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BACKGROUND: The association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival. METHODS: We conducted a population-based family case-control study in Australia between 2011 and 2016 and included 710 cases, 303 siblings and 186 spouse/partner controls. We assessed dietary intake of animal products prior to diagnosis (the year before last) using a structured food frequency questionnaire and followed-up cases over a median of 6.9 years using record linkage to national death data. We examined associations with the likelihood of FL using logistic regression and used Cox regression to assess association with all-cause and FL-specific mortality among cases. RESULTS: We observed an increased likelihood of FL with increasing daily quantity of oily fish consumption in the year before last (highest category OR = 1.96, CI = 1.02-3.77; p-trend 0.06) among cases and sibling controls, but no associations with spouse/partner controls. We found no association between the likelihood of FL and the consumption of other types of fish or seafood, meats or dairy foods and fats. In FL cases, we found no association between meat or oily fish intake and all-cause or FL-specific mortality. CONCLUSION: Our study showed suggestive evidence of a positive association between oily fish intake and the likelihood of FL, but findings varied by control type. Further investigation of the potential role of environmental contaminants in oily fish on FL etiology is warranted.

Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the Part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being <=grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment due to adverse events. Response was assessed by an independent review committee (IRC) for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This study is registered on www.clinicaltrials.gov (NCT02343120).Copyright © 2022 American Society of Hematology.

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: MZL is the second most common lymphoma in older pts. Choosing an optimal treatment can be challenging because of patient-or disease-related risk factors and treatment-related toxicities (Curr Opin Oncol. 2019;31(5):386-393). Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition, which may improve efficacy outcomes and minimize toxicities, such as cardiac arrythmias and bleeding events. Zanubrutinib received accelerated approval from the United States FDA for the treatment of pts with R/R MZL (Haematologica . 2022;107(1):35-43). Aim(s): We aim to present a subgroup analysis of efficacy and safety of zanubrutinib in pts aged >=65 years with R/R MZL enrolled in MAGNOLIA (BGB-3111-214; NCT03846427). Method(s): MAGNOLIA is a phase 2, multicenter, single-arm study of adults with R/R MZL who had received >=1 line of therapy including >=1 CD20-directed regimen. All were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary endpoint was overall response rate (ORR; complete response [CR] and partial response [PR]) determined by an independent review committee (IRC) in accordance with the Lugano classification. Secondary endpoints include ORR by investigator assessment (INV), duration of response (DOR), progression-free survival (PFS), and safety. All pts gave informed consent. Result(s): As of 18 January 2021, a total of 68 pts were enrolled (Table). Forty (61%) pts were >=65 years old with a median age of 73 (range, 65-85); 18 pts were >=75 years old. Median number of prior therapies was 2 (range, 1-6) and 10 (25%) pts were refractory to last therapy. Most pts received prior rituximab + cyclophosphamide + vincristine + prednisone (48%) or bendamustine + rituximab (30%), while 5 (13%) pts received rituximab monotherapy. MZL

Introduction: Zanubrutinib is a highly selective irreversible inhibitor of Bruton tyrosine kinase which has shown significant activity in lymphoid malignancies in early phase studies. We report here the long-term follow-up outcomes of zanubrutinib in various lines of therapy in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Method(s): This post hoc analysis pooled patients with treatment-naive (TN) or relapsed/refractory (R/R) CLL/SLL receiving zanubrutinib monotherapy from three phase 1/2 studies (BGB-3111-1002, BGB-3111-AU-003, BGB-3111-205). Result(s): A total of 211 patients with CLL/SLL (TN 19, R/R 192) were included. After weighting (TN 19, R/R 24), the overall response rate (ORR) was 95.4% and significantly higher in the TN group than in the R/R group (100 vs. 91.0%, p < 0.0001). ORR was also significantly higher in the TN group than in the one prior line of therapy group (100 vs. 98.9%, p < 0.0001). Among those with R/R disease, the ORR was 97.8% in patients with one prior line of therapy (n = 79) and 90.7% in those with > 1 prior lines of therapy (n = 85; p = 0.080). The median follow-up times were 50.1, 35.7, and 45.9 months for TN, R/R and all cohorts, respectively. Progression-free survival and overall survival were significantly longer in the TN group and only one prior line of therapy group compared with the > 1 prior lines of therapy group (all p < 0.05) and were similar in the TN group compared with the one prior line therapy group. Efficacy was similar regardless of the presence of genomic aberrations. Most frequent grade >= 3 adverse events were infections (41.7%), neutropenia (34.1%), and thrombocytopenia (9.4%). Atrial fibrillation occurred in only 1.9% of patients. Conclusion(s): With extended follow-up, zanubrutinib yielded long-term benefits and demonstrated a favorable safety profile for patients with TN or RR CLL/SLL. Earlier utilization of zanubrutinib was associated with better outcomes. Trial Registration

Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton's tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit-risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

PURPOSE The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström’s macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade $ 3 adverse events of clinical interest generally decreased over time. CONCLUSION In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.

Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

The association between smoking and alcohol consumption and follicular lymphoma (FL) incidence and clinical outcome is uncertain. We conducted a population-based family case-control study (709 cases: 490 controls) in Australia. We assessed lifetime history of smoking and recent alcohol consumption and followed-up cases (median = 83 months). We examined associations with FL risk using unconditional logistic regression and with all-cause and FL-specific mortality of cases using Cox regression. FL risk was associated with ever smoking (OR = 1.38, 95%CI = 1.08−1.74), former smoking (OR = 1.36, 95%CI = 1.05−1.77), smoking initiation before age 17 (OR = 1.47, 95%CI = 1.06−2.05), the highest categories of cigarettes smoked per day (OR = 1.44, 95%CI = 1.04−2.01), smoking duration (OR = 1.53, 95%CI = 1.07−2.18) and pack-years (OR = 1.56, 95%CI = 1.10−2.22). For never smokers, FL risk increased for those exposed indoors to >2 smokers during childhood (OR = 1.84, 95%CI = 1.11−3.04). For cases, current smoking and the highest categories of smoking duration and lifetime cigarette exposure were associated with elevated all-cause mortality. The hazard ratio for current smoking and FL-specific mortality was 2.97 (95%CI = 0.91−9.72). We found no association between recent alcohol consumption and FL risk, all-cause or FL-specific mortality. Our study showed consistent evidence of an association between smoking and increased FL risk and possibly also FL-specific mortality. Strengthening anti-smoking policies and interventions may reduce the population burden of FL.

PURPOSE: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes. RESULTS: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R-GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). CONCLUSIONS: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908.

BACKGROUND: Lymphoma is a malignancy of lymphocytes and lymphoid tissues comprising a heterogeneous group of diseases, with up to 80 entities now described. Lymphoma is the 6th most common cancer in Australia, affecting patients of all ages, with rising incidence rates. With the proliferation of efficacious novel agents, therapeutic strategies are increasingly diverse and survival is improving. There is a clear need for contemporary robust and detailed data on diagnostic, investigational and management strategies for this disease in Australia, New Zealand and worldwide, to inform and benchmark local and international standards of care. Clinical quality registries can provide these data, and support development of strategies to address variations in management, including serving as platforms for clinical trials and other research activities. The Lymphoma and Related Diseases Registry (LaRDR) was developed to capture details of patient demographics, disease characteristics, and management throughout their disease course and therapy and to develop outcome benchmarks nationally and internationally for lymphoma. This report describes the aims, development and implementation of the LaRDR, as well as challenges addressed in the process. METHODS: The LaRDR was established in 2016 as a multicentre, collaborative project at sites across Australia with a secure online database which collects prospective data on patients with a new diagnosis of lymphoma or chronic lymphocytic leukaemia (CLL). LaRDR development required multidisciplinary participation including specialist haematology, information technology, and biostatistical support, as well as secure funding. Here we describe the database development, data entry, ethics approval process, registry governance and support for participating sites and the coordinating centre. RESULTS: To date more than 5,300 patients have been enrolled from 28 sites in Australia and New Zealand. Multiple challenges arose during the development, wh

AIM: To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE). METHODS: A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35-71) years using a 20 mg/m2 test dose administered 1-3 days prior to HDM (predominantly 180 mg/m2). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann-Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined. RESULTS: Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p < 0.005). Test dose administration within 15 min of reconstitution (n = 5) was associated with significantly lower PE than administration times of 16-60 min (n = 22), p < 0.05. Test and HDM infusion concentrations were lower in patients with large PE (> ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively). CONCLUSION: Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation.

The management of Hodgkin lymphoma (HL) has undergone significant changes in recent years. Due to the predilection of HL to affect younger patients, balancing cure and treatment-related morbidity is a constant source of concern for physicians and patients alike. Positron emission tomography adapted therapy has been developed for both early and advanced stage HL to try and improve the outcome of treatment, while minimising toxicities. The aim of this review is to digest the plethora of studies recently conducted and provide some clear, evidence-based practice statements to simplify the management of HL.Copyright © 2021 Royal Australasian College of Physicians.

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.

The phase I/II AU-003 study in patients with treatment-naive (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47.2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95.9% (TN, 100%; R/R, 95%) with 18.7% achieving complete response (CR). Ongoing response at 3 years was reported in 85.7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87.5% (CR 16.7%). The 2- and 3-year progression-free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade >=3 adverse events were neutropenia (15.4%), pneumonia (9.8%), hypertension (8.9%) and anaemia (6.5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade >=3 neutropenia and Grade >=3 infection decreased over time. With a median follow-up of ~4 years, responses remain clinically meaningful and durable and long-term tolerability to zanubrutinib therapy continues.Copyright © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Zanubrutinib, a highly selective Bruton tyrosine kinase inhibitor, was evaluated in a phase 1/2 study in patients with various B-cell malignancies. In the subgroup of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL), zanubrutinib was administered as 160 mg twice daily (n 5 14), 320 mg once daily (n 5 18), or #160 mg total dose (n 5 5). Herein, we report results for patients receiving a total daily dose of 320 mg (N 5 32). Median study follow-up was 18.8 months. Eighteen patients discontinued treatment, 10 because of progressive disease and 8 because of adverse events (AEs); 1 AE (peripheral edema) was considered to be related to zanubrutinib treatment. The most common AEs were diarrhea (43.8%), contusion (37.5%), constipation (31.3%), and upper respiratory tract infection (31.3%). Infection was the most commonly reported AE of interest (18.8% of patients experienced grade $3 infection). At least 1 AE of grade $3 was reported in 59.4% of patients; grade $3 AEs that were reported in .2 patients were anemia (12.5%), pneumonia (9.4%), and myalgia (9.4%). Overall response rate was 84%, with 25% achieving a complete response. Median duration of response was 18.5 months. Median progression-free survival (PFS) was 21.1 months. Zanubrutinib was well tolerated and demonstrated activity in patients with R/R MCL. The trial is registered at www.clinicaltrials.gov as #NCT02343120.Copyright © 2021 American Society of Hematology. All rights reserved.

Background: Inhibitors of Bruton tyrosine kinase (BTK) have established therapeutic activity in patients with WM. Zanubrutinib, a potent and selective BTK inhibitor was evaluated in a phase 1/2 study in treatment-naive (TN) and relapsed/refractory (R/R) patients with WM. Method(s): Patients had TN or R/R WM and required treatment as per International Workshop on WM (IWWM) criteria. Treatment consisted of oral zanubrutinib at 160 mg twice daily (n = 50) or 320 mg once daily (n = 23) until disease progression or unacceptable toxicity. Efficacy endpoints included the proportion of patients achieving a complete response (CR) or very good partial response (VGPR) in accordance with IWWM-6 criteria. Efficacy analyses were conducted on the 73 patients evaluable (24 TN, 49 R/R). Result(s): Between September 2014 and August 2018, 77 patients with WM (24 TN and 53 R/R) began treatment with zanubrutinib (55% aged > 65 years; 21% aged > 75 years). At a median follow up of 32.7 months, 73% remain on treatment. Reasons for treatment discontinuation included adverse events (AE) in 13% (only one related), disease progression (10.4%), and other (3.9%). Results are presented for TN and R/R combined. The overall response rate was 96% and VGPR/CR rate was 45%. The rates of VGPR/CR increased over time; 22% at 6 mos, 33% at 12 months and 45% at 24 months. Three-year progression-free survival (PFS) was 81%, and overall survival (OS) was 85%. The most commonly reported AEs were upper respiratory tract infection (52%), contusion (33%, all grade 1) and cough (22%). AEs of interest include neutropenia (18.2%), major hemorrhage (4%), atrial fibrillation/flutter (5%), and grade 3 diarrhea (3%). Conclusion(s): Long-term follow up with continued zanubrutinib treatment demonstrated deep and durable responses in the majority of WM patients. The rates of VGPR/CR increased with prolonged therapy. Disease progression was uncommon. The safety profile of long-term zanubrutinib therapy in these patients w

Background: Prophylactic immunoglobulin (Ig) replacement and prophylactic oral antibiotics (PA) are used to prevent infections in patients with haematological malignancies and acquired hypogammaglobulinemia. Ig has been shown to reduce infection risk, but is costly and in limited supply. PA have been shown to reduce infection risk in other patient populations and are less expensive, but have side-effects and can increase antimicrobial resistance rates. Guidelines and clinical practice vary internationally, with some recommending a trial of PA prior to commencing Ig replacement, and others omitting PA. The efficacy, safety and cost-effectiveness of Ig and PA have not been directly compared in a randomised controlled trial (RCT) in patients with acquired hypogammaglobulinemia secondary to haematological malignancies. Aim(s): To determine the feasibility of delivering PA as an alternative to Ig replacement in patients with haematological malignancies and acquired hypogammaglobulinemia. Method(s): Phase II, multicentre, feasibility RCT (ACTRN12616001723471). Eligible patients had acquired hypogammaglobulinemia due to a haematological malignancy, a history of recurrent or severe bacterial infections or an IgG level <4g/L (excluding paraprotein), and had a life expectancy more than 12 months. Exclusion criteria included prior allogeneic haematopoietic stem cell transplant and prior Ig replacement in the preceding 3 months. Patients were randomised to receive Ig (0.4g/kg IV every 4 weeks, modified to achieve an IgG trough level >= lower limit of reference range; or 0.1g/kg/week SC, modified to achieve an IgG trough level of >= lower limit of reference rage) or daily oral prophylactic antibiotics (trimethoprim-sulfamethoxazole 160mg/800mg, with 100mg doxycycline as an alternative for hypersensitivity) for 12 months at a 1:2 ratio. Randomisation was stratified by site. Patients allocated to PA were allowed to cross over to Ig if they experienced a CTCAE >= Grade 3 infection.