EHA 2017

Professor McCarthy (Roswell Park Cancer Institute, New York, USA) and Professor Ruiz-Argüelles (Centro de Hematologia y Medicina Interna, Mexico) discuss the latest maintenance strategies in multiple myeloma and how these advances impact the treatment landscape in less developed countries. It is noted that the current standard of care in Mexico after initial therapy is mostly thalidomide and dexamethasone (d) until the patient becomes intolerant to thalidomide at which point they switch to lenalidomide (R). Citing cost as reason for this strategy, Professor Ruiz-Argüelles states how this is an issue for patients in less economically developed countries - amounting to half of the world’s population. Discussing the latest advances from EHA, conversation moves on to new data presented of ixazomib plus Rd followed by maintenance with single agent ixazomib, as well as current trials involving ixazomib. Whilst agreeing this would be a ‘better option’ than thalidomide, cost continues to play a role in treatment decisions, with dosing schedules highlighted as a potential solution to this problem. Clinical trials also represent a route of access to novel treatments, with availability of multinational clinical trials in developing countries being ‘critical’ to increase knowledge in those countries and improve treatment options for patients.

Professor Heinz Ludwig (Wilhelminenspital, Center for Oncology and Hematology, Vienna, Austria) is joined by Professor Wee Joo Chng (National University Cancer Institute, Singapore) and Professor James Chim (Queen Mary Hospital, University of Hong Kong, Hong Kong), to discuss the latest progress in relapsed and refractory multiple myeloma (RRMM). Recent trials investigating combination therapies in RRMM were discussed such as ASPIRE, ENDEAVOUR and TOURMALINE-MM1. Trials such as these have brought about various approvals for new treatments in RRMM, with Professor Chng noting how in Singapore this has led to ‘a lot of choices for physicians and a lot of hope for patients’. However, it is highlighted that challenges remain for physicians over how to use these drugs (due to a lack of head to head comparisons) and for patients over how to access them. Professor Chim confirms this latter point, citing a lack of clinical trial experience and pricing issues in Hong Kong as barriers to patient access. Professor Chng provided detail around the TOURMALINE-MM1 study of the oral proteasome inhibitor ixazomib, which showed superior PFS with ixazomib plus lenalidomide and dexamethasone (Rd) verses Rd. It was noted how similar responses were seen in high-risk patients to standard risk patients, however questions remain over the ease of access for patients to receive this therapy. Finding other suitable combinations could be a potential solution, with Professor Ludwig discussing results of a trial looking at ixazomib plus thalidomide and dexamethasone. The large Chinese extension study has been able to confirm results seen in TOURMALINE-MM1, leading Prof Ludwig to suggest that ixazomib will now be implemented in different protocols. Professor Chim highlights positive results recently seen with daratumumab in the POLLUX study, showing response rates of 90% that could be attributed to an expanded mechanism of action. The importance of immuno-therapy was discussed, with promising new data presented at EHA evaluating the use of pembrolizumab plus Rd in RRMM. The panel then discuss results looking at CAR T-Cell therapy, presented by the Chinese Group at ASCO and EHA and noting how this therapeutic option could ‘potentially be the future’.

Professor Joy Ho (Royal Prince Alfred Hospital, Sydney, Australia) and Professor Je-Jung Lee (Chairman, Korean Multiple Myeloma Working Party) discuss current treatment paradigms in newly diagnosed multiple myeloma (NDMM), recent advances in combination therapy from EHA and the potential impact on clinical practice in countries including Australia and South Korea. Current treatment practices for transplant eligible and transplant ineligible patients were discussed, noting key regional variations to what patients are prescribed. Looking at recent advances in combination therapies presented at EHA, discussion moved on to the long-term follow-up of NDMM patients taking weekly ixazomib, lenalidomide and dexamethasone (Rd) who had not undergone stem cell transplantation (SCT). Professor Lee noted how this study showed ‘impressive results’ with patients who went on to receive maintenance with single-agent ixazomib at the end of the induction period showing an ORR of 100%, including 44% VGPR and 32% CR. It was also noted that safety was ‘acceptable’ and the oral regimen was ‘very compatible for the patient’, especially for the elderly. It was noted that due to clinical trial involvement across Australia and Korea in the relapsed setting, there has been experience with ixazomib. Although data remains immature, Professor Ho suggested that this could provide another option in frontline therapy, however the availability of novel treatments remains an issue. Another study presented at EHA was the UK NCRI Myeloma XI trial comparing, in transplant eligible (TE) patients, the induction quadruplet carfilzomib, cyclophosphamide, lenalidomide and dexamethasone (KCRd) to the sequential strategy of triplet immunomodulatory combinations (with thalidomide or lenalidomide) followed by additional pre-transplant consolidation with PI triplet therapy for those with a suboptimal response.

Dr Cramer speaks with ecancer at EHA 2017 about the results from CLL-BAG, a trial of bendamustine, obinotuzumab and venetoclax for CLL. She describes the patient population in the trial as including relapsed and treatment naïve patients, and outlines the treatment dosage and schedule: debulking with bendamustine before staggered venetoclax and obiniotuzumab to prevent immune exhaustion. Dr Cramer reports a 95% overall response rate, with 87% of patients reaching minimum residual disease, though notes a chance of secondary skin cancers among the adverse events following treatment.

Sarah Liptrott spoke to ecancer at EHA 2017 about patient engagement and advocacy, following her role as co-chair of a conference session on bringing patient perspectives into trial design,

Dr Nastoupil talks with ecancer at EHA 2017 about the phase 1 trial that evaluates the safety/efficacy of the triplet combination of a novel anti-CD20 mAb PI3Kδ BTK inhibitor (ibrutinib) in pts with B-cell malignancies. This is the first known triplet combination of an anti-CD20 mAb PI3Kδ BTK inhibitor. The combination of UTX, TGR-1202, and ibrutinib has been well tolerated with activity observed across heavily pre-treated and high-risk B-cell malignancies.

Dr Gallipoli talks with ecancer at EHA 2017 about his work on FLT3 mutated acute myeloid leukaemia. He discusses how, without sugar, AML relies on glutamine metabolism, mostly channelled towards glutathione production, while also supporting the citric acid cycle, and both these fates contribute to its protective effects following FLT3 TK inhibition by counteracting oxidative damage and sustaining cellular metabolism. Dr Gallipoli highlights how unveiling this pathway may be lead to targets for future therapies

Dr Maddocks speaks with ecancer at EHA 2017 about results from a single-armed phase II trial of combined immunomodulatory lenalidomide with anti-CD19 antibody MOR208 to treat refractory diffuse large B cell lymphoma (DLBCL). She describes the monotherapy successes of both drugs leading to expectations of combined efficacy, with overall responses at a median of 3 months now being reported as 58%, with 27% achieving complete response.

Dr Topp talks to ecancer at EHA 2017 about a randomised phase 3 trial that compares blinatumomab, a bispecific T-cell engager antibody construct and standard of care (SOC) chemotherapy in patients with Philadelphia chromosome−negative relapsed/refractory B-precursor acute lymphoblastic leukaemia. Blinatumomab showed improved overall survival rates in the study, which Dr Topp discussed with ecancer at EHA 2016, and here Dr Topp discusses here how the toxicity profile is consistent with that previously reported for relapsed/refractory acute lymphoblastic leukaemia, including manageable CRS and neurologic events.

Dr Danilov speaks with ecancer at EHA 2017 about a possible driver of resistance to B cell receptor kinases through BAFF-mediated upregulation of Bcl-2. BAFF, a ligand for tumour necrosis factor receptors alongside APRIL, induces NFκB expression, which Dr Danilov places in a pathway which may be blocked by SYK inhibitors. He introduces a possible therapy in entospletinib, and considers what role dual JAK/SYK inhibitor cerdulatinib might play.

Erik Aerts talks with ecancer at EHA 2017 about the need to incorporate all healthcare professionals into nursing care in order to boost patient advocacy. To view and download the learning programme visit the Hemcare website.

Prof Hauer speaks with ecancer at EHA 2017 about results from a mouse model which suggests that infection in childhood following infant development in clean environments may increase the likelihood of developing paediatric leukaemia. She considers how the timing of exposure to an immune challenge may act as this trigger, based on observations of a surge in cases as children entry pre-school, and what further experiments can be done to identify the exact mechanism or pathogen responsible.

Dr Lazo-Langner talks with ecancer at EHA 2017 about weighing the risk of bleeding or clotting in cancer patients after a thrombotic event. Looking at data from almost 7000 patients, he identifies a small risk of bleeding among patients linked to a significant increase in mortality. Dr Lazo-Langner considers the approaches necessary to manage bleeding and clotting risks in geriatric oncology, and the overlap of other common drugs with bleed risks, including NSAIDs.

Dr Atansio speaks with ecancer at EHA 2017 to report on the 4 year review of ibrutinib for CLL in patients who had previously received tyrosine kinase therapy.

Dr Borchmann speaks at an EHA 2017 press session about the German Hodgkin Study Group HD18 trial to establish non-inferiority of PET guided chemotherapy for 4 cycles compared to current 8 week schedules. He describes how, at 5 years, PFS, OS and toxicity profiles all favour the reduced fraction, with only 2 of 500 patients developing a secondary lesion and improved quality of life for many patients. With the 4 cycle regimen proving at least as good as 8 cycles, Dr Borchmann encourages this as the new standard for advanced Hodgkin lymphoma in patients under 60.

Prof Salles presents results at EHA 2017 from a global trial of efficacy and safety for patients with relapsed or refractory DLBCL treated with CTL019 CAR T cells. For patients who had relapsed after two prior therapies and were ineligible for stem cell transplants, Prof Salles describes the reprogrammed T cell regimen as durable response rates among the 43% achieving complete response and 16% reaching partial response.

Dr Lin presents results at an EHA 2017 press session from the ZUMA 1 trial, discussing the clinical and biological outcomes of patients with aggressive, relapsed NHL treated with an engineered T Cell regimen. The T cells, axicabtagene ciloleucel (axi-cel; KTE-C19), were producible for 99% of patients, and caused significant clinical benefit.

Dr Lazo-Langner presents results to a press session at EHA 2017 from a comparative trial to assess the risk of bleeding or clotting events in cancer patients. Treatment with anti-coagulants in a trial group of almost 7000 patients resulted in a significantly higher mortality risk compared to that of thrombotic events. Dr Lazo-Langner cautions against the use of blood thinners in cancer patients over 65, though looks for confirmation in further trials.

Dr Hamlin speaks at a press conference at EHA 2017 about a phase II multicenter trial of a dual SYK/JAK inhibitor cerdulatinib for patients with relapsed CLL, indolent NHL and follicular lymphoma. He identifies an overall response rate of 50% for patients treated with 30mg BID, with some patients receiving a modified dose to reduce adverse events while preserving response.

Dr Kotrova presents results at an EHA 2017 press conference on T cell diversity as a predictor for blinatumomab response. Through next generation sequencing from 140 patients, she highlights differing response rates at 29 days of treatment, though results at day 15 of treatment are not significant enough to predict ongoing response.

Dr Hauer speaks at an EHA 2017 press conference about a mouse model of childhood leukaemia, based on exposure to common infections. For mice engineered to express pre-leukaemic genotype PAX5± and TEL-AML1, infection was found to be an essential trigger for disease progression.

Dr Lin speaks with ecancer at EHA 2017 about clinical and biologic outcomes in patients with refractory aggressive Non-Hodgkin Lymphoma (NHL) treated with CAR T cell therapy. She notes an objective response rate of 82% and a complete response rate well about historic control rates. Dr Lin notes cytokine release syndrome and neurologic events, common to CAR T therapies, were reversible, and that 99% of patients were able to receive the treatment.

Prof Hehlmann speaks with ecancer at EHA 2017 about the 10 year survival data of patients receiving imatinib at 400mg or 800mg, after or in combination with IFN or with AraC. With no significant difference between survival at 10 years for patients on 400mg or 800mg of imatinib, both at 80% and most deaths occurring due to non-disease related reasons, Prof Hehlmann describes life expectancy for patients with CML as "not even living the disease, it is as good as cured". He notes the quicker response to higher doses of imatinib post-diagnosis, but given the non-superiority for long term survival and greater short-term potency of second generation TKIs, Prof Hehlmann finds no reason for the higher dose.

Dr Hamlin speaks with ecancer at EHA 2017 about a novel dual JAK/SYK inhibitor, cerdulatinib. He identifies an overall response rate of 50% across all patients in the trial, with responses up to 67% among those with follicular lymphoma, with manageable toxicity profile that responded to dose reduction without loss of efficacy.

Dr Pawlyn talks to ecancer at EHA 2017 about the the results from the Myeloma XI trial looking at lenalidomide versus thalidomide in combination with cyclophosphamide and dexamethasone. Dr Pawlyn discusses how lenalidomide has fewer side effects than thalidomide, whilst retaining the benefits of oral administration, enabling long-term treatment that has been associated with better disease control.

Dr Montalban-Bravo speaks with ecancer at EHA 2017 about genomic sequencing of over 200 patients at diagnosis, identifying mutational markers which may predict response to hypomethylating agents He describes that mutations in TET family proteins and p53 were among the most common aberrations, and discusses how treatment pathways can be uncovered through sequencing analysis.

Dr Stein speaks with ecancer at EHA 2017 about the results of a phase 1/2 study looking at using enasidenib, an oral, selective, small-molecule inhibitor of mIDH2 proteins, to combat mutant-IDH2 relapsed or refractory acute myeloid leukaemia.

Dr Altman speaks with ecancer at EHA 2017 about AML patients with FLT3 (Fms-like tyrosine kinase 3) mutations treated with gilteritinib, a highly selective FLT3/AXL inhibitor. She describes next generation sequencing of patient samples to identify internal tandem duplications (ITD), which can be gauged against FLT3 expression as a marker of treatment response (ITD ratio). Overall, molecular responses to gilteritinib correlated with clinical response and improved OS, and Dr Altman considers the future clincal prospects for FLT3 treatment in relapsed AML patients.

Prof Terpos speaks with ecancer at EHA 2017 about the comparative trial of denosumab and zoledronic acid for skeletal disease in new multiple myeloma diagnoses. Prof Terpos describes how, from a randomised trial of 1718 patients, the progression to skeletal disease at 15 months was equivalent in both arms, with denosumab meeting its non-inferiority goals. Those receiving denosumab were also found to have reduced renal toxicity, and, in an exploratory assessment, progression free survival was also favourable.

Dr Weisel speaks with ecancer at EHA 2017 about the trial of daratumumab in triplet combinations against standard of care for relapsed/refractory multiple myeloma. After an extended followup, Dr Weisel report s a mPFS of 16.7 months compared to 7.1 months. Patients with only 1 prior treatment were among the best responders, and Dr Weisel notes the recent EMA approval of this combination as a possible course of care for any suitable patients.

Dr Weisel speaks with ecancer at EHA 2017 about the ENDEAVOR trial, a head to head comparison of bortezomib or carfilzomib with dexamethasone in relapsed/refractory multiple myeloma.

Dr Daver talks to ecancer at EHA 2017 about how blocking PD-1/PD-L1 pathways enhances anti-leukaemia responses in murine AML. PD-1 positive CD8 T-cells are increased in bone marrow of patients with AML. Azacytidine up-regulates PD-1 and interferon-gamma signaling in AML and the up-regulation of PD-1 has been associated with emergence of resistance to azacytidine. He states that full dose AZA and nivolumab are tolerable and produce an encouraging response rate with durable responses in relapsed AML with poor risk features.