Special Issue

© Springer-Verlag 2021 www.memoinoncology.com www.memoinoncology.com 01/21 memo – inHaematology SPECIAL ISSUE Congress Report ASH 2020 A GLOBAL CONGRESS DIGEST ON TARGETED THERAPIES IN B-CELL MALIGNANCIES Report from the virtual American Society of Hematology (ASH) Annual Meeting, December 5–8, 2020 IMPRESSUM/PUBLISHER Media owner and publisher: Springer-Verlag GmbH, Professional Media, Prinz-Eugen-Straße 8–10, 1040 Vienna, Austria, Tel.: +43(0)1/330 24 15-0, Fax: +43(0)1/330 24 26, Internet: www.springernature.com, www.SpringerMedizin.at. Copyright: © 2021 Springer-Verlag GmbH Austria. Springer Medizin is a Part of Springer Nature. Managing Directors: Joachim Krieger, Juliane Ritt, Dr. Alois Sillaber. Medical Writer: Judith Moser, MD. Corporate Publishing: Elise Haidenthaller. Editorial Support: Anna Fenzl, PhD. Layout: Katharina Bruckner. Published in: Vienna. The editors of “memo, magazine of european medical oncology” assume no responsibility for this supplement. 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ASH 2020 special issue Table of Contents 3 Preface 3 What is new in Waldenström’s macroglobulinemia? 5 Management of CLL patients: BTK inhibition and beyond 12 Insights from early clinical trials on targeted treatment in B-cell malignancies 14 Approaching marginal zone lymphoma from various angles 16 Advancing treatment in patients with mantle cell lymphoma 19 Interview: Finding the way among a multitude of targets and regimens 20 PD-1 inhibition and (Non-)Hodgkin lymphoma: promising outcomes in an emerging field 22 Bone marrow microenvironment: culprit and target © ipopba / Getty Images iStock Editorial Board: Heinz Ludwig, MD, Wilhelminen Hospital, Vienna, Austria Shirley D’Sa, MD, University College London Hospital, London, UK Lecture Board for this issue: Paul Barr, MD, University of Rochester, Rochester, NY, USA Jorge J. Castillo, MD, Dana-Farber Cancer Institute, Boston, USA Chan Cheah, MBBS, University of Western, Perth, Australia Paolo Ghia, MD, PhD, University of Torino, Torino, Italy Preetesh Jain, MD, PhD, University of Texas, Texas, USA Stephen Opat, MD, Monash University, Monash, Australia Kerry Rogers, MD, Ohio State University, Ohio, USA Kerry Savage, MD, BSC, University of British Columbia Biology, Vancouver, Canada Alessandra Tedeschi, MD, Niguarda Cancer Center, Milan, Italy Stefan Vogt, MD, Department of Oncological Rehabilitation, Bad Erlach, Austria Supported by BeiGene Ltd. in the form of an unrestricted grant 2 1/2021 © Springer-Verlag memo special issue ASH 2020 chronic lymphocytic leukemia, marginal Preface zone lymphoma, and mantle cell lymphoma. Later-generation BTK Dear Colleagues, inhibitors designed to achieve optimized selectivity offer advantages with respect The ASH Annual Meeting and to tolerability and efficacy compared to Exposition is the premier event for first-generation BTK inhibition. Benefits presentation of novel data on malignant have been observed with these agents and non-malignant hematologic irrespective of factors such as pre- diseases, attracting up to 30,000 treatment or cytogenetic risk. specialists from all over the world. The Progress is also ongoing regarding 62nd ASH Annual Meeting was planned other drug classes such as PI3Kδ Fotostudio Wilke to be held on December 5–8, 2020 in inhibitors and anti-CD20 antibodies that © San Diego, California, but due to the complement the armamentarium COVID-19 pandemic had been trans- available for the treatment of various in the field of hematologic diseases formed to an all-virtual event. Attendees B-cell malignancies. Immune checkpoint enables the assessment of new regimens had access to thousands of scientific inhibition might also play a role in the that might represent a major step abstracts highlighting cutting-edge future, although a variety of inhibitory forward in terms of patient life research in hematology. This publi- receptors apart from PD-1 and PD-L1 are expectancy and quality of life. cation summarizes work presented in still awaiting investigation in terms of the field of B-cell malignancies with a their clinical usefulness as targets for Heinz Ludwig, MD focus on targeted therapies. drug therapy. Director of the Wilhelminen Inhibition of the Bruton’s tyrosine ki- Naturally, combinations are a major Cancer Research Institute nase (BTK) has been implemented as a area of research given the importance of Department of Medicine I, mainstay of treatment in various types achieving deep remission that allows for Center for Oncology, Hematology of hematologic malignancies, including long-lasting disease-free survival. The and Palliative Care Waldenström’s macroglobulinemia, wide range of drugs already established Wilhelminen Hospital, Vienna, Austria What is new in Waldenström’s macroglobulinemia? Constitutive activation of the Bruton’s rituximab in WM patients who were ibrutinib, as 32 enrolled in a treatment tyrosine kinase (BTK) pathway has been either treatment-naïve or pretreated; the extension program and 36 continued to shown to induce malignant cell survival latter had to be rituximab-sensitive (i.e., receive ibrutinib in a commercial in patients with Waldenström’s not refractory to the last prior rituximab- setting. macroglobulinemia (WM) [1, 2]. The based therapy and no treatment with Even 5 years after the initiation of the disease is based on the accumulation of rituximab within the last 12 months trial, median progression-free survival IgM-secreting clonal lymphoplas macy- before the first study dose). Each arm (PFS) had not been reached in the tic cells in the bone marrow and included 75 individuals. After a median experimental arm. Compared to the extramedullary sites [3]. MYD88L265P follow-up of 26.5 months, the primary median PFS of 20.3 months observed mutations (> 90 % of cases) and analysis of iNNOVATE demonstrated with placebo plus rituximab, this CXCR4WHIM-like mutations (approxi- superiority of the combination over translated into a 75 % risk reduction mately 27 % of cases) have been rituximab monotherapy [7]. These data (HR, 0.25; p < 0.0001; Figure). At 54 established as the pathologic hallmarks formed the basis for the approval of months, PFS rates were 68 % vs. 25 %. In of WM [4-6]. ibrutinib plus rituximab in the United both arms, the PFS benefit did not States and Europe. depend on the genotype (i.e., any iNNOVATE: At ASH 2020, Buske et al. reported combinations of MYD88L265P or MYD88 ibrutinib plus rituximab the final analysis of the study after an wildtype and CXCRWHIM or CXCR4 overall follow-up of 63 months [8]. The wildtype). Moreover, ibrutinib plus BTK inhibition with ibrutinib has protocol permitted cross-over to single- rituximab improved PFS irrespective of dramatically changed the treatment agent ibrutinib after disease progression the prior treatment status; in both pre- landscape in WM. The phase III in the control arm. Indeed, 35 (47 %) of treated and not pretreated patients, PFS iNNOVATE study compared ibrutinib these patients crossed over. After study was superior in all prespecified sub- plus rituximab with placebo plus closure, 68 (45 %) remained on groups that received the combination. memo © Springer-Verlag 1/2021 3 ASH 2020 special issue 100 54-month PFS rate: 68 % vs. 25 % 80 Ibrutinib-rituximab 60 40 Placebo-rituxumab Ibrutinib-rituximab Placebo-rituxumab Progression-free survival (%) Progression-free 20 Median PFS, months Not reached 20.3 HR (95 % CI) 0.250 (0.148–0.420) Log-rank p value < 0.0001 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time (months) Figure: Progression-free survival benefit with ibrutinib plus rituximab vs. placebo plus rituximab Rapid and sustained dose reductions and treatment discon- After a median follow-up of 18.6 improvements tinuation became necessary in 5 % each. months, zanubrutinib demonstrated Eighty-eight percent of AEs that led to pronounced and durable efficacy. Responses occurred early on in the ibrutinib dose reductions subsequently Almost 70 % of patients developed experimental arm, with median time to resolved. In their conclusion, the authors MMR, with 32.6 % experiencing very major response amounting to 3 months noted that ibrutinib plus rituximab good partial remission (Table). vs. 6 months in the control arm. Overall, showed ongoing superiority across dif- Responses were achieved quickly; the major response rates were 76 % vs. ferent clinical outcomes in patients with median time to overall response was 31 % for the two arms. The proportion of Waldenström’s macroglobulinemia. 2.76 months. Neither median PFS nor patients experiencing very good partial the median duration of major response responses increased over time with Phase II data for zanubrutinib had been reached yet. At 12 months, ibrutinib plus rituximab. Again, responses 78.3 % of patients were progression-free, were largely independent of the genotype The selective,

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