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Background: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous hematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS. Methods: Patients with primary/secondary progressive MS from 7 AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise- censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARR), using Andersen-Gill proportional hazards models and conditional negative binomial model. Findings: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (hazard ratio 1.49, 95% confidence interval [95%CI] 0.70-3.14) and improvement (hazard ratio 1.50, 95%CI 0.22-10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±standard deviation 0.08±0.28 vs. 0.08±0.25; hazard ratio 1.05, 95%CI 0.39-2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required ICU admission, and 36 patients experienced complications after discharge. No treatment-related deaths were reported. Conclusion: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity.

IMPORTANCE: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). OBJECTIVE: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. DESIGN, SETTING, AND PARTICIPANTS: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. EXPOSURE: AHSCT vs fingolimod, natalizumab, or ocrelizumab. MAIN OUTCOMES: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. RESULTS: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Method(s): SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 x 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (<65 y vs >=65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent...Copyright © 2021 American Society of Hematology

BACKGROUND Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcgamma receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of >=50x103 per cubic millimeter and an increase from baseline of >=20x103 per cubic millimeter without the use of rescue medication). RESULTS Sixty patients were enrolled. At baseline, the median platelet count was 15x103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50x103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50x103 per cubic millimeter was 65%. CONCLUSIONS Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400

Introduction: Bruton's tyrosine kinase (BTK) inhibition is an emerging standard of care for WM. The ASPEN trial (NCT03053440) is a randomized phase 3 study comparing zanubrutinib, a potent and selective BTK inhibitor, versus ibrutinib, a first generation BTK inhibitor, in patients with WM. Method(s): Patients with MYD88 mutation-positive (MYD88mut+) WM were randomly assigned 1:1 to receive zanubrutinib (160 mg twice daily) or ibrutinib (420 mg once daily). Patients without MYD88 mutations were assigned to a separate cohort, received zanubrutinib, and are reported separately. Randomization was stratified by CXCR4 mutational status and the number of lines of prior therapy (0 vs 1-3 vs >3). The primary end point was the proportion of patients achieving a complete response or very good partial response (CR+VGPR). Sample size was calculated to provide 81% power to detect a difference in CR+VGPR rate of 35% vs 15% in the subset of patients with relapsed or refractory WM. Primary analysis was planned to occur at ~12 months after the last patient enrolled. Result(s): In total, 201 patients were randomized from Jan 2017 to Jul 2018. The treatment groups were well balanced for important baseline factors, with the exception of more elderly patients (aged >75 years, 33.3% vs 22.2%) and more anemia (hemoglobin <=110 g/L, 65.7% vs 53.5%) in the zanubrutinib arm. At a median follow-up of 19.4 months, the rate of VGPR (no CRs were observed) was 28.4% vs 19.2% with zanubrutinib vs ibrutinib, respectively (2-sided P=0.09). Rates of atrial fibrillation, contusion, diarrhea, edema peripheral, hemorrhage, muscle spasms, pneumonia, and adverse events leading to discontinuation or death were lower with zanubrutinib. The rate of neutropenia was higher with zanubrutinib (Table), but grade >=3 infection rates were similar (17.8% vs 19.4%). Conclusion(s): ASPEN is the largest phase 3 trial of BTK inhibitors in WM and the first head-to-head comparison of BTK inhibitors in any disease. Although

Introduction: Inhibitors of Bruton's tyrosine kinase (BTK) have shown significant activity in patients with MYD88 mutation-positive (MYD-88mut+) WM. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations (N Engl J Med. 2015;372:1430). The ASPEN trial (NCT03053440) evaluated zanubrutinib, a potent and selective BTK inhibitor, in patients with MYD88WT WM. Here, we present the safety and efficacy of zanubrutinib in these patients. Method(s): At study entry, bone marrow MYD88 mutations were assessed by a central laboratory (NeoGenomics). Based on these results, patients were assigned to cohort 1 (MYD88mut+) or cohort 2 (MYD88WT or unknown mutation status). Patients received zanubrutinib 160 mg twice daily until disease progression. Result(s): In total, 28 patients were enrolled in cohort 2, of which 26 were centrally confirmed as MYD88WT. Median age of patients was 72 years; five patients were treatment-naive and 23 patients had relapsed/refractory (>=1 prior therapy) WM. Most patients had intermediate-risk (39.3%) or high-risk (42.9%) disease, as defined by the International Prognostic Scoring System for WM. At median follow-up of 17.9 months, two patients discontinued zanubrutinib due to adverse events (AEs), and six experienced disease progression; there were no cases of disease transformation. In patients with confirmed MYD88WT, the overall response rate by independent review was 80.8%, with a major response rate of 50.0%, including a very good partial response rate of 26.9%. The progression-free survival event-free rate at 12 months was 72.4%. The most frequently reported AEs were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection. Major hemorrhage was reported in two patients, and atrial fibrillation was reported in one patient. There were no fatal AEs. Conclusion(s): Zanubrutinib showed clinically meaningful antitumor activity, including achieving major responses

Zanubrutinib (zanu) is a selective nextgeneration Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimal off-target effects. SEQUOIA (NCT03336333) is an open-label, global phase 3 study that randomised treatment naive (TN) patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m2 on day 1 and 2 and rituximab 375 mg/m2 in cycle 1, 500 mg/m2 in cycles 2-6 for 6 x 28-day cycles (BR). Adult patients who met International Workshop on CLL (iwCLL) criteria for treatment were eligible if they were >= 65 years or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridisation was required. Patients were stratified by age (<65 years vs. >=65 years), Binet Stage (C vs. A/B), immunoglobulin heavy chain gene (IGHV) mutational status and geographical region. The primary end-point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end-points included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS) and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria and Lugano criteria respectively. Adverse events (AEs) were recorded until disease progression. From 31 Oct 2017-22 Jul 2019, 479 patients without del(17p) were randomised to zanu ( n = 241) and BR ( n = 238). Treatment groups were well balanced for demographical and disease characteristics (zanu vs. BR): median age, 70.0 years vs. 70.0 years; unmutated IGHV, 53.4% (125/234) vs. 52.4% (121/231); and del(11q), 17.8% vs. 19.3%. At median followup (26.2 months), PFS was significantly prolonged with zanu versus BR as assessed by IRC (hazard ratio [HR] 0.42, 95% CI 0.28-0.63, 2-sided p < 0.0001), and INV (HR 0.42, 95% CI 0.27-0.66, 2-sided p = 0

Background: ZANU is a potent and selective next-generation Bruton tyrosine kinase inhibitor (BTKi) designed to have greater affinity to BTK while minimizing off-target inhibition of TEC-and EGFR-family kinases. ASPEN (NCT03053440) is a randomized, open-label, phase 3 study comparing ZANU with the first-generation BTKi IBR in pts with WM. We present data with a median follow-up of 43 months. Aim(s): To compare the efficacy and safety of ZANU vs IBR in pts with MYD88 mutant (MYD88mut) WM and ZANU in pts with wild-type MYD88 (MYD88wt) WM. Method(s): Pts with MYD88mut WM were assigned to cohort 1 and randomized 1:1 to receive ZANU 160 mg twice daily or IBR 420 mg once daily. Pts with MYD88wt were assigned to cohort 2 and received ZANU 160 mg twice daily until disease progression. Randomization was stratified by CXCR4 mutational status by Sanger sequencing and lines of prior therapy (0, 1-3, or >3). All pts gave informed consent. The primary endpoint was proportion of pts achieving very good partial response or better (VGPR + complete response [CR]). Primary analysis occurred at 19 months median follow-up, and final analysis is planned to occur ~4 years after the first pt enrolled. Result(s): A total of 201 pts (102 ZANU; 99 IBR) were enrolled in cohort 1 and 28 pts in cohort 2. Baseline characteristics in cohort 1 differed between pts treated with ZANU vs IBR in CXCR4 mutations by next-generation sequencing (32% vs 20%, or 33 of 98 vs 20 of 92 available samples, respectively) and pts aged >75 years (33% vs 22%, respectively). Median duration of treatment was 42 months (ZANU) and 41 months (IBR), with 67% and 58% remaining on treatment, respectively. The VGPR+CR rate by investigator was 36% with ZANU vs 22% with IBR (descriptive p = 0.02) in cohort 1, and 31% in cohort 2. One pt in cohort 2 obtained a CR. In pts with wild-type (65 ZANU; 72 IBR) or mutant CXCR4 (33 ZANU; 20 IBR) from cohort 1, VGPR+CR rates with ZANU vs IBR were 45% vs 28% (p = 0.04) and 21% vs 5% (p = 0.

Background: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. Method(s): We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13.1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13.1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided alpha of 0.05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. Finding(s): Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13.1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26.2 months (IQR 23.7

Contains fulltext : 251609.pdf (Publisher’s version ) (Open Access), BACKGROUND: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). METHODS: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0-100 days, 101 days-1 year, and >1 year after the first transplant. RESULTS: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4-108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1-7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3-5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. CONCLUSIONS: Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies.

Context: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. Design: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. Main Outcome Measures: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. Results: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naive patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade >= 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

Patients with Waldenstrom macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/ refractory; 5 treatment-naive) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.Copyright © 2020 by The American Society of Hematology

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenstrom macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ++1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P 5 .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ++3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.Copyright © 2020 American Society of Hematology. All rights reserved.

[Formula presented] Introduction Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts <=60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and

INTRODUCTION: The prognostic value of B-cell lymphoma 2 (BCL2) expression in de novo diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy is of interest to define a target patient population for clinical development of BCL2 inhibitors. We aimed to develop a reproducible immunohistochemistry algorithm and assay to determine BCL2 protein expression and assess the prognostic value of BCL2 in newly diagnosed DLBCL cohorts. PATIENTS AND METHODS: The prospectively defined algorithm incorporated BCL2 staining intensity and percentage of BCL2-positive cells. Functionally relevant cutoffs were based on the sensitivity of lymphoma cell lines to venetoclax. This assay was highly reproducible across laboratories. The prognostic impact of BCL2 expression was assessed in DLBCL patients from the phase 3 MAIN (n = 230) and GOYA (n = 366) trials, and a population-based registry (n = 310). RESULTS: Approximately 50% of tumors were BCL2 positive, with a higher frequency in high International Prognostic Index (IPI) and activated B-cell-like DLBCL subgroups. BCL2 expression was associated with poorer progression-free survival in the MAIN study (hazard ratio [HR], 1.66; 95% confidence interval [CI], 0.81-3.40; multivariate Cox regression adjusted for IPI and cell of origin). This trend was confirmed in the GOYA and registry cohorts in adjusted multivariate analyses (GOYA: HR, 1.72; 95% CI, 1.05-2.82; registry: HR, 1.89; 95% CI, 1.29-2.78). Patients with BCL2 immunohistochemistry-positive and IPI-high disease had the poorest prognosis: 3-year progression-free survival rates were 51% (GOYA) and 37% (registry). CONCLUSION: Findings support use of our BCL2 immunohistochemistry scoring system and assay to select patients with BCL2-positive tumors for future studies.

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase III SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42–86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0–26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI: 79.0–94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI: 88.4–98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered as clinicaltrials.gov Identifier: NCT03336333.