, Pharmacyclics, and TG Therapeutics. Dr. Henry has no relevant disclosures. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: Nicole Lamanna, MD The anti-apoptotic protein B-cell lymphoma 2 (BCL2) is a key regulator of the intrinsic apoptotic pathway and is often overexpressed in chronic lymphocytic leukemia (CLL) cells. That’s why BCL2 represents an important therapeutic target for CLL, and joining Dr. Charles Turck to look at Venetoclax, a treatment option that targets this protein is Dr. Nicole Lamanna, an Associate Clinical Professor of Medicine at Columbia University Medical Center in New York.

In this week’s episode, we will review a study that describes how transfer of whole mitochondria from hematopoietic stem cells to bone marrow mesenchymal stem cells helps regenerate the stroma and its capacity to sustain hematopoietic recovery in irradiated mice undergoing stem cell transplant, examine the potential benefit of adding the BCL2-inhibitor, venetoclax, to standard treatment regimens for patients with relapsed or refractory follicular lymphoma, and finally, we will learn more about how NCOA4, the autophagic receptor for ferritin, is necessary for the mobilization of liver iron stores during stress erythropoiesis.

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.

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.

In this episode, Naval G. Daver, MD, discusses promising investigational agents and treatment combinations in clinical trials for patients with newly diagnosed and relapsed/refractory AML, including:FLT3 inhibitors crenolanib and quizartinibAnti-CD47 antibody magrolimabIMGN632, a CD123 antibody–drug conjugateAnti-CD70 antibody cusatuzumabAPR-246, targeting the TP53 mutationContent is part of an online CME program supported by an educational grant from Daiichi-Sankyo.Link to full program, including a ClinicalThought commentary:  https://bit.ly/2Y2uCG2

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.29.226308v1?rss=1 Authors: Joel, I. y., Adigun, T. O., AJIBOLA, A. O., BANKOLE, O. O., OZOJIOFOR, U. O., REMI-ESAN, I. A., SULAIMON, L. A. Abstract: Evading apoptosis is one of the hallmarks of cancer cells, therefore a lot of therapeutic strategies have been developed to induce cell death in these cells. BCL2 family protein governs the intrinsic pathway of cell death. The BCL2 family protein possess both pro and anti-apoptosis members. BCL2 protein, a pioneering member of the anti-apoptosis protein has been implicated in several cancerous cells; with dozens of small-molecule inhibitors developed to inhibit its activity. BCL2 family protein processes BH domains (1-4) for heterodimerization and homodimerization amidst it family members and targeting the BH4 domain is an established new strategy for cancer therapy; however, only BDA366 has been reported so far as a BH4 binding molecule. Using Computer-aided drug discovery techniques (Molecular docking, QM-polarized docking, Induced-fit docking, QM-MM optimization, and QM electronic descriptors) we screened M sample (~ 99,000 compounds) of the SCUBIDOO database to find ligands that interact with the BH4 domain of BCL2 protein with high affinity, we identified 11 putative BH4 specific small molecules with binding affinity ranging from ~ -84kcal/mol to -64kcal/mol with a putative binding hypothesis with BH4 amino acid residues: ASP10, ARG12, GLU13, MET16, LYS17, and HIS20 Copy rights belong to original authors. Visit the link for more info

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.

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  

Prof Cools speaks with ecancer about the molecular pathways through which early T precursor ALL may be treated. He describes the origin of ETP-ALL and cell surface markers which characterise its near-stemness, and introduces mutations which drive tumourigenesis. These include JAK-STAT, IL7 and BCL2 pathways, and Prof Cools introduces XPO1, an organelle shuttling protein, which may also be a useful target for treating HIV.

Prof Stilgenbauer talks to ecancertv at ASH 2015 about the results of an international multicentre phase II study that evaluated the use of the anti-Bcl2-targeting therapy venetoclax as monotherapy in patients with very high-risk relapsed or refractory chronic lymphocytic leukaemia (CLL). All of the 107 patients that participated in the trial had CLL with the 17p deletion which is known to confer a worse prognosis than if the deletion is not present. The overall response rate to venetoclax monotherapy was 79.4% and the first-in-class agent induced deep remissions, including complete remission and undetectable minimal residual disease, to a degree that has been unheard of before now, Prof Stilgenbauer says in the interview. He notes that venetoclax was very well tolerated but that its use needs careful handling as it induces remission very rapidly.

Dr Kumar talks to ecancertv at ASH 2015 about the potential use of the oral Bcl-2 inhibitor venetoclax in patients with relapsed or refractory multiple myeloma. In the interview he notes that venetoclax has been studied in clinical trials in chronic lymphocytic leukaemia (CLL) but there is evidence to show that the Bcl-2 protein that it targets is also expressed by myeloma cells. Dr Kumar talks about two studies presented at the meeting investigating the use of venetoclax in patients with relapsed/refractory multiple myeloma. The first, a phase I/II study involving 37 patients, aimed to test the safety and find the best dose of the drug to use as monotherapy. The second, a phase Ib involving 41 patients, looking at using venetoclax in combination with bortezomib and dexamethasone. Preliminary results of these trials suggest that venetoclax had a tolerable safety profile with no new safety signals. They also suggest the drug has potential single agent activity and might work well in combination with bortezomib and dexamethasone.

From the Vector-Borne Viruses Symposium in Hamilton, Montana, Dickson and Vincent speak with Diane Griffin about her career and her work on understanding viral infections of the central nervous system. Hosts: Vincent Racaniello and Dickson Despommier Guest: Diane Griffin   Become a patron of TWiV! Links for this episode Vector-Borne Viruses Symposium Diane Griffin Adoptive immunization of immunosuppressed mice infected with Sindbis virus Role of the immune response in age-dependent resistance of mice to encephalitis due to Sindbis virus Antibody-mediated clearance of alphavirus infection from neurons Persistence of viral RNA in mouse brains after recovery from acute alphavirus encephalitis Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene Bc1-2 protects mice against fatal alphavirus encephalitis This episode is brought to you by Blue Apron. Blue Apron is the #1 fresh ingredient and recipe delivery service in the country. See what’s on the menu this week and get 3 meals free with your first purchase – WITH FREE SHIPPING – by going to blueapron.com/twiv. Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Thu, 10 Dec 2015 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/19090/ https://edoc.ub.uni-muenchen.de/19090/7/Laseur_Christine.pdf Laseur, Christine

This podcast summarizes and places in clinical context two studies describing straightforward immunohistochemical methods to risk-stratify diffuse large B-cell lymphoma.

Monomeric actin controls the activity of the transcription factor Serum Response Factor (SRF) via its coactivator MAL/MRTF-A. Upon signal induction, MAL is released from actin, binds SRF and activates target gene expression. In order to characterise the physiological role of this signalling pathway, I screened on a genome wide basis for target genes by transcriptome analysis. A combination of actin binding drugs (Cytochalasin D and Latrunculin B), targeting monomeric actin, was used to specifically and differentially interfere with the complex between MAL and actin. 210 genes primarily controlled by monomeric actin were identified in mouse fibroblasts. Among them more than 30% have been already found in screens for SRF target genes, supporting the validity of the screening approach. As expected, a lot of genes were involved in cytoskeleton organization. However, genes having anti-proliferative or pro-apoptotic features were identified surprisingly to the same extent. Consistently, I could demonstrate an antiproliferative function of MAL. More specifically, several genes interfering with the MAPK pathway were identified. One of them was Mig6/Errfi1, a negative regulator of EGF receptors. Mig6 induction by LPA or FCS revealed to be dependent on MAL, monomeric actin and the small GTPases Rho. Activated forms of MAL or SRF were sufficient to induce Mig6 expression. Subsequently, a Mig6 promoter element was found to be necessary to mediate MAL/SRF induction. Moreover, induction of Mig6 through the Actin-MAL pathway led to the downregulation of the mitogenic EGFR-MAP kinase cascade. For the first time a transcriptional link between G-actin levels sensed by MAL and the regulation of EGFR signalling was established. Furthermore, after having demonstrated that MAL induces apoptosis, I focused on the characterisation of two proapototic targets identified in the screen: Bok and Noxa. Bok and Noxa were induced by activators of the Rho-Actin-Mal-Srf pathway on a MAL dependent manner. The study of the Bok promoter revealed the existence of a response element that was necessary for the induction by MAL-SRF. Interestingly, apoptotic inducers like staurosporine, TNFα, or the DNA damaging agent Doxorubicin triggered MAL-SRF mediated transcription. As SRF controls the expression of the anti-apoptotic genes Bcl2 and Mcl1, the results from this work places thus SRF as a key transcription factor controlling the balance between pro and anti apoptotic genes in response to external cues.

During my PhD thesis I was working on the identification of novel apoptosis-inducing genes by using a novel genetic expression screen (Grimm and Leder, 1997). One of the identified genes turned out to be a evolutionary conserved cDNA that codes for a novel BH3-only protein of 219 amino acid residues which was named Spike, for Small protein with inherent killing effect. Spike was then in the course of my PhD thesis extensively characterised, molecularly and biochemically. In summary, upon overexpression in mammalian cells Spike efficiently leads to all features of apoptosis, such as phenotypic alterations, cytochrome c release, caspase activation and DNA degradation. It was shown that Spike localised to the endoplasmic reticulum, where it interacts with a recently identified apoptosis regulating protein complex, consisting of Bap31, Bcl-2, Bcl-XL and an ER-specific isoform of caspase-8: pro-caspase 8L (Breckenridge et al. 2002). Although no direct interaction with anti-apoptotic members of the Bcl2-family could be observed, the importance of the BH3-like sequence for the apoptosis-inducing activity of Spike was demonstrated by using point mutations of conserved amino acid residues of this motif (Mund et al. 2003). Instead of directly interacting with anti-apoptotic members of the Bcl-2 family Spike is able to interfere with the complex formation between Bap31 and Bcl-XL. Based on these data I proposed a model according to which the complex on Bap31 is controlled by Bcl-2/Bcl-XL as long as they are associated. Displacement of Bcl-2/Bcl-XL from Bap31 by Spike leads to the formation of a pro-apoptotic complex. In addition, Spike appears to be implicated in the cell death signal of the Fas receptor. I observed that a dominant-negative version of Spike and a highly effective anti-sense oligonucleotide significantly reduced Fas-mediated DNA fragmentation whereas no reduction was detected in TNFa-induced cell death (Mund et al. 2003).