© 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
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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
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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
to be held on December 5–8, 2020 in inhibitors and anti-CD20 antibodies that © Fotostudio Wilke 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 lymphoplasm acy 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.
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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, irreversible next- and 88.1 % showed ongoing major and prior treatment status. generation BTK inhibitor zanubrutinib responses. The MMR benefit of IgM levels decreased rapidly during has been designed to maximize BTK zanubrutinib was generally consistent the first year of treatment. Maximum occupancy and minimize off-target across subgroups. Treatment-related changes were -33.5 g/L for the inhibition of other kinases [9-11]. A AEs mainly included neutropenia, combination at 56 months and -26.9 g/L pivotal, single-arm, open-label, thrombocytopenia, infections, and for rituximab monotherapy at 57 multicenter phase II trial evaluated diarrhea. The safety and tolerability months. Also, a larger fraction of zanubrutinib 160 mg twice daily until profiles of zanubrutinib corresponded patients treated in the experimental progression in 44 Chinese patients with to those reported previously in WM arm experienced sustained hemoglobin relapsed and refractory WM [12]. They patients. Study drug discontinuation improvement, which was defined as had received ≥ 1 prior line of standard was required in 11.4 %. increases of ≥ 20 g/L (or ≥ 5 g/L if chemotherapy-containing treatment These results have been submitted to baseline levels were ≤ 110 g/L) that and had failed to achieve at least minor the Chinese National Medical Product persisted for ≥ 8 weeks without the need response or had progressed after Administration for approval of of blood transfusions or growth factors. response to the most recent regimen. zanubrutinib in patients with WM. The This was the case for both the total The major response rate (MMR) was European approval in this indication group (77 % vs. 43 %; p < 0.0001) and the defined as the primary endpoint; this based on the phase III ASPEN trial is group with low baseline hemoglobin included complete, partial, and very expected for summer 2021 [13, 14]. levels (95 % vs. 56 %; p < 0.0001). Median good partial responses as assessed by an overall survival (OS) had not been independent review committee. Chinese real-world reached yet in either treatment arm. The Seventy-five percent of patients had observation 54-month OS rates were 86 % vs. 84 %. intermediate or high risk according to After 63 months of follow-up, the com- the WM prognostic score. A median of 2 A large, multicenter, retrospective study bination maintained a manageable safety prior systemic regimens had been conducted in China assessed the clinical profile, and no new safety signals administered. The study also enrolled presentation, frontline treatment, emerged. The incidences of the main ad- MYD88-wildtype patients, who made up outcome and prognosis of WM in verse events (AEs) including diarrhea, ar- 15.9 % of the total population. Anemia patients diagnosed between January thralgia and hypertension decreased over (hemoglobin ≤ 110 g/L) was present at 2003 and December 2019 at 35 tertiary time. In year 4–5, AE-related ibrutinib baseline in 75 %. hospitals in 22 provinces [15]. Overall,
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TABLE represented 10.2 % of the total. Best overall response with zanubrutinib as assessed by independent Chemoimmunotherapy (e.g., rituximab/ review committee (IRC) dexamethasone/cyclophosphamide, rituximab/prednisone/cyclophos Efficacy per IRC n = 43 phamide, R-COP, R-CHOP, rituximab/ Best overall response, n (%) fludarabine/cyclophosphamide) - Complete response 0 accounted for 36.0 %. In 53.8 %, other combinations were used, with - Very good partial response 14 (32.6) bortezomib-based regimens ranging - Partial response 16 (37.2) first, followed by fludarabine/ - Minor response 4 (9.3) cyclophosphamide, CHOP and immuno modulatory agents plus dexamethasone. - Stable disease 4 (9.3) After a median follow-up of 32 - Progressive disease 2 (4.7) months, the estimated 3-year OS rate was 83 %. Most of the established - Unknown 3 (7.0) prognostic factors according to rIPSS Complete + very good partial response rate, n (%) 14 (32.6) indicated worse prognosis in this Major response rate (partial response or better), n (%) 30 (69.8) population. These included LDH levels ≥ 250 IU/L, albumin levels < 3.5 g/dL, β-2 Overall response rate (minor response or better), n (%) 34 (79.1) microglobulin ≥ 4 mg/L, and age > 65 years. The median OS of patients aged 1,141 patients with a median age of 63 Documented treatment information ≤ 65 years had not been reached yet, years were enrolled. Forty percent were was available for 734 patients. Due to the while this was 132 months and 61 older than 65 years. The male-to-female heterogeneous clinical presentations months for those aged 66-75 years and ratio was 2.7:1. According to the revised and the rarity of the disease, frontline > 75 years, respectively. Also, platelet International Prognostic Scoring System treatment choices showed a considerable counts ≤ 100 x 109/L constituted a (rIPSS), most of the patients had low variety. Monotherapies such as prognostic factor. n (n = 342) and intermediate (n = 325) risk. chlorambucil, ibrutinib and rituximab
REFERENCES
1 Rickert RC, New insights into pre-BCR and 6 Roccaro AM et al., C1013G/CXCR4 acts as a 11 Mu S et al., Effect of rifampin and itracona- BCR signalling with relevance to B cell malignan- driver mutation of tumor progression and modu- zole on the pharmacokinetics of zanubrutinib (a cies. Nat Rev Immunol 2013; 13(8): 578-591 lator of drug resistance in lymphoplasmacytic Bruton’s tyrosine kinase inhibitor) in Asian and 2 Argyropoulos KV et al., Clonal B cells in Wal- lymphoma. Blood 2014; 123: 4120-4131 non-Asian healthy subjects. Cancer Chemother denström’s macroglobulinemia exhibit functional 7 Dimopoulos MA et al., Phase 3 trial of ibrutinib Pharmacol 2020; 85: 391-399 features of chronic active B-cell receptor signal- plus rituximab in Waldenström’s macroglobuline- 12 An G et al., Safety and efficacy of the Bruton ing. Leukemia 2016; 30(5): 1116-1125 mia. N Engl J Med 2018; 378(25): 2399-2410 tyrosine kinase inhibitor zanubrutinib (BGB-3111) 3 Janz S, Waldenström macroglobulinemia: clini- 8 Buske C et al., Five-year follow-up of ibrutinib in patients with Waldenström macroglobulinemia cal and immunological aspects, natural history, plus rituximab vs placebo plus rituximab for Wal- from a phase 2 trial. ASH 2020, abstract 2940 cell of origin, and emerging mouse models. ISRN denström’s macroglobulinemia: final analysis 13 Dimopoulos M et al., ASPEN: Results of Hematol 2013; 2013: 815325 from the randomized phase 3 iNNOVATETM study. phase 3 randomized trial of zanubrutinib versus 4 Treon SP et al., MYD88 L265P somatic muta- ASH 2020, abstract 336 ibrutinib for patients with Waldenström mac- tion in Waldenstrom’s macroglobulinemia. N Engl 9 Guo Y et al., Discovery of zanubrutinib (BGB- roglobulinemia. EHA 2020, abstract S225 J Med 2012; 367: 826-833 3111), a novel, potent, and selective covalent in- 14 Dimopoulos M et al., Updated results of the 5 Hunter ZR et al., The genomic landscape of hibitor of bruton’s tyrosine kinase. J Med Chem ASPEN trial from a cohort of patients with MYD88 Waldenstrom macroglobulinemia is characterized 2019; 62(17): 7923-7940 wild-type Waldenström macroglobulinemia. EHA by highly recurring MYD88 and WHIM-like 10 Tam CS et al., Phase 1 study of the selective 2020, abstract EP1180 CXCR4 mutations, and small somatic deletions BTK inhibitor zanubrutinib in B-cell malignancies 15 Cao XX et al., Treatment and outcome pat- associated with B-cell lymphomagenesis. Blood and safety and efficacy evaluation in CLL. Blood terns of patients with Waldenström’s macroglob- 2014; 123: 1637-1646 2019; 134(11): 851-859 ulinemia: a large, multicenter retrospective review in China. ASH 2020, abstract 2053
Management of CLL patients: BTK inhibition and beyond
BTK inhibitors, the Bcl-2 inhibitor vene- Ibrutinib, as the first-generation repre- proval in the US and Europe for the toclax and anti-CD20 antibodies such as sentative of the BTK inhibitor class, is a treatment of patients with CLL, while obinutuzumab have dramatically therapeutic mainstay, although it has zanubrutinib was approved in China in changed the therapeutic landscape of notable shortcomings that led to the in- this indication in 2020. BTK-inhibitor– chronic lymphocytic leukemia (CLL)/ troduction of second-generation agents. based doublets and triplets are being small lymphocytic lymphoma (SLL). Acalabrutinib has already received ap- evaluated in clinical trials, particularly
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with a view to achieving undetectable 100 12 cycles of combined ibrutinib + venetoclax minimal residual disease that allows for Additional randomized treatment 80 fixed-duration therapy and treatment 66 % 69 %
discontinuation. At the same time, new 19 % 60 34 % agents such as orelabrutinib and LOXO- 45 % n = 6 42 % n = 11 305 are being tested in the clinical set- 10 %
uMRD (%) 40 ting. Progress is also ongoing with re- n = 3 32 % 31 % 45 % 50 % spect to the expansion of PI3Kd 20 inhibitory options and the development n = 10 n = 10 n = 14 n = 16 of novel anti-CD20 antibodies. 0 Ibrutinib Ibrutinib + Ibrutinib Ibrutinib + (n = 31) venetoclax (n = 31) venetoclax Ibrutinib-based therapy (n = 32) (n = 32) Bone marrow Peripheral blood
CAPTIVATE: ibrutinib plus Figure 1: Increases in best overall uMRD rates with additional randomized treatment in the uMRD not venetoclax confirmed population of the CAPTIVATE study
To date, ibrutinib is the only targeted who obtained confirmed uMRD. The inhibitors investigated the efficacy of therapy to demonstrate significant OS overall median follow-up on the study the addition of ibrutinib to venetoclax in benefit as a first-line treatment of pa- was 31.3 months. At 30 months, the PFS terms of MRD [5]. Thirty-eight patients tients with CLL included in randomized rates were > 95 % across all four ran received venetoclax for 12 months; at phase III studies [1, 2]. The interna- domized arms. This compared favorably that time, response and MRD status tional, phase II CAPTIVATE trial evalu- to other first-line fixed-duration regi- were evaluated. Those who had ated 12 cycles of ibrutinib plus veneto- mens including rituximab, fludarabine achieved complete response (CR)/par- clax in the first-line setting to explore and cyclophosphamide (3-year PFS, tial response (PR) and uMRD stopped the question of whether deep remission 73 %) [2] and venetoclax plus obinutu- treatment, while those with CR/PR and can be achieved with 1-year fixed treat- zumab (3-year PFS, 82 %) [4]. detectable MRD continued venetoclax ment duration to allow for treatment For patients who did not achieve therapy and added ibrutinib. MRD was discontinuation. At ASH 2020, Wierda et confirmed uMRD at the end of 12 cycles periodically evaluated, and patients al. presented the primary analysis for of ibrutinib plus venetoclax, improve- who obtained uMRD in both peripheral the minimal residual disease (MRD) co- ment in MRD status was observed with blood and bone marrow at any time dis- hort [3]. In this cohort (n = 149), treat- continued administration of the combi- continued treatment. Patients with de- ment with ibrutinib plus venetoclax for nation vs. single-agent ibrutinib. In the tectable MRD at the end of the 12-month 12 cycles after a 3-month lead-in with bone marrow, the additional ran combination period went on to receive ibrutinib only was followed by random domized treatment led to a 34 % in- single-agent ibrutinib. ization based on the MRD status. Pa- crease in uMRD in patients receiving This sequential MRD-guided ap- tients with confirmed undetectable ibrutinib plus venetoclax, whereas this proach proved to be feasible. uMRD was MRD (uMRD) received either placebo was only 10 % in the ibrutinib-only arm obtained by 45 % of patients after 12 or ibrutinib in a double-blind manner, (Figure 1). The uMRD rate in the pe- months of venetoclax monotherapy. while those in whom uMRD was not ripheral blood increased by 19 % in the Among the remaining patients, 84 % confirmed underwent open-label ran combination arm vs. 0 % in the mono- achieved uMRD with venetoclax plus domization to either ibrutinib or ibruti- therapy arm. AEs generally lessened af- ibrutinib. In total, MRD was achieved in nib plus venetoclax. The primary end- ter the first 6 months of ibrutinib plus 87 % with either the monotherapy or the point was the 1-year disease-free venetoclax treatment irrespective of the combination. Overall, 95 % of patients survival (DFS) rate in patients with con- subsequent randomized regimen. Few responded. Only 2 clinical relapses oc- firmed uMRD randomized to placebo patients required dose adjustment or curred after uMRD during the 27-month vs. ibrutinib. discontinuation. Grade ≥ 3 AEs were follow-up. The authors noted that re- Fifty-eight percent of patients in the uncommon. Based on these findings, sponses to venetoclax retreatment re- MRD cohort achieved confirmed uMRD the authors concluded that ibrutinib main to be established; also, the biolog- in the peripheral blood and bone mar- plus venetoclax is an all-oral, once- ical characteristics of patients with row after 12 cycles of ibrutinib and daily, chemotherapy-free, fixed-dura- persistent MRD and early MRD relapse venetoclax. Within this group, the 1-year tion regimen that provided highly con- after treatment discontinuation will be DFS rates did not differ significantly be- cordant, deep MRD remissions in bone investigated. tween placebo and ibrutinib after a me- marrow and blood in first-line CLL. dian follow-up of 16.6 months post-ran- Obinutuzumab, ibrutinib & domization (100 % vs. 95.3 % for MRD-guided treatment venetoclax ibrutinib and placebo, respectively; intensification p = 0.1475). According to the authors, The fixed-duration triple combination the 95 % rate in the placebo arm sup- A single-arm, phase II study including of ibrutinib, venetoclax and obinutu- ports a fixed-duration treatment ap- patients with relapsed/refractory (r/r) zumab was tested in a phase II study en- proach and discontinuation in patients CLL who were naïve to BTK and Bcl-2 rolling patients with treatment-naïve
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(n = 25) and r/r CLL (n = 25). Obinutu- cluding deletion 17p, TP53 mutations frequent AEs of all grades. Most AEs of zumab was administered in cycles 1-8, and unmutated IGHV status. Median interest including infections, hemor- ibrutinib in cycles 2-14, and venetoclax OS had not been reached yet in either rhage, neutropenia, and hypertension in cycles 3-14. Rogers et al. presented treatment arm. The overall response were low-grade. No tumor lysis syn- the 3-year update at the ASH 2020 Con- rates (ORRs) did not differ (80 % vs. drome (TLS) occurred. gress [6]. The CR rates with uMRD (i.e., 84 %), although the median duration of After 16 cycles, the ORRs were 92 % the primary endpoint) were 28 % in response was longer with acalabrutinib and 100 % for AVR and AVO, respec- both treatment-naïve and r/r patients. than with IdR/BR (not reached vs. 18 tively. Half of patients in each cohort Fifty-six percent and 44 %, respectively, months; HR, 0.19). At 18 months, 85.4 % had achieved CR or CRi at the time of showed uMRD in both blood and bone vs. 49.4 % of patients responded. data cutoff. All of those with CR/CRi ob- marrow. Overall, 84 % and 88 %, respec- Both acalabrutinib and BR showed tained uMRD in the blood at the time of tively, achieved PR, CR or CR with in- higher tolerability than IdR. Compared CR/CRi or earlier. At cycle 10, only 1 of complete marrow recovery (CRi). At 36 to IdR, grade ≥ 3 AEs, treatment-related 12 patients (8 %) in each cohort re- months, the PFS rate was 95 % in both AEs and AEs leading to drug discontin- mained MRD-positive in the blood. Six groups, and OS rates amounted to 95 % uation or dose delays occurred less fre- cycles later, none of the patients in the and 100 % for treatment-naïve and r/r quently with acalabrutinib and BR. As AVR cohort and one patient in the AVO patients, respectively. These findings in- the authors summarized, these data cohort were MRD-positive. The overall dicated durability of responses with the support the use of acalabrutinib in pa- uMRD rate was 71 % (67 % and 75 % in triplet therapy. Two cases of disease tients with r/r CLL including those with patients treated with AVR and AVO, re- progression occurred in the r/r group, at high-risk features. spectively). Median duration of re- 24 and 36 months. sponse, PFS, and OS had not been This suggested that a time-limited Triple acalabrutinib combinations: reached in either group. treatment of 14 cycles with the three- phase Ib The authors concluded that the triple drug combination can result in contin- combination therapy with acalabrutinib ued durable remissions. Additional fol- Acalabrutinib was tested in various com- plus an anti-CD20 antibody and a Bcl-2 low-up is required to determine the binations in the phase Ib ACE-CL-003 inhibitor is feasible based on tolerability median PFS and duration of benefit to study. Woyach et al. presented data on and yielded high CR and uMRD rates in patients. Ibrutinib plus venetoclax and two cohorts of the trial, namely cohort 3 both r/r and treatment-naïve patients obinutuzumab is currently being com- evaluating acalabrutinib plus venetoclax with CLL. pared to ibrutinib plus obinutuzumab and rituximab (AVR) in patients with r/r in two phase III cooperative group trials CLL and cohort 4 that assessed acalabru- Phase II data on AVO in treatment- (NCT03701282 and NCT03737981). tinib plus venetoclax and obinutuzumab naïve patients (AVO) in the treatment-naïve setting [8]. Regimens including second- Each cohort contained 12 patients. With AVO as front-line CLL treatment is cur- generation BTK inhibitors regard to safety, which was the primary rently being assessed in a phase II trial. endpoint, AEs turned out as expected Acalabrutinib is administered for 15 cy- Acalabrutinib: final results of based on each individual agent’s safety cles, obinutuzumab from cycle 2 to 8, ASCEND profiles. One patient in either cohort dis- and venetoclax from cycle 4 to 15. If CR continued treatment due to AEs. Head- with uMRD has been obtained after the At ASH 2020, Ghia et al. reported the fi- ache, diarrhea and nausea were the most 15th cycle, acalabrutinib and venetoclax nal results of the ASCEND trial that compared the second-generation, 100 highly selective, covalent BTK inhibitor Acalabrutinib: median PFS, not reached acalabrutinib (n = 155) with idelalisib plus rituximab (IdR; n = 119) or benda- 80 mustine plus rituximab (BR; n = 36) ac- cording to investigator’s choice in pa- Acalabrutinib 60 BR: median PFS, 18.6 months tients with r/r CLL [7]. After a median IdR BR follow-up of 22 months, the results em- Acalabrutinib vs. IdR phasized the favorable efficacy and 40 HR (95 % CI), 0.27 (0.18, 0.41) safety of the BTK inhibitor compared to p < 0.0001 IdR: median PFS, 16.2 months standard-of-care regimens. Median PFS had not been reached with acalabruti- survival (%) Progression-free 20 Acalabrutinib vs. BR HR (95 % CI), 0.29 (0.17, 0.50) nib, while this was 16.2 months with IdR p < 0.0001 and 18.6 months with BR (p < 0.0001 for 0 both comparisons; Figure 2). At 18 0 1 2 3 4 5 6 7 8 9 11 1210 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 months, PFS rates were 82 % vs. 48 % for acalabrutinib and IdR/BR, respectively. Time (months) PFS benefits were also observed in pa- Figure 2: Superior progression-free survival for acalabrutinib versus bendamustin/rituximab (BR) and tients with high-risk genetic features in- idelalisib/rituximab (IdR)
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are discontinued but can be resumed Cycle 1 day 1 Cycle 4 day 1 upon MRD positivity. The MRD status is Baseline Pre-venetoclax initiation tested every 3 months. Patients who continue to show MRD-positive CR 7 % 7 % Low risk and/or PR after 15 cycles receive the Medium risk doublet regimen for another 8 cycles. High risk This is followed by a response reassess- 30 % ment and the same allocation, with acalabrutinib and venetoclax adminis- tered until progression in case of MRD positivity. Stable disease or progression 64 % 91 % prompt patient removal from the study. The study population is enriched for high-risk disease, with substantial pro- portions of patients showing unmutated IGHV status, TP53 mutation, and other Figure 3: Reduction in tumor lysis syndrome risk based on the 3-cycle lead-in with acalabrutinib and aberrations. A recent protocol amend- obinutuzumab ment restricted additional enrollment to patients with TP53-aberrant disease + obinutuzumab; IO), CLL14 (veneto- which reflects an ongoing need for more in a new cohort. clax + obinutuzumab; VO), and ELE- efficacious therapies [15]. The updated analysis reported at VATE-TN (acalabrutinib monotherapy The global, phase III, open-label, ran- ASH 2020 yielded uMRD rates of 76.5 % and acalabrutinib + obinutuzumab; domized SEQUOIA study aimed at eval- and 83.9 % in bone marrow and blood, AO). Data were available for a total pop- uating first-line use of the second-gener- respectively, after 15 cycles of therapy in ulation of 1,191 individuals. ation BTK inhibitor zanubrutinib in the overall cohort (n = 44) [9]. In pa- PFS did not differ between time-lim- CLL/SLL patients with and without dele- tients with TP53 aberrations (n = 17), ited (VO) and continuous therapy (IO tion 17p. Zanubrutinib was designed to these were 70 % and 90 %, respectively. and acalabrutinib monotherapy). How- maximize BTK occupancy and minimize After a median follow-up of 19 cycles, ever, those treated with AO fared better off-target inhibition of TEC and EGFR no patients had progressed or devel- with respect to PFS than the groups re- family kinases [16, 17]. Patients included oped recurrent MRD. The depth of re- ceiving IO and VO. A subgroup analysis in Arm C of the SEQUOIA trial had dele- sponse increased over time. At cycle 16, focusing on patients with TP53 aberra- tion 17p and received zanubrutinib CR/CRi rates were 44 % and 40 % in the tions demonstrated similar PFS out- monotherapy. Brown et al. presented total cohort and in the patients with comes irrespective of the targeted agent the updated results for this group after a TP53 aberrations, respectively. AVO used. Also, the incidence of grade 3–4 median follow-up of 22 months [18]. showed a favorable safety profile with AEs did not vary significantly across Among 109 enrolled patients, 95 were low risk of grade ≥ 3 infections, atrial fi- ibrutinib, acalabrutinib and venetoclax still on study treatment at the time of the brillation, and infusion-related reac- treatment. Ongoing studies will further analysis. Single-agent zanubrutinib gave tions (2 % each). The 3-cycle lead-in delineate the position of different tar- rise to an ORR of 94.5 % and a CR/CRi with acalabrutinib and obinutuzumab geted therapies and schedule of admin- rate of 6.4 % that had increased from the effectively reduced TLS risk at the time istration in CLL therapy based on effi- initial CR/CRi rate of 1.9 % estimated 1 of venetoclax initiation (Figure 3). No cacy, availability, safety, cost, treatment year earlier [19]. Almost 88 % of patients TLS event was observed due to veneto- objectives, and patient choice. showed ongoing responses for at least 18 clax. A phase III trial of AVO vs. AV vs. months. The 18-month PFS and OS rates chemoimmunotherapy is currently re- SEQUOIA: were 90.6 % and 95.4 %, respectively. cruiting (NCT03836261). zanubrutinib in deletion 17p PFS was analyzed by IGHV mutation and karyotype status. With limited fol- Meta-analysis of time-limited vs. Patients with CLL/SLL who harbor dele- low-up, the findings appeared similar continuous agents tion 17p have an unfavorable prognosis between patients with unmutated vs. and respond poorly to standard chemo- mutated IGHV as well as between pa- Molica et al. performed a systematic lit- immunotherapy [11, 12]. BTK and Bcl-2 tients with complex vs. non-complex erature review and network meta-anal- inhibitors have been shown to improve karyotype. The tolerability of zanubruti- ysis to estimate the relative efficacy and outcomes for patients with deletion 17p nib monotherapy was generally consist- safety of targeted agents approved by [13, 14]. However, the first-generation ent with previous observations reported the FDA and/or EMA for upfront ther- BTK inhibitor ibrutinib demonstrates for patients with various B-cell malig- apy of CLL (i.e., ibrutinib, acalabrutinib, limited efficacy in this population. Real- nancies [17, 20-22]. and venetoclax) [10]. In particular, time- world data presented at ASH 2020 Based on the encouraging results ob- limited venetoclax-based regimens strengthen the evidence indicating infe- tained in Arm C, Arm D of the SEQUOIA were compared with continuous BTK rior survival with first-line ibrutinib in study was devised to evaluate zanubru- inhibitor-based therapy based on the deletion 17p-positive patients com- tinib plus venetoclax [23]. At present, following trials: ILLUMINATE (ibrutinib pared to those without deletion 17p, patients are being recruited into this
8 1/2021 © Springer-Verlag memo special issue ASH 2020
OR 91.9 % OR 97.2 % OR 100 % OR 100 % rhea, hypertension and atrial fibrilla- CR/CRI 0 % CR/CRI 25 % CR/CRI 54.1 % CR/CRI 54.5 % tion/flutter. 100 CR Another comparison across patients 90 CRi PR with 1 prior line of treatment and those 80 after ≥ 2 prior lines yielded similar re- 70 sults. Here, the ORR was numerically
60 higher in the early lines (97 % vs. 88.3 %; p = 0.05), while median PFS was signifi- 50 cantly longer (HR, 0.13; p < 0.001). The 40 24-month PFS rates amounted to 95 % 30
Response rates (%) and 75.3 %, respectively. Again, OS did 20 not differ. Exposure-adjusted safety pro-
10 files were generally similar for both groups, although patients after only 1 0 2 months 6 months Best response At treatment treatment line showed lower rates of (n = 37) (n = 36) (n = 37) discontinuation (n = 33) AEs of special interest. CR: complete response; CRi: complete response with incomplete marrow recovery; PR: partial response Emerging BTK-inhibiting Figure 4: Response rates according to iwCLL criteria observed in the BOVen study agents arm in 8 countries worldwide, with ment at progression. The frequency of planned enrollment of approximately uMRD confirmed in blood and marrow Robust results for orelabrutinib 50 individuals. After 3 months of zanu- constituted the primary outcome. brutinib monotherapy, venetoclax is In 89.2 % of 37 evaluable patients, The ongoing, multicenter, open-label, added for 12-24 cycles. Restaging and uMRD was achieved in both blood and single-arm, phase II ICP-CL-00103 MRD measurements are performed reg- marrow, and the treatment was discon- study is evaluating the novel, highly se- ularly at 3-monthly intervals. Patients tinued after a median of 10 months. All lective, irreversible BTK inhibitor orela- who achieve confirmed uMRD in blood of the patients responded, with 54.5 % brutinib in 80 patients with r/r CLL. Ac- and bone marrow are allowed to dis- achieving CR/CRi at the time of treat- cording to the update provided by Xu et continue zanubrutinib and venetoclax ment discontinuation (Figure 4). al. at the ASH 2020 Congress, the results therapy after a minimum of 27 and 12 BOVen was well tolerated; only few confirmed the efficacy of orelabrutinib cycles, respectively. grade ≥ 3 treatment-emergent AEs oc- [26]. At a median follow-up of 14.3 curred. Among 34 patients who achieved months, the ORR according to inde- Zanubrutinib, obinutuzumab, and uMRD in peripheral blood by flow cy- pendent review was 91.3 %, and CR/CRi venetoclax: BOVen tometry, 97 % obtained uMRD accord- was obtained in 10 %. Disease control ing to immunosequencing at a cutoff of resulted in 95 %. Over time, the CR rates Ibrutinib plus venetoclax doublets as < 10-5. Rapid clearance with a ≥ 400-fold increased significantly. Also, very high well as triplets with obinutuzumab are decrease within 6 cycles of starting the ORRs occurred in cytogenetic high-risk active but associated with characteristic BOVen triplet was highly predictive of subgroups (deletion 17p, 100 %; TP53 toxicities. The BOVen study was con- uMRD and might thus identify a favora- mutation, 100 %; deletion 11q, 94.7 %; ducted based on the hypothesis that ble patient group. unmutated IGHV, 93.9 %). first-line treatment with zanubrutinib, Neither median PFS nor median du- obinutuzumab, and venetoclax (BOVen) Early vs. late use of zanubrutinib ration of response had been reached at will achieve frequent uMRD, and MRD- the time of data cutoff. At 12 months, the driven treatment discontinuation will al- Pooled data from two phase I studies PFS rate was 81.1 %, and 77.1 % of pa- low for durable responses off treatment (NCT02343120 and NCT03189524) and tients responded. Orelabrutinib showed [24]. Venetoclax was introduced in cycle one phase II study (NCT03206918) in- a robust safety profile and was found to 3 after a 2-month lead-in with zanubru- vestigating zanubrutinib monotherapy be well tolerated with low rates of off- tinib and obinutuzumab. Patients com- in CLL/SLL patients showed that supe- target side effects. Neutropenia, throm- pleted 8 cycles of obinutuzumab and 6 rior outcomes can be obtained with this bocytopenia and upper respiratory tract cycles of the triple combination. There- agent in earlier lines [25]. Treatment- infection occurred most commonly. No after, the management was determined naïve patients had a significantly higher events were reported regarding atrial fi- by pre-specified MRD endpoints with a ORR than those with relapsed/refrac- brillation/flutter and grade ≥ 3 hyper- minimum and maximum duration of tory disease (100 % vs. 90.6 %; p < 0.001), tension. Grade ≥ 3 diarrhea occurred in therapy of 8 and 24 months, respectively. and median PFS was numerically longer one case, and major hemorrhage was If uMRD according to flow cytometry (HR, 0.32; p = 0.14). For OS, the compar- seen in 2 cases. (< 10-4) was present, the patients re- ison revealed no difference. In general, ceived 2 additional cycles. In case of on- treatment-naïve patients showed a bet- LOXO-305: BRUIN going confirmed uMRD at the time of ter exposure-adjusted safety profile that the next blood MRD test, they discontin- those with r/r CLL, particularly regard- The phase I/II BRUIN study demon- ued therapy with the option for retreat- ing AEs of special interest such as diar- strated promising efficacy of the novel,
memo © Springer-Verlag 1/2021 9 ASH 2020 special issue
non-covalent BTK inhibitor LOXO-305 in TABLE CLL/SLL patients previously treated with BRUIN study: responses obtained with LOXO-305 in all patients and in the all classes of available therapy [27]. BTK-inhibitor–pretreated group BRUIN included 170 patients whose All CLL/SLL patients n = 139 number of prior lines of systemic therapy ranged from 1 to 11. Eighty-six percent Overall response rate, % (95 % CI) 63 (55-71) had already received BTK inhibition, Best response with progressive disease representing the most common reason for treatment - Complete response, n (%) 0 discontinuation (67 %). High-risk molec- - Partial response, n (%) 69 (50) ular features were present in considera- - Partial response with lymphocytosis, n (%) 19 (14) ble percentages of patients. The safety and tolerability of LOXO- - Stable disease 45 (32) 305 were favorable and consistent with BTK-pretreated CLL/SLL patients n = 121 the design of this agent as a highly selec- Overall response rate, % (95 % CI) 62 (53-71) tive and non-covalent BTK inhibitor. No dose-limited toxicities occurred, and Best response only 1.5 % of patients discontinued - Complete response, n (%) 0 LOXO-305 due to treatment-related AEs. A daily dose of 200 mg was selected - Partial response, n (%) 57 (47) as the recommended phase II dose. - Partial response with lymphocytosis, n (%) 18 (15) LOXO-305 showed efficacy regard- - Stable disease, n (%) 41 (34) less of BTK pretreatment and use of other prior agents, the reason for BTK inhibition discontinuation (i.e., pro- distinct mechanisms of action have consisting of obinutuzumab and chlor gression vs. intolerance), and the pres- been evaluated. However, studies of ambucil (n = 211) in patients with treat- ence of the BTK C481 mutation status. previous generations of PI3Kδ inhibi- ment-naïve or r/r CLL [33]. PFS accord- In the total population and the BTK-pre- tors in treatment-naïve CLL patients ing to independent review committee treated group, the ORRs were 63 % and have shown substantial toxicity [28, 29]. was defined as the primary endpoint. In 62 %, respectively (Table). Responses Umbralisib, an oral dual inhibitor of both arms, 57 % and 43 % of patients increased over time and were ongoing PI3Kδ and casein kinase-1ε, exhibits were treatment-naïve and pretreated, in 94 % of responders after a median fol- improved selectivity for the delta iso- respectively. The median numbers of low-up of 6 months. Median PFS had form of PI3K, with low rates of immune- prior therapies were 2 and 1 for U2 and not been reached yet. mediated toxicities and discontinua- obinutuzumab plus chlorambucil, re- tions due to AEs [30, 31]. The spectively. Novel agents targeting PI3Kδ combination of umbralisib and ublitux- and CD20 imab, which is a novel anti-CD20 mono Durable responses regardless of clonal antibody offering enhanced anti- subgroup UNITY-CLL body-dependent cellular cytotoxicity, has demonstrated promising activity in In terms of the primary endpoint, the As not all patients are ideal candidates heavily pretreated CLL patients [32]. novel combination was superior to obi- for BTK and Bcl-2 inhibitors, other The UNITY-CLL study compared nutuzumab plus chlorambucil in the agents such as phosphatidylinositol- umbralisib plus ublituximab (U2; ITT population, with a median PFS of 3-kinase-delta (PI3Kδ) inhibitors with n = 210) with chemoimmunotherapy 31.9 vs. 17.9 months (HR, 0.546;
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p < 0.0001; Figure 5). At 2 years, the PFS rates were 60.8 % vs. 40.4 %. The treat- 100 ment-naïve population derived greater 80 + Censored PFS benefits in both arms (38.5 vs. 26.1 Median follow-up of 36.7 months months; HR, 0.482; p < 0.001) than the pretreated population (19.5 vs. 12.9 60 months; HR, 0.601; p < 0.01), although the differences between the regimens 40 were significant for both groups. Median PFS HR 2-year (95 % CI) (95 % CI) PFS % Moreover, the ORR observed with U2 U2 31.9 Progression-free survival (%) Progression-free 20 n = 210 (28.2–35.8) 0.546 60.8 exceeded the response rate achieved in (0.413–0.720) O + Chl 17.9 p < 0.0001 40.4 the control arm (83.3 % vs. 68.7 %; n = 211 (16.1–22.6) p < 0.001); this also applied to the pro- 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 portions of patients with CR/CRi (5 % vs. 1 %). ORRs favored the novel regi- Time since randomization (months) men in both treatment-naïve and previ- Figure 5: UNITY-CLL: progression-free survival with umbralisib plus ublituximab compared to ously treated patients. In the population obinutuzumab plus chlorambucil who had received prior BTK inhibition, those in the U2 arm fared comparatively and diarrhea showed substantial rates plets including combinations with better (ORR, 57 % vs. 25 %). Also, re- (13 % and 12 %, respectively). While di- venetoclax and BTK inhibitors. sponses were durable, with 62 % still re- arrhea occurred more frequently in the sponding at 2 years. Disease control re- treatment-naïve population than in the U2 followed by venetoclax sulted in 93 %. Grade ≥ 3 AEs occurred previously treated patients, the opposite more commonly with the novel combi- was true for neutropenia. Based on the observation that targeting nation (82 % vs. 66 %), which might be In their conclusion, the authors of PI3K might prevent drug resistance to explained by the fact that median expo- noted that UNITY-CLL is the first ran Bcl-2 inhibition [34, 35], a multicenter, sure was more than 4 times longer than domized trial of a PI3Kδ inhibitor in phase I/II, dose-escalation trial investi- in the control arm (21 vs. 5 months). The treatment-naïve CLL, thus establishing gated U2 in combination with veneto- most common AEs observed in the ex- a new mechanism of action in this set- clax [36]. Patients with r/r CLL received perimental arm included diarrhea, nau- ting. The non-chemotherapy U2 regi- a fixed dose of ublituximab (900 mg) sea, and infusion-related reactions. At men is highly active in CLL patients and and two dose levels of umbralisib the grade 3/4 level, only neutropenia is being explored as a backbone for tri- (600 mg and 800 mg) for 3 cycles
13 O’Brien S et al., Ibrutinib for patients with re- lapsed or refractory mantle-cell lymphoma with 20: S105-107 (abstract CLL-091) lapsed or refractory chronic lymphocytic leukae- zanubrutinib, a selective inhibitor of Bruton’s ty- 29 Lampson BL et al., Efficacy results of a mia with 17p deletion (RESONATE-17): a phase rosine kinase. Clin Cancer Res 2020; 26(16): phase 2 trial of first-line idelalisib plus ofatu- 2, open-label, multicentre study. Lancet Oncol 4216-4224 mumab in chronic lymphocytic leukemia. Blood 2016; 17(10): 1409-1418 22 Tam CS et al., Pooled analysis of safety data Adv 2019; 3(7): 1167-1174 14 Stilgenbauer S et al., Venetoclax for patients from monotherapy studies of the Bruton tyrosine 30 Burris HA et al., Umbralisib, a novel PI3Kδ with chronic lymphocytic leukemia with 17p de- kinase (BTK) inhibitor, zanubrutinib (BGB-3111), and casein kinase-1ε inhibitor, in relapsed or re- letion: results from the full population of a phase in B-cell malignancies. EHA 2019; abstract: fractory chronic lymphocytic leukaemia and lym- II pivotal trial. J Clin Oncol 2018; 36(19): 1973- PS1159 phoma: an open-label, phase 1, dose-escala- 1980 23 Tam CS et al., Zanubrutinib in combination tion, first-in-human study. Lancet Oncol 2018; 15 Mato A et al., A clinical practice comparison with venetoclax for patients with treatment-naïve 19(4): 486-496 of patients with CLL/SLL with and without chronic lymphocytic leukemia or small lympho- 31 Davids MS et al., An integrated safety analy- del(17p) receiving first-line treatment with ibruti- cytic lymphoma and del(17p): Arm D of the SE- sis of the next generation PI3Kδ inhibitor um- nib. ASH 2020, abstract 2498 QUOIA (BGB-3111-304) trial. ASH 2020, ab- bralisib (TGR-1202) in patients with relapsed/re- 16 Guo Y et al., Discovery of zanubrutinib stract 1318 fractory lymphoid malignancies. Blood 2017: (BGB-3111), a novel, potent, and selective cova- 24 Soumerai JD et al., MRD-driven time-limited 130(Suppl 1): 4037-4037 lent inhibitor of Bruton’s tyrosine kinase. J Med therapy with zanubrutinib, obinutuzumab, and 32 Lunning M et al., Ublituximab and umbral- Chem 2019; 62(17): 7923-7940 venetoclax (BOVen) in previously untreated isib in relapsed/refractory B-cell non-Hodg- 17 Tam CS et al., Phase 1 study of the selective chronic lymphocytic leukemia. ASH 2020, ab- kin lymphoma and chronic lymphocytic leu- BTK inhibitor zanubrutinib in B-cell malignancies stract 1307 kemia. Blood 2019; 134(21): 1811-1820 and safety and efficacy evaluation in CLL. Blood 25 Xu W et al., Earlier use of zanubrutinib mon- 33 Gribben JG et al., Phase 3 study of umbral- 2019; 134(11): 851-859 otherapy in patients with chronic lymphocytic isib combined with ublituximab vs obinutu- 18 Brown JR et al., Efficacy and safety of zanu- leukemia/small lymphocytic lymphoma associ- zumab plus chlorambucil in patients with brutinib in patients with treatment-naïve chronic ated with greater efficacy: a pooled analysis chronic lymphocyctic leukemia: results from lymphocytic leukemia (CLL) or small lympho- from 3 studies. ASH 2020, abstract 2229 UNITY-CLL. ASH 2020, abstract 543 cytic lymphoma (SLL) with del(17p): follow-up 26 Xu W et al., Updates results from the phase 34 Cervantes-Gomez F et al., Pharmacological results from Arm C of the SEQUOIA (BGB-3111- II study of orelabrutinib monotherapy in Chinese and protein profiling suggests venetoclax (ABT- 304) trial. ASH 2020, abstract 1306 patients with relapsed or refractory chronic lym- 199) as optimal partner with ibrutinib in chronic 19 Tam CS et al., Efficacy and safety of zanu- phocytic leukemia/small cell lymphoma. ASH lymphocytic leukemia. Cancer Res 2015; 21(16): brutinib in patients with treatment-naïve chronic 2020, abstract 1320 3705-3715 lymphocytic (CLL) or small lymphocytic lym- 27 Mato AR et al., LOXO-305, a next genera- 35 Choudhary GS et al., MCL-1 and BCL-xL- phoma (SLL) with del(17p): initial results from tion, highly selective non-covalent BTK inhibitor dependent resistance to the BCL-2 inhibitor Arm C of the SEQUOIA (BGB-3111-304) trial. in previously treated CLL/SLL: results from the ABT-199 can be overcome by preventing PI3K/ Blood 2019; 134(Supplement_1): 499 phase 1/2 BRUIN study. ASH 2020, abstract 542 AKT/mTOR activation in lymphoid malignancies. 20 Tam CS et al., A randomized phase 3 trial of 28 Ghia P et al., Acalabrutinib versus idelalisib Cell Death Dis 2015; 6(1): e1593 zanubrutinib vs ibrutinib in symptomatic Wal- plus rituximab (IdR) or bendamustine plus rituxi- 36 Barr PM et al., A phase 1/2 study of umbral- denström macroglobulinemia: the ASPEN study. mab (BR) in relapsed/refractory (R/R) chronic isib, ublituximab and venetoclax in patients with Blood 2020; 136(18): 2038-2050 lymphocytic leukemia (CLL): ASCEND final re- relapsed or refractory chronic lymphocytic leu- 21 Song Y et al., Treatment of patients with re- sults. Clin Lymphoma Myeloma Leukemia 2020; kemia. ASH 2020, abstract 3137 memo © Springer-Verlag 1/2021 11 ASH 2020 special issue
(induction/debulking period). This was were evaluable for safety and efficacy, (i.e., 52 % of the total population). All of followed by the consolidation period respectively. The primary objective of the patients responded, and the CR rate encompassing 9 cycles of venetoclax at the trial was the safety of the venetoclax at cycle 12 was 41 %. At that time, MRD the standard dose of 400 mg after a addition after U2 induction. was undetectable in 96 % and 77 % in 5-week ramp up. The protocol was U2 and venetoclax were shown to be the blood and bone marrow, respec- amended to add ublixitumab infusions well tolerated at the phase II doses. Only tively. on day 1 of cycle 4, 5 and 6, which coin- 7 % of patients discontinued the regi- To date, only 1 patient has progressed cided with the venetoclax treatment pe- men prior to cycle 12. Also, U2 induc- 10 months after achieving uMRD in the riod. After the total 12-cycle treatment tion mitigated the TLS risk; after the in- blood and marrow and the discontinua- period, patients underwent full re- duction phase, this risk showed an 81 % tion of therapy. Retreatment strategies sponse assessment including MRD test- relative reduction. No patient devel- are being investigated. The regimen is ing of their blood and marrow. Treat- oped clinical or laboratory TLS during further explored in the setting of Rich- ment was stopped in patients with the venetoclax ramp up. The regimen ter’s transformation and in mantle cell uMRD, whereas those with detectable demonstrated encouraging efficacy in lymphoma. Also, a phase II study assess- MRD continued on single-agent um- the patient cohort including those who ing U2 plus venetoclax is ongoing in bralisib. Forty-three and 39 patients were refractory to prior BTK inhibition treatment-naïve and r/r CLL patients. n
Insights from early clinical trials on targeted treatment in B-cell malignancies
DTRM-555: oral, once-daily, triplet combination DTRM-12 200 mg/d, everolimus fixed-dose combination consisting of DTRM-12, the mTOR in- 5 mg/d and pomalidomide 2 mg/d were hibitor everolimus, and the immuno established as the recommended phase Richter’s transformation (RT), which de- modulating agent pomalidomide. II dose of the DTRM-555 regimen. This scribes transformation of CLL/SLL to A phase I clinical trial was conducted combination had an acceptable safety diffuse large B-cell lymphoma (DLBCL) to test this concept in patients with B- profile, which meant that the primary or Hodgkin lymphoma, is a rare event cell non-Hodgkin lymphomas (NHLs) or endpoint of the study was met. The occurring in approximately 5–7 % of CLL CLL for whom no standard therapies main safety findings were expected and cases [1]. However, defined standards of were available. In stage 1 of the trial, manageable. Mostly, hematologic AEs care are lacking, and outcomes are gen- DTRM-12 doses were escalated between occurred, with grade 3/4 neutropenia erally poor once patients are refractory 50 and 300 mg/d. Stage 2 was devoted to and grade 3/4 thrombocytopenia to rituximab plus chemotherapy. A new testing DTRM-12 in escalating doses emerging in 54 % and 37 %, respectively. strategy is the synthetic lethality ap- plus everolimus 5 mg/d. Finally, in stage No patient discontinued combination proach that describes simultaneous in- 3, the combination of DTRM-12 in esca- therapy due to an AE. Pharmacokinetic hibition of multiple pathways leading to lating doses plus everolimus 5 mg/d and analyses demonstrated that plasma cell death. Both the primary aberrant pomalidomide 2 mg/d on 21 out of 28 concentrations of DTRM-12 were linear pathway and compensatory pathways days was examined. The ultimate goal of and unaffected by the coadministration are inhibited. the phase II was the production of a sin- of everolimus and pomalidomide. The Analyses using an independent, iter- gle, fixed-dose combination tablet. pharmacokinetic data supported the ative screening and optimization pro- once-daily dosing of DTRM-12, with an cess were used to assess combinations of Viable regimen in RT and estimated half-life of 5–9 hours. targeted agents based on DTRM-12, a DLBCL Best overall responses were 46 % and novel, covalent, selective BTK inhibitor 45 % for patients with RT and DLBCL, that has been specifically designed as a At ASH 2020, Mato et al. presented the respectively. In the RT population, 1 backbone for combination therapies [2]. data on patients enrolled in phase I with and 4 patients achieved CR and PR, re- After in vitro and in vivo screening, the a diagnosis of RT (n = 13) or de novo spectively. For the DLBCL group, this best candidate triplet was selected for DLBCL (n = 11) [2]. All patients were applied to 2 and 3 individuals, respec- clinical trials. Preclinical studies showed pretreated with an anti-CD20 antibody, tively. Overall, 43 % of patients had that concurrent BTK inhibition, mTOR and all DLBCL patients had received R- ≥ 50 % reductions in the sum of the inhibition and the use of an immuno CHOP, as had 69 % of RT patients. BTK products of the greatest diameters of modulating agent at low doses can syn- inhibitors and the Bcl-2 inhibitor vene- lymph nodes (Figure). Even patients ergistically kill malignant B cells. The toclax had also been used in substantial with 10 prior treatment lines experi- DTRM-555 regimen was designed as an proportions prior to study entry. enced durable responses. Overall, the
12 1/2021 © Springer-Verlag memo special issue ASH 2020
triple fixed-dose combination tablet 80 DTRM-555 showed encouraging clini- RT 60 DLBCL cal activity in a high-risk, heavily pre- treated RT/DLBCL population. The tab- 40 let is currently in the final stage of 20 development. Once-daily, oral dosing provides a convenient treatment sched- 0 ule for patients and might therefore im- prove adherence to therapy. -20
-40 Safety of zanubrutinib after ibrutinib/acalabrutinib -60
-80 A multicenter, single-arm, open-label phase II study evaluated the next-gener- -100 ation BTK inhibitor zanubrutinib in 60 Figure: Depth of nodal response observed with DTRM-555 treatment in patients who had Richter’s patients with previously treated B-cell transformation or de novo DLBCL malignancies who had discontinued ibrutinib and/or acalabrutinib due to patient discontinued treatment due to BTK inhibition, chemotherapy, anti- AEs [3]. Tolerability issues are a com- adverse events. CD20 antibodies, CAR-T cell therapy, and mon cause of treatment discontinuation Compared with prior BTK inhibitor stem cell transplantation. Progressive with respect to these two agents [4, 5]. treatment, zanubrutinib maintained re- disease was the reason for discontinua- The primary objective was the assess- sponses (44.4 %) or improved them tion of BTK inhibitor pretreatment in 67– ment of the safety of zanubrutinib com- (50 %). At a median follow-up of 3.5 79 % of cases. pared with the ibrutinib and/or acala- months, 96.9 % of patients remained on The pharmacokinetic analysis was brutinib intolerance AE profile. Due to study. As the authors noted, these data conducted within a dose range from 25 its improved selectivity, zanubrutinib suggest that zanubrutinib might provide to 300 mg/d. Here, plasma exposures of was assumed to provide greater tolera- a therapeutic option in patients intoler- LOXO-305 were shown to be dose-de- bility with reduced recurrence and se- ant to other BTK inhibitors. pendent and linear. They exceeded BTK verity of BTK-inhibitor–emergent AEs. IC90 throughout dosing intervals at The population included 25 patients LOXO-305: doses ≥ 100 mg/d. LOXO-305 showed a with CLL/SLL, two with mantle cell lym- durable responses in MCL favorable safety profile consistent with phoma (MCL), and five with Walden- its design as a highly selective and non- ström’s macroglobulinemia (WM). The highly potent and selective non-co- covalent BTK inhibitor. No dose-limit- According to the analysis, zanubruti- valent BTK inhibitor LOXO-305 was as- ing toxicities were reported, and no nib was tolerable and effective. Intoler- sessed in 323 patients with CLL/SLL, maximum tolerated dose was identi- able AEs experienced on ibrutinib and/ MCL, WM, and other NHLs participat- fied. LOXO-305 200 mg/d was selected or acalabrutinib were unlikely to recur ing in the phase I/II BRUIN study. At as the recommended phase II dose. while on zanubrutinib; no recurrence ASH 2020, Wang et al. presented the ef- Rates of AEs of special interest such as was noted for 88 % of ibrutinib-intoler- ficacy results for 61 patients with MCL, bruising, rash, arthralgia and hemor- ant events and 50 % of acalabrutinib-in- 26 with WM and 66 with other NHLs, rhage were low. Among 323 patients, tolerant events. Among the events that and safety results for all 323 patients [6]. only 5 (1.5 %) discontinued LOXO-305 did recur, 88 % of ibrutinib events and In the efficacy population, all patients due to treatment-related AEs. 50 % of acalabrutinib events showed were pretreated. The median numbers of LOXO-305 demonstrated promising lower severity. None of the grade 4 intol- prior lines of systemic therapies were 3, 3, efficacy independent of prior therapy. erant events recurred on zanubrutinib. and 4 for those with MCL, WM and other ORRs were 52 % and 68 % for patients Out of 25 grade 3 events, only 2 recurred. NHLs. Previous treatments included all with MCL and WM, respectively. In the No serious AEs were observed, and no available classes of therapy including group with other NHLs, they ranged
TABLE Responses elicited with LOXO-305 treatment in patients with various non-Hodgkin lymphomas Richter’s transformation Follicular lymphoma Marginal zone lymphoma DLBCL (n = 8) (n = 8) (n = 9) (n = 25) Overall response rate, % (95 % CI) 75 (35-97) 50 (16-84) 22 (3-60) 24 (9-45) Best Response - Complete response, n (%) 0 2 (25) 0 4 (16) - Partial response, n (%) 6 (75) 2 (25) 2 (22) 2 (8) - Stable disease, n (%) 1 (13) 1 (13) 7 (78) 2 (8)
memo © Springer-Verlag 1/2021 13 ASH 2020 special issue
from 22 % for marginal zone lymphoma TG-1701 with the dual PI3Kδ/CK-1ε in- observed. Regarding efficacy, mono- to 75 % for Richter’s transformation (Ta- hibitor umbralisib and ublituximab, a therapy at doses of 100–400 mg gave rise ble). Notably, LOXO-305 led to durable glycoengineered anti-CD20 antibody, to an ORR of 52 %. In the disease-spe- responses in BTK-pretreated patients demonstrated inhibition of tumor growth cific cohorts treated with TG-1701 with MCL in whom outcomes are gener- in BTK-resistant xenograft models [10]. 200 mg, ORRs for patients with CLL, ally poor following progression on cova- Cheah et al. reported phase I study results MCL and WM were 95 %, 50 %, and lent BTK inhibitors such as ibrutinib [7, for TG-1701 as monotherapy and in com- 95 %, respectively. For the dose-escala- 8]. BTK-pretreated MCL patients bination with umbralisib and ublituxi- tion triplet combination consisting of achieved complete remissions in 25 %, mab (U2) in patients with B-cell lym- TG-1701 and U2, the ORR was 79 %, in- and 83 % of responders were still re- phoma or CLL that warranted systemic cluding complete remissions in 22 %. At sponding and on treatment at 6 months. therapy [11]. Parallel dose escalation was the time of the analysis, most patients Overall, the analysis showed that LOXO- conducted in both monotherapy (n = 25; were still on study. 305 is well tolerated and exhibits 100–400 mg/d) and combination cohorts Overall, TG-1701 exhibited an en- promising efficacy in heavily pretreated (n = 16; 100–300 mg/d). Disease-specific couraging safety profile, with clinical patients with various NHLs. A longer cohorts were expanded at 200 mg and and pharmacodynamic activity at all follow-up is required to better under- 300 mg of single-agent TG-1701 for pa- evaluated dose levels that support once- stand the safety profile associated with tients with CLL (n = 20), MCL (n = 21), daily dosing. The maximum tolerated chronic administration. and WM (n = 20). All patients in the dose dose had not been reached in the mono escalation phase had relapsed and refrac- therapy arm. Also, the combination with TG-1701 as single agent and in tory disease, while several individuals in U2 was well tolerated, and dose escala- combination with U2 each disease-specific cohort were treat- tion continues. Combination treatment ment-naïve. was associated with encouraging clini- Another investigational next-generation The safety profile was generally fa- cal activity, including early complete re- BTK inhibitor is TG-1701, a once-daily, vorable, and no patient discontinued sponses. This study continues enroll- covalently bound agent. Compared with therapy due to AEs. For both TG-1701 ment, and future registrations trials are ibrutinib, it was shown to exhibit superior monotherapy and the triplet combina- being planned. n selectivity [9]. The triple combination of tion, grade ≥ 3 AEs were infrequently
REFERENCES
1 Tsimberidou AM, Keating MJ, Richter syn- 5 Yazdy MS et al., Toxicities and outcomes of 8 Martin P et al., Post ibrutinib outcomes in pa- drome: biology, incidence, and therapeutic strat- acalabrutinib-treated patients with chronic lym- tients with mantle cell lymphoma. Blood 2016; egies. Cancer 2005; 103(2): 216-228 phocytic leukemia: a retrospective analysis of 127: 1559-1563 2 Mato AR et al., A once daily, oral, triple com- real world patients. Blood 2019; 134(Supple- 9 Normant E et al., TG-1701, a novel, orally bination of BTK inhibitor, mTOR inhibitor and ment_1): 4311 available, and covalently bound BTK inhibitor. IMID for treatment of relapsed/refractory Rich- 6 Wang ML et al., LOXO-305, a next genera- EHA 2018, abstract PF638 ter’s transformation and de novo diffuse large B- tion, highly selective, non-covalent BTK inhibitor 10 Ribeiro ML et al., TG-1701, a novel irreversi- cell lymphoma. ASH 2020, abstract 126 in previously treated mantle cell lymphoma, Wal- ble Bruton’s kinase inhibitor, cooperates with 3 Shadman M et al., Phase 2 study of zanubru- denström’s macroglobulinemia, and other Non- ublituximab-driven ADCC and ADCP in in vitro tinib in patients with previously treated B-cell Hodgkin lymphomas: results from the phase 1/2 and in vivo models of ibrutinib-resistant mantle malignancies intolerance to ibrutinib/acalabruti- BRUIN study. ASH 2020, abstract 117 cell lymphoma. AACR 2020, abstract 2205 nib. ASH 2020, abstract 2947 7 Cheah CY et al., Patients with mantle cell 11 Cheah CY et al., Clinical activity of TG-1701, 4 Mato AR et al., Toxicities and outcomes of lymphoma failing ibrutinib are unlikely to re- as monotherapy and in combination with 616 ibrutinib-treated patients in the United spond to salvage chemotherapy and have poor ublituximab and umbralisib, in patients with B- States: a real-world analysis. Haematologica outcomes. Ann Oncol 2015; 26: 1175-1179 cell malignancies. ASH 2020, abstract 1130 2018; 103(5): 874-879
Approaching marginal zone lymphoma from various angles
Approximately 10 % of Non-Hodgkin therapeutic strategies for patients with inhibitor parsaclisib have the potential lymphomas are classified as marginal MZL have been difficult to define. to change the course of disease in a zone lymphoma (MZL) [1]. This is a Advanced disease is largely considered considerable proportion of patients. heterogeneous malignancy with three incurable, with continuing patterns of main subtypes (i.e., extranodal, nodal, relapse and remission. However, phase MAGNOLIA: patients with splenic) arising from memory B cells in II data presented at the ASH 2020 high-risk features the marginal zone of secondary Congress showed that emerging lymphoid follicles [2, 3]. Due to its rarity treatment options such as the BTK BTK inhibition has been hypothesized to and heterogeneous nature, the optimal inhibitor zanubrutinib and the PI3Kδ work in MZL patients based on the ob-
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servation that B-cell-receptor–mediated TABLE signaling is a critical step in the patho- Best overall response by investigator observed with zanubrutinib in the genesis of this disease [4]. Indeed, the MAGNOLIA study first-generation BTK inhibitor ibrutinib Best response n = 66 was shown to be active in the relapsed/ refractory (r/r) setting [5] and has been ORR (complete or partial response), n (%) 49 (74.2) granted accelerated approval by the FDA 95 % CI (61.99, 84.22) as monotherapy in patients pretreated - Complete response 16 (24.2) with ≤ 1 anti-CD20-based regimen. - Partial response 33 (50.0) In an early-phase study, the next- generation BTK inhibitor zanubrutinib - Stable disease 10 (15.2) induced an 80 % ORR in 20 patients with - Progressive disease 5 (7.6) r/r MZL [6]. Therefore, the multicenter, - Disease control rate 59 (89.4) open-label, single-arm, phase II MAGNOLIA study investigated single- - Discontinued prior to first assessment/missing 2 (2.9) agent zanubrutinib 160 mg twice daily Time to response (months), median (range) 2.8 (1.7-11.1) in 68 patients with r/r MZL who had Study follow-up (months), median (range) 10.7 (1.6-16.7) received ≤ 1 prior line of CD20-directed therapy. ORR by independent review committee (IRC) using the Lugano 65 % in those after ≥ 3 treatment lines, prevailed. One patient each developed classification was defined as the primary and 71 % in those with refractory disease. atrial fibrillation and atrial flutter. No outcome. At ASH 2020, Opat et al. re- Almost 80 % of the entire group were still major hemorrhages and no cases of ported the response findings according responding at 6 months. hypertension were observed. to investigator assessment after a me- Median PFS and OS had not been dian follow-up of 10.7 months, while the reached yet. At 9 months, 67 % of pa- Preliminary results from blinded response assessment by IRC tients were progression-free, and at 12 CITADEL-204 was ongoing [7]. months, 94 % were alive. Zanubrutinib MAGNOLIA generally enrolled pa- showed a favorable AE profile and was The potent, highly selective, next-gener- tients with high-risk features. Sixty per- generally well tolerated, which is also ation PI3Kδ inhibitor parsaclisib has cent were aged ≥ 65 years, and 28 % were mirrored by the 99.6 % median relative shown promising clinical activity in r/r even 75 years or older. Two thirds and dose intensity. Grade ≥ 3 treatment- B-cell lymphomas including MZL in one third had relapsed and refractory dis- emergent AEs (TEAEs) occurred in early trials [8]. Therefore, the open-label, ease, respectively. All subtypes of MZL 38.2 %. In 23.5 %, dose interruptions phase II CITADEL-204 study assessed were included, with 38.2 % showing the were performed, while no patient re- two parsaclisib treatment schedules in nodal subtype that conveys a poorer quired dose reductions. Only 2.9 % dis- patients with r/r MZL who had received prognosis than the extranodal subtype. continued treatment due to TEAEs. ≥ 1 prior systemic therapy including ≥ 1 Lymphoma involvement in bone marrow Among TEAEs of interest, infection, anti-CD20 antibody as monotherapy or was present in 42.6 %. A median of 2 lines hemorrhage, diarrhea and neutropenia chemoimmunotherapy combination. of systemic therapy had been adminis- tered prior to study inclusion. At the time 1.0 of the analysis, 44 patients remained on 0.9 All treated patients Daily group treatment. 0.8 0.7 Clinical benefit of almost 90 % 0.6 0.5 Zanubrutinib proved to be highly active 0.4 in this population. Overall, 74.2 % of pa- 0.3 tients responded, with complete remis- PFS probability 0.2 sions resulting in 24.2 % (Table). Clinical 0.1 benefit (complete and partial responses 0.0 plus stable disease) was observed in Number at risk Daily group 72 61 55 47 40 28 15 10 8 5 1 1 0 89.4 %. Median time to response was All patients 100 85 74 65 57 43 29 19 15 7 2 2 0 short at 2.8 months. The majority of pa- 0 2 4 6 8 10 12 14 16 18 20 22 24 tients developed reductions in their tu- Time to event, months mor burden. Responses were generally consistent across subgroups with respect All treated patients Daily group to MZL subtype, age, number of prior (n = 100) (n = 72) Median PFS (95 % CI), months lines of systemic therapy and nature of 19.4 (13.7–NE) NR (11.0–NE) prior treatment, among others. The ORRs Figure: Progression-free survival in all patients treated with parsaclisib and in the cohort receiving were 89 % in patients aged ≥ 75 years, continuous daily parsaclisib doses
memo © Springer-Verlag 1/2021 15 ASH 2020 special issue
The study was designed to include a 14.9 months, for all treated patients and daily group, neither median duration of BTK-inhibitor–naïve and an ibrutinib- the daily group, respectively. response nor median PFS (Figure) had experienced cohort. However, the latter been reached yet. was eventually terminated due to Rapid and durable responses Parsaclisib showed a manageable slower-than-expected enrollment. safety profile. Diarrhea, cough and rash Patients enrolled in the study were in- The ORR by independent review was were observed as the most common itially allocated to either parsaclisib 57.0 % and 56.9 % in all patients and the AEs. The most common grade ≥ 3 AEs 20 mg daily for 8 weeks followed by daily group, respectively. Complete re- were diarrhea and neutropenia. Among 20 mg once weekly (weekly group) or mission resulted in 6.0 % and 5.6 %, re- serious TEAEs, pneumonia (7 %), colitis parsaclisib 20 mg daily for 8 weeks fol- spectively. ORRs did not differ signifi- (5 %), diarrhea (5 %) and febrile lowed by 2.5 mg daily continuously cantly across patients with nodal, neutropenia (5 %) showed the highest (daily group). The daily group regimen extranodal and splenic MZL; this also incidence. A total of 27 patients was selected as the preferred regimen applied to the groups who were refrac- discontinued treatment due to TEAEs, during the study, and all subsequent pa- tory to prior therapy and those who had with diarrhea or colitis events occurring tients were enrolled into this group. ORR relapsed on it. Sixty-seven percent of re- in 14 individuals. The median time to constituted the primary endpoint. At sponders had either complete or partial onset of grade ≥ 3 diarrhea/colitis events ASH 2020, Phillips et al. presented pre- responses already at the time of the first was 5.3 months, and the median time to liminary efficacy and safety data from assessment. Median time to first re- improvement to grade ≤ 2 was 12.0 days. the BTK inhibitor-naïve cohort for all sponse was 8.1 weeks. In the total group, In their conclusion, the authors noted treated patients (n = 100) and the daily median duration of response and me- that parsaclisib represents a potential group (n = 72) [9]. At data cutoff, the me- dian PFS were 12.0 months and 19.4 new treatment option and first-in-class dian duration of follow-up was 16.7 and months (Figure), respectively. In the PI3Kδ inhibitor for MZL patients. n
REFERENCES
4 Seiler T, Dreyling M, Bruton’s tyrosine kinase 7 Opat S et al., Efficacy and safety of 1 Leslie LA et al., Contemporary management inhibitors in B-cell lymphoma: current zanubrutinib in patients with relapsed/ of nodal and primary splenic marginal zone experience and future perspectives. Expert refractory marginal zone lymphoma: initial re- lymphoma. Expert Rev Hematol 2019; 12(12): Opin Investig Drugs 2017; 26(8): 909-915 sults of the MAGNOLIA (BGB-3111-214) trial. 1011-1022 5 Noy A et al., Targeting Bruton tyrosine kinase ASH 2020, abstract 339 2 Denlinger NM et al., Management of with ibrutinib in relapsed/refractory marginal 8 Forero-Torres A et al., Parsaclisib, a potent relapsed/refractory marginal zone lymphoma: zone lymphoma. Blood 2017; 129(16): 2224- and highly selective PI3Kδ inhibitor, in patients focus on ibrutinib. Cancer Manag Res 2018; 2232 with relapsed or refractory B-cell malignancies. 10: 615-624 6 Tedeschi A et al., Phase 1/2 study of single- Blood 2019; 133(16): 1742-1752 3 Kahl B, Yang D, Marginal zone lymphomas: agent zanubrutinib in patients with relapsed/ 9 Phillips T et al., Phase 2 study evaluating the management of nodal, splenic, and MALT refractory marginal zone lymphoma. EHA efficacy and safety of parsaciclib in patients with NHL. Hematology Am Soc Hematol Educ 2020, abstract EP1165 relapsed or refractory marginal zone lymphoma Program 2008: 359-364 (CITADEL-204). ASH 2020, abstract 338
Advancing treatment in patients with mantle cell lymphoma
Update on acalabrutinib A total of 124 patients with r/r MCL were 36-month OS rate was 60.5 %. Six of 30 monotherapy enrolled. At a median follow-up of 38.1 patients (20 %) with available samples months, 55 (44 %) remained on study, maintained complete remission and un- High relapse rates after standard-of-care with 24 (19 %) still receiving acalabru detectable minimal residual disease at regimens in the frontline setting are typ- tinib. the last assessment. ical of mantle cell lymphoma (MCL), According to the updated findings, Moreover, the extended follow-up which is an aggressive, rare, B-cell Non- treatment efficacy was largely conveyed no new safety concerns. The Hodgkin lymphoma [1-4]. The second- maintained. The ORR was 81 %, as it had AE profile was basically unchanged, with generation, highly selective BTK inhibi- been after the 26-month follow-up at the infections and bleeding events occurring tor acalabrutinib has been approved in time of the primary analysis (Table) [5]. as the most common toxicities. More the US for the treatment of patients with Complete responses had increased from than half of patients with any bleeding MCL after ≥ 1 prior therapy based on the 43 % to 48 %. Median duration of event were receiving anticoagulant single-arm, open-label, multicenter, response amounted to 28.6 months. At medication. AEs led to dose delays in 50 phase II ACE-LY-004 study [5]. At ASH 36 months, 41.9 % of patients responded, patients (40 %) and dose modifications 2020, Wang et al. reported updated effi- and 37.2 % were progression-free. in 2 (2 %). There were 57 deaths (46 %), cacy and safety results from this trial Median PFS was 22.0 months. Median most commonly due to disease after an additional year of follow-up [6]. OS had not been reached yet, and the progression (n = 38; 31 %). Overall, these
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TABLE response had not been reached yet at the Updated response rates with acalabrutinib monotherapy for the treatment time of the analysis. of relapsed/refractory mantle cell lymphoma Orelabrutinib showed a favorable safety profile. Treatment-related AEs All patients (n = 124) leading to dose reductions and study 26-month 38-month drug discontinuation occurred in 6.6 % follow-up follow-up and 2.8 %, respectively. Thrombo n (%) n (%) cytopenia, neutropenia and upper res- Overall response rate (complete + partial response) 100 (81) 101 (81) piratory tract infections were most com- Best response monly reported. Among AEs of special interest, hemorrhage was most common - Complete response 53 (43) 59 (48) but was restricted to grade 1 and 2. More- - Partial response 47 (38) 42 (84) over, no grade ≥ 3 atrial fibrillation/flut- - Stable disease 11 (9) 10 (8) ter or grade ≥ 3 diarrhea occurred. Grade ≥ 3 infections were observed in 12.3 %. - Progressive disease 10 (8) 10 (8) As the authors noted in their conclusion, - Not evaluable 3 (2) 3 (2) the pronounced efficacy and improved safety of orelabrutinib resulting from its high target selectivity, combined with data confirmed the safety and efficacy of administered, chemotherapy-free option the convenience of daily dosing, mark acalabrutinib in patients with r/r MCL. for transplant-ineligible elderly patients this agent as a preferable option for the with non-blastoid (Ki-67 < 50 %) MCL. treatment of patients with B-cell malig- Frontline ibrutinib + rituximab The increased incidence of arrhythmia nancies. in the elderly observed in the study was likely due to the high number of cardiovascular risk Parsaclisib in BTK-inhibitor– Many elderly patients suffering from factors in this population. This suggested pretreated patients… MCL are transplant-ineligible and not that baseline cardiac evaluation and car- suitable for intensive chemoimmuno diovascular risk factor modification The CITADEL-205 study evaluated the therapy due to comorbidities. The should be performed in the context of highly selective, next-generation PI3Kδ combined use of ibrutinib and rituximab treatment with ibrutinib and rituximab. inhibitor parsaclisib in the setting of r/r was tested in a single-center, phase II The long-term follow-up will reveal the MCL. Cohort 1 of the study contained study containing 50 previously untreated impact of the combined treatment on patients who had previously received MCL patients aged ≥ 65 years with ECOG safety and relapse patterns. BTK inhibition, while those in Cohort 2 performance status ≤ 2 and normal or- were BTK-inhibitor–naïve. In both gan function [7]. Their median age was Orelabrutinib gives rise to high groups, 1–3 prior lines of systemic ther- 71 years. Bone marrow involvement was CR rates apy had been administered. Parsaclisib present in 94 %. Twenty-five percent had 20 mg for 8 weeks was followed by either a Ki-67 index ≥ 30-50 %. A multicenter, open-label, phase II study 20 mg once weekly (weekly group) or Overall, 90 % of patients responded to tested the efficacy and safety of the novel, 2.5 mg once daily continuously (daily the treatment, with 62 % and 28 % highly selective, irreversible BTK group). During the study, the daily achieving complete and partial remis- inhibitor orelabrutinib as monotherapy group dose was selected as the pre- sions, respectively. MRD negativity at the in Chinese patients with r/r MCL [8]. The ferred dosing regimen, and patients in time of the best response was 87 %. Me- safety population comprised 106 the weekly group were allowed to switch dian PFS and OS had not been reached patients, and 99 made up the efficacy to the daily group. The findings for the yet at a median follow-up of 43 months. population. Orelabrutinib was overall and daily groups were reported Out of 4 patients who progressed, 3 administered at doses of 100 mg twice at ASH 2020 for Cohorts 1 and 2 sepa- showed transformation to the blastoid/ daily (n = 20) and 150 mg/d (n = 86). rately. pleomorphic variant. Two had Ki-67 The treatment gave rise to marked Zinzani et al. presented the results ≥ 30 %, one was TP53-mutated, and an- responses and durable remissions. At for the BTK-inhibitor–pretreated Cohort other had FAT1 and SF3B1 mutations. 16.4 months, the ORR was 87.9 %, with a 1 which consisted of a total of 53 Five patients died off study; in 3 cases, CR rate of 34.3 % by CT-based imaging. patients, with 41 treated in the daily this was due to progression, and in 2, the These results represented slight increases group [9]. The ORRs according to etiology was unknown. Among AEs, fa- compared to the ORR and CR of 85.9 % independent review were 25 % and 29 % tigue, diarrhea and myalgia occurred and 30.3 %, respectively, observed at 10.5 (Figure) for the overall and daily most frequently. Seventeen patients months. Complete responses according groups, respectively. CRs resulted in 2 % (34 %) developed atrial fibrillation. Me- to PET-CT had even been achieved in each, and PRs and 23 % and 27 %, dian time to onset from the start of treat- 42.9 %. The disease control rate added up respectively. Forty-seven percent of all ment was 9.4 months. to 93.9 %. At 12 months, 70.8 % of patients treated patients and 51 % of those in the The authors noted that ibrutinib plus were progression-free, and 88.7 % were daily group had regression of target rituximab is a highly effective, easily alive. Median PFS and duration of lesions. Median duration of response
memo © Springer-Verlag 1/2021 17 ASH 2020 special issue
2 % Complete response
5 % 4 % 12 % Complete response 27 % 27 % 20 % Partial Stable response disease
2 % 17 % Complete response 60 % Stable Partial 24 % disease Partial response Stable disease response Progressive disease Not evaluable Not assessed
Figure: CITADEL-205: responses obtained with parsaclisib in BTK-inhibitor–pretreated patients (left) and not pretreated patients (right; daily dosing groups)
amounted to 3.7 months in both groups; 77 individuals made up the total and 18 months, 69 % and 68 % of patients, likewise, median PFS was 3.7 across all daily groups, respectively. Responses respectively, were alive. patients. Median OS was 11.2 in both were observed in 70 % and 71 %, respec- Overall, parsaclisib showed clinical the total cohort and the daily group. Es- tively, with 15 % and 12 % obtaining CR, activity in both cohorts with r/r MCL. timated survival rates at 18 months were respectively (Figure). Partial responses The efficacy of treatment was deemed 32 % and 37 %, respectively. occurred in 56 % and 60 %, respectively. excellent in the BTK-inhibitor–naïve Eighty-four percent and 87 %, respec- setting. Here, the authors concluded … and those without BTK tively, developed regression of their tar- that parsaclisib represents a potential inhibitor pretreatment get lesions. Median duration of re- new option and is a first-in-class PI3Kδ sponse was 14.7 and 9.0 months, inhibitor in the setting of MCL. In both For Cohort 2 that contained BTK-inhib- respectively, and median PFS was 11.1 Cohort 1 and 2, the new agent demon- itor–naïve patients, Mehta et al. re- months in both groups. Median OS had strated an acceptable safety profile and ported the findings [10]. Here, 108 and not been reached yet in either group. At was generally well tolerated. n
REFERENCES
1 Swerdlow SH et al., The 2016 revision of the refractory mantle cell lymphoma. Curr Oncol 8 Song Y et al., Long-term safety and efficacy World Health Organization classification of 2019; 26(2): e233-240 of orelabrutinib monotherapy in Chinese patients lymphoid neoplasms. Blood 2016; 127(20): 5 Wang M et al., Durable response with single- with relapsed or refractory mantle cell 2375-2390 agent acalabrutinib in patients with relapsed or lymphoma: a multicenter, open-label, phase II 2 Vose JM, Mantle cell lymphoma: 2017 update refractory mantle cell lymphoma. Leukemia study. ASH 2020, abstract 2048 on diagnosis, risk-stratification, and clinical 2019; 33(11): 2762-2766 9 Zinzani PL et al., Phase 2 study evaluating management. Am J Hematol 2017; 92(8): 806- 6 Wang M et al., Acalabrutinib monotherapy in the efficacy and safety of parsaclisib in patients 813 patients with relapsed/refractory mantle cell with relapsed or refractory mantle cell lymphoma 3 Jain P, Wang M, Mantle cell lymphoma: 2019 lymphoma: long-term efficacy and safety results previously treated with ibrutinib (CITADEL-205). update on the diagnosis, pathogenesis, from a phase 2 study. ASH 2020, abstract 2040 ASH 2020, abstract 2044 prognostication, and management. Am J 7 Jain P et al., Combination of ibrutinib with 10 Mehta A et al., Phase 2 study evaluating the Hematol 2019; 94(6): 710-725 rituximab in previously untreated older patients efficacy and safety of parsaclisib in patients with 4 Owen C et al., Review of Bruton tyrosine with mantle cell lymphoma – a phase II clinical relapsed or refractory mantle cell lymphoma not kinase inhibitors for the treatment of relapsed or trial. ASH 2020, abstract 2042 previously treated with a BTK inhibitor (CITADEL-205). ASH 2020, abstract 1121
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Interview: Stephen Opat, MD, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia
Finding the way among a multitude of targets and regimens
Under which conditions might pa- one option and combination time-lim- tients with chronic lymphocytic leu- ited therapy is another; it is really hard kemia achieve long-term treatment- to say which one will win out. However, free remission? many patients have been on BTK in I would like to address two factors here. hibitor therapy for several years and The first one relates to favorable disease have achieved great disease control. biology. Patients who have mutated im- munoglobulin genes or lack TP53 muta- What are the strengths and limitations tions or 17p loss are more likely to expe- of immune checkpoint inhibition in rience treatment-free remission. The B-cell malignancies from the current other main factor is treatment capable point of view? of inducing deep remission, which is This area is still emerging. We have seen usually combination therapy. Histori- own © author’s very good responses in primary medi cally, the fludarabine/cyclophospha- Stephen Opat, MD, astinal lymphoma and Hodgkin’s dis- mide/rituximab regimen was the gold School of Clinical Sciences at Monash Health, ease [6-8]. However, most studies to standard with which patients could Monash University, Melbourne, Australia date have involved the PD-1 and PD-L1 achieve deep remissions. However, we checkpoints, although there are many have several fixed-duration options. The time of the 5-year update that was re- other inhibitory receptors such as CLL14 study investigated venetoclax cently published [5]. However, only 60 % CTLA-4, TIM-3, TIGIT, and BTLA that plus obinutuzumab, while CAPTIVATE were still receiving the study drug. The can be explored. This also includes the assessed ibrutinib plus venetoclax. Also, follow-up is still relatively short. I think agonist receptors 4-1BB, LAG-3, OX40 the combination of acalabrutinib, vene- single-agent BTK inhibitors will be a and CD27, the macrophage checkpoint toclax and obinutuzumab was tested. good option for several patients, par- CD47, and NK ligands. The main prob- These combinations achieved undetect- ticularly for those with comorbidities. It lem with these drugs is induction of au- able minimal residual disease in large is being said that combinations tend to toimmunity, which can involve any or- proportions of patients [1-4], which cor- have more side effects; for instance, the gan system. Immune-related toxicities relates with long treatment-free remis- rates of neutropenia are higher if you include rash, colitis, pneumonitis, or sions. combine venetoclax with other drugs. even endocrine insufficiency. Some of the newer BTK inhibitors have This entire area of immune check- Where do you see BTK inhibition in a favorable safety profile and might thus point inhibition is a fantastic emerging the management of B-cell malignan- be more suited to long-term usage. A area. However, our knowledge is early, cies 3 years from now? number of long-term toxicities have not and we still have a long way to go. Some This is a very difficult question. If you been elucidated yet. There is a risk of in- patients are already deriving benefit, look at the data, you see that in the RES- fection, hypertension and arrhythmias, and I think there will be many more ONATE-2 trial investigating first-line and there is also a question about sec- once we have worked out what the best ibrutinib in patients with CLL/SLL, 70 % ond primary malignancies. Continu- combinations are and in which patients of patients were progression-free at the ously administered BTK inhibitors are they should be used. n
REFERENCES
1 Al-Sawaf O et al., Fixed-duration venetoclax- lapsed/refractory chronic lymphocytic leukemia. cacy and safety from the phase II CheckMate obinutuzumab for previously untreated chronic ASH 2020, abstract 1312 436 Study. J Clin Oncol 2019; 37: 3081-3089 lymphocyctic leukaemia: follow-up of efficacy 4 Davids MS et al., Updated safety and efficacy 7 Moskowitz AJ et al., Brentuximab vedotin and safety results from the multicenter, open-la- results from a phase 2 study of acalabrutinib, and nivolumab for relapsed or refractory classic bel, randomized phase 3 CLL14 trial. EHA 2020, venetoclax and obinutuzumab (AVO) for frontline Hodgkin Lymphoma: long-term follow-up results abstract S155 treatment of chronic lymphocytic leukemia from the single-arm phase 1/2 study. Blood 2 Wierda WG et al., Ibrutinib plus venetoclax for (CLL). ASH 2020, abstract 2216 2019; 134 (Supplement_1): 238 first-line treatment of chronic lymphocytic leuke- 5 Burger JA et al., Long-term efficacy and 8 Kuruvilla J et al., Effect of pembrolizumab mia/small lymphocyctic lymphoma: 1-year dis- safety of first-line ibrutinib treatment for patients monotherapy compared with brentuximab vedo- ease-free survival results from the MRD cohort with CLL/SLL: 5 years of follow-up from the tin on patients with relapsed/refractory classical of the phase 2 CAPTIVATE study. ASH 2020, ab- phase 3 RESONATE-2 study. Leukemia 2020; Hodgkin lymphoma by prior lines of therapy: an stract 123 34: 787-798 exploratory analysis of the randomized phase 3 3 Woyach JA et al., Acalabrutinib in combina- 6 Zinzani PL et al., Nivolumab combined with KEYNOTE-204 study. ASH 2020, abstract 1158 tion with venetoclax and obinutuzumab or rituxi- brentuximab vedotin for relapsed/refractory pri- mab in patients with treatment-naïve or re- mary mediastinal large B-cell lymphoma: effi-
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PD-1 inhibition and (Non-)Hodgkin lymphoma: promising outcomes in an emerging field
Nivolumab plus BV for MGZL TABLE treatment KEYNOTE-204: progression-free survival with pembrolizumab vs. brentuximab vedotin (BV) according to the number of prior treatment lines Mediastinal gray zone lymphoma 1 prior line of therapy ≥ 2 prior lines of therapy (MGZL) is an extremely rare type of Non-Hodgkin lymphoma with a pre- Primary analysis (including clinical and imaging data following ASCT or allogeneic SCT) dominance in young men [1]. This dis- Pembrolizumab BV Pembrolizumab BV ease exhibits transitional features be- Median PFS (months) 16.4 8.4 12.6 8.2 tween nodular sclerosis classical Hodgkin lymphoma (cHL) and primary 12-month PFS rates (%) 58.9 37.4 52.8 35.3 mediastinal B-cell lymphoma (PMBL) Hazard ratio 0.70 0.66 [2, 3]. However, compared to PMBL, survival of patients with MGZL is infe- Secondary analysis (excluding clinical and imaging data following ASCT or allogeneic SCT) rior after conventional chemotherapy Pembrolizumab BV Pembrolizumab BV [4]. The phase II Checkmate 436 trial has Median PFS (months) 11.7 8.3 12.6 8.2 established high response rates for the anti-PD-L1 antibody nivolumab in 12-month PFS rates (%) 49.5 28.3 50.5 34.1 combination with the antibody-drug Hazard ratio 0.62 0.63 conjugate brentuximab vedotin (BV) in adult patients with r/r PMBL [5]. Simi- larly, nivolumab plus BV conferred fa- reported for nivolumab plus BV in r/r label, international, randomized, phase vorable results in patients with r/r cHL PMBL and r/r cHL [5, 6, 8]. All patients III KEYNOTE-204 study tested the PD-1 treated in the phase I/II setting [6]. who achieved CR were bridged to he- inhibitor pembrolizumab as monother- In a separate cohort of the Check- matopoietic cell transplantation (i.e., 4 apy (n = 151) against the antibody-drug Mate 436 study, patients with r/r MGZL to allogeneic SCTs and 1 to ASCT). conjugate brentuximab vedotin (BV; received nivolumab 240 mg plus BV Median OS had not been reached n = 153) in patients with r/r cHL. Treat- 1.8 mg/kg 3-weekly until disease pro- yet; at 6 months, 80 % of patients were ment was administered for up to 35 cy- gression. The primary efficacy and alive. Duration of response and PFS cles in both arms. The primary analysis safety analysis for the MGZL cohort could not be estimated reliably due to presented at ASCO 2020 already showed (n = 10) was reported at ASH 2020 [7]. earlier censoring of patients who re- a statistically significant and clinically Refractory disease was present in 7 pa- ceived subsequent therapies. The safety meaningful PFS benefit for pembroli- tients (70 %), and the median number of profile of the combination was tolerable zumab compared to BV (13.2 vs. 8.3 prior systemic cancer therapies was 2. and consistent with previous reports [5, months; HR, 0.65; p = 0.00271) [14]. At None of the patients had undergone au- 6, 8]. Cytopenia, paresthesia and pe- ASH 2020, Kuruvilla et al. presented a tologous stem cell transplantation ripheral sensory neuropathy occurred. post-hoc exploratory analysis of the (ASCT). No grade 4 AEs were observed. One pa- study that assessed the outcomes ac- tient was diagnosed with grade 3 febrile cording to the number of prior lines of Findings that favor bridging neutropenia, and another developed therapy [15]. Within the group of 55 pa- rash that was the only reported im- tients who had previously been treated At database lock, all patients had dis- mune-mediated AE and resolved with- with one line, 27 and 28 had received continued treatment. The reasons in- out systemic steroids. Based on these pembrolizumab and BV, respectively. cluded disease progression (n = 5), findings, the authors concluded that The cohort of patients after ≥ 2 treatment maximum clinical benefit (n = 3), allo- nivolumab plus BV represents a poten- lines (n = 249) comprised 124 and 125 geneic SCT (n = 1) and ASCT (n = 1). All tial option for bridging to stem cell individuals randomized to the check- of those with maximum clinical benefit transplant in patients with chemother- point inhibitor and BV, respectively. had achieved complete remission and apy-refractory MGZL. Single-agent pembrolizumab was proceeded to allogeneic SCT. The ORR shown to improve clinical outcomes obtained in the total group was high at cHL: pembrolizumab vs. BV compared with BV regardless of the 70 %; complete and partial responses number of prior therapies. This held occurred in 50 % and 20 %, respectively. Prognosis is poor for patients with re- true irrespective of whether patients Also, time to CR was short (1.2–4.8 lapsed/refractory cHL who have failed who went on to receive consolidative months). As the authors noted, these ASCT, have primary refractory disease or ASCT or allogeneic SCT were included findings were consistent with the results are ineligible for ASCT [9-13]. The open- in the data set or not (Table). Risk re-
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ductions ranged between 30 % and p = 0.04
38 %. Overall, these results were consist- 0.8 ent with the primary analysis [14]. Like- wise, ORRs were similar regardless of the treatment line. After one line, 66.7 % 0.4 vs. 53.6 % of patients responded, and af- ter ≥ 2 lines, this was true for 65.3 % vs. 54.4 %. Reponses lasted for a median of 0.0 20.7 vs. 14.1 months and 20.5 vs. 11.2 months, respectively. The safety profiles score gene signature of both agents were generally similar inflammation signature Tumor -0.4 across the subgroups. No unexpected safety signals occurred. Also, subsequent ASCT was assessed Patients with Patients without by prior line of therapy. In the group of complete remission complete remission patients after one line, 25.9 % and 33.3 % of patients in the pembrolizumab and Figure: Significantly increased inflammation of the tumor microenvironment in patients who developed complete response on tislelizumab treatment BV groups, respectively, underwent ASCT. For those with ≥ 2 pretreatment macrophages, T cells and other immune body-dependent cellular phagocytosis lines, this applied to 19.0 % and 20.0%, cells [16]. Limited efficacy of anti-PD-1 (ADCP), and thus its anti-tumor activity respectively. As the authors noted in antibodies with a wild-type Fc region was not compromised [19]. A pivotal their conclusion, these findings confirm such as nivolumab and pembrolizumab phase II trial investigating tislelizumab that patients with r/r cHL after only one might be due to binding to FcγR on mac- in Chinese patients with cHL that had prior line of therapy who are ineligible rophages, as this compromises the failed or were no candidates for high- for ASCT appear to benefit from pem- agents’ antitumor activity through acti- dose chemotherapy/ASCT revealed an brolizumab monotherapy. vation of antibody-dependent macro- ORR of 87.1 %, with a CR rate of 62.9 % phage-mediated killing of T effector [20]. The study reported at ASH 2020 ex- Effect of TME on tislelizumab cells [17, 18]. The anti-PD-1 antibody plored whether FcγR expression on efficacy tislelizumab has been specifically engi- macrophages in the cHL TME impacts neered to minimize binding to FcγR on the efficacy of tislelizumab [21]. More- Histologically, cHL has been shown to macrophages. over, additional biomarkers associated be characterized by low tumor cellular- Preclinical data showed that in mac- with CRs were assessed. Multiplex im- ity (1–5 %) and a dominant tumor mi- rophage- and T-cell–enriched condi- munohistochemistry (mIHC) and gene croenvironment (TME) composed of tions, tislelizumab did not induce anti- expression profiling (GEP) were used to
REFERENCES
1 Quintanilla-Martinez L, Fend F. Mediastinal lymphoma. Blood 2018; 131(11): 1183-1194 Hodgkin lymphoma by prior lines of therapy: an gray zone lymphoma. Haematologica 2011; 9 Fermé C et al., Intensive salvage therapy with exploratory analysis of the randomized phase 3 96(4): 496-499 high-dose chemotherapy for patients with ad- KEYNOTE-204 study. ASH 2020, abstract 1158 2 Eberle FC et al., Methylation profiling of medi- vanced Hodgkin’s disease in relapse or failure 16 Aoki T et al., Single-cell transcriptome analy- astinal gray zone lymphoma reveals a distinctive after initial chemotherapy: results of the Groupe sis reveals disease-defining T-cell subsets in the signature with elements shared by classical d’Etudes des Lymphomes de l’Adulte H89 Trial. tumor microenvironment of classic Hodgkin lym- Hodgkin’s lymphoma and primary mediastinal J Clin Oncol 2002; 20(2): 467-475 phoma. Cancer Discov 2020; 10(3): 406-421 large B-cell lymphoma. Haematologica 2011; 10 Goodman KA et al., Long-term effects of 17 Dahan R et al., FcγRs modulate the anti-tu- 96(4): 558-566 high-dose chemotherapy and radiation for re- mor activity of antibodies targeting the PD-1/ 3 Melani C et al., PD-1 blockade in mediastinal lapsed and refractory Hodgkin’s lymphoma. J PD-L1 axis. Cancer Cell 2015; 28(3): 285-295 gray-zone lymphoma. N Engl J Med 2017; Clin Oncol 2008; 26(32): 5240-5247 18 Arlauckas SP et al., In vivo imaging reveals 377(1): 89-91 11 Santoro A et al., Five-year results of the BE- a tumor-associated macrophage-mediated re- 4 Wilson WH et al., A prospective study of me- GEV salvage regimen in relapsed/refractory sistance pathway in anti-PD-1 therapy. Sci diastinal gray-zone lymphoma. Blood 2014; classical Hodgkin lymphoma. Blood Adv 2020; Transl Med 2017; 9(389): eeal3604 124(10): 1563-1569 4(1): 136-140 19 Zhang T et al., The binding of an anti-PD-1 5 Zinzani PL et al., Nivolumab combined with 12 Puig N et al., Different response to salvage antibody to FcγRΙ has a profound impact on its brentuximab vedotin for relapsed/refractory pri- chemotherapy but similar post-transplant out- biological functions. Cancer Immunol Immu- mary mediastinal large B-cell lymphoma: effi- comes in patients with relapsed and refractory nother 2018; 67(7): 1079-1090 cacy and safety from the phase II CheckMate Hodgkin’s lymphoma. Haematologica 2010; 20 Song Y, et al., Treatment of relapsed or re- 436 Study. J Clin Oncol 2019; 37(33): 3081-3089 95(9): 1496-1502 fractory classical Hodgkin lymphoma with the 6 Moskowitz AJ et al., Brentuximab vedotin 13 Younes A et al., Results of a pivotal phase II anti-PD-1, tislelizumab: results of a phase 2, sin- and nivolumab for relapsed or refractory classic study of brentuximab vedotin for patients with gle-arm, multicenter study. Leukemia 2020; Hodgkin Lymphoma: long-term follow-up results relapsed or refractory Hodgkin’s lymphoma. J 34(2): 533-542 from the single-arm phase 1/2 study. Blood Clin Oncol 2012; 30(18): 2183-2189 21 Song Y et al., Tumor microenvironment as- 2019; 134 (Supplement_1): 238 14 Kuruvilla J et al., KEYNOTE-204: Rand- sociated with complete response to tislelizumab 7 Santoro A et al., Nivolumab combined with omized, open-label, phase III study of pembroli- monotherapy in relapsed/refractory classical brentuximab vedotin for relapsed/refractory me- zumab (pembro) versus brentuximab vedotin Hodgkin lymphoma reveals a potentially differ- diastinal gray zone lymphoma: primary efficacy (BV) in relapsed or refractory classic Hodgkin ent mechanism of action. ASH 2020, abstract and safety analysis of the phase 2 CheckMate lymphoma (R/R cHL). J Clin Oncol 2020; 1116 436 study. ASH 2020, abstract 2045 38(suppl), 8005 8 Herrara AF et al., Interim results of brentuxi- 15 Kuruvilla J et al., Effect of pembrolizumab mab vedotin in combination with nivolumab in monotherapy compared with brentuximab vedo- patients with relapsed or refractory Hodgkin tin on patients with relapsed/refractory classical
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analyze samples from 70 patients in- the CD8+ T-cell–high TME where AD- T-cell infiltration according to mIHC cluded the BGB-A317-203 trial. Among CP-induced effector T-cell clearance is and tumor inflammation signature gene these, 41 and 36 were mIHC- and more likely. The CR rates were 86.6 % vs. signatures in the TME by GEP corre- GEP-evaluable, respectively. 85.7 % for high and low numbers of sponded with higher CR rates (Figure). In accordance with the characteris- FcγR1+ macrophages, respectively. Moreover, mixed cellularity and nodal tics of tislelizumab, the agent demon- Multiple biomarkers were identified sclerosis histological subtypes showed strated high CR rates regardless of FcγR that correlated with complete responses specific gene signatures associated with expression levels on macrophages in to tislelizumab treatment. Higher CD8+ complete response. n
Bone marrow microenvironment: culprit and target
Apart from factors such as genetic events we believe that a mechanism within the that contribute to the malignant transforma- malignant cell uses the microenvironment to tion in Waldenström’s macroglobulinemia achieve a survival advantage. I feel that ibru- (WM), the bone marrow microenvironment tinib and many other medications work by has been identified as a crucial player in WM suppressing the disease’s impact on the disease progression [1]. Similarly, it appears microenvironment. to be essential for the emergence and Much research is going on concerning progression of multiple myeloma (MM) and the possibility of targeting the disease by constitutes a significant reason why MM targeting the microenvironment. From my patients are not amenable to cure but inevi- perspective, this specific approach has tably develop relapses [2]. Delineation of been more successful in MM than it has malignant cell growth in the context of the been in WM, but I believe that we are on our bone marrow microenvironment has there- own © author’s way to identifying agents that can poten- fore moved into the focus of research ap- Jorge J. Castillo, MD tially help in this scenario. Hopefully, we can proximately 15 years ago as it might enable Dana-Farber Cancer Institute combine these with BTK inhibitors, Bcl-2 Boston, USA the design of more efficient therapeutic inhibitors and other agents to achieve more strategies for both MM and WM. profound and long-lasting responses. According to our understanding, immuno treat a patient with WM and 80 % infiltration modulatory agents such as thalidomide and of the bone marrow who is very anemic be- lenalidomide that are being used to treat cause the marrow does not provide suffi- MM patients exert effects by modifying the cient space to produce an appropriate REFERENCES microenvironment. Likewise, I believe that quantity of red cells. Three to 6 months into ibrutinib, when used in patients with WM, therapy, the patient’s hemoglobin is back to 1 Jalali S, Ansell SM, Bone marrow microenvi- not only works by inhibiting BTK, which is normal or much improved, and the IgM lev- ronment in Waldenstrom’s macroglobulinemia. Best Pract Res Clin Haematol 2016; 29(2): 148- an important aspect, but also regulates the els have decreased by 50 % or 70 %. How- 155 microenvironment to some degree. Obser- ever, when we perform another bone mar- 2 Mondello P et al., Bone marrow microenvi- ronment is a crucial player for myelomagenesis vations we make in clinical routine support row biopsy on this patient, we find that the and disease progression. Oncotarget 2017; this assumption. For example, we would degree of infiltration is still 80 %. Therefore, 8(12): 20394-20409
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Steven P. Treon, MD, explains about inno Alessandra Tedeschi, MD, summarizes the vative approaches in the treatment of results from the MAGNOLIA and iNNOVATE Waldenström’s macroglobulinemia, future trials, relates to recent advances in the aspects and the successful use of BTK management of marginal zone lymphoma inhibition within niche groups of patients and discusses the effect of the introduction with WM, and potential benefits of BTK in of BTK inhibition on the prognosis of patients hibitors regarding COVID-19 complications. with Waldenström’s macroglobulinemia.
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Stephen Opat, MD, discusses the require Jorge Castillo, MD, relates to recent de ments for treatment-free long-term velopments with respect to follicular lym remission in the setting of CLL and talks phoma, multiple myeloma and Walden about the future of BTK inhibitors and ström’s macroglobulinemia, current insights promising combinations in B-cell mali into CAR-T cell therapy in the setting of gnancies in general, as well as the strengths multiple myeloma, and the future of anti- and limitations of immune checkpoint CD38 antibody treatment in patients with inhibitors. Waldenström’s macroglobulinemia.
Forthcoming Special Issue This special issue will be offering a synopsis from the EHA 2021 that will be held in June 2021. The report promises to make for stimulating reading, as the EHA Congress itself draws on the input from a number of partner organizations, representing a multidisciplinary approach to cancer treatment and care. Stay tuned for the latest news in hematology and its subspecialties. EHA 2021 Annual Meeting JUNE 9–17, 2021