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In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Competing Interests: P. G. reports fees for consulting and honoraria from AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, Janssen, Loxo@Lilly, Merck Sharp & Dohme Corp., and Roche; and research funding from AbbVie, AstraZeneca, and Janssen; and is an editor for HemaSphere. C. O. reports honoraria from AbbVie, AstraZeneca, BeiGene, Gilead, Incyte, Janssen, Merck, and Roche. J. N. A. reports fees for consulting from AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, Epizyme, Genentech, Janssen, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics; research funding from BeiGene, Celgene, Genentech, Janssen, and TG Therapeutics; and has served on the speakers' bureau for AbbVie, BeiGene, Janssen, and Pharmacyclics LLC, an AbbVie Company. J. C. B. reports honoraria from Janssen and fees for consulting from AbbVie, AstraZeneca, BeiGene, and MEI Pharma; and research funding from Oncternal Therapeutics, Pharmacyclics LLC, an AbbVie Company, and VelosBio/Merck. P. M. B. reports fees for consulting from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, Gilead, Janssen, MEI Pharma, Merck, MorphoSys, Seattle Genetics, and TG Therapeutics; and research funding from AstraZeneca and TG Therapeutics. C. S. reports no conflicts of interest. A. S. reports employment and stock ownership with AbbVie. C. A. reports employment with AbbVie and stock ownership with AbbVie and Bristol Myers Squibb. G. S. K. reports employment with AbbVie and Bristol Myers Squibb; stock ownership with AbbVie, Bristol Myers Squibb, Dynavax, Inovio, and Moderna; and travel and accommodation expenses from AbbVie and Bristol Myers Squibb. J. A. B. reports honoraria from Gilead, Janssen, Novartis, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics; consulting fees from BeiGene, Gilead, Janssen, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics; research funding from AstraZeneca, BeiGene, and Pharmacyclics LLC, an AbbVie Company; served on the speakers' bureau for BeiGene, Gilead, Janssen, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics; and received travel and accommodation expenses from Gilead, Janssen, Novartis, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics.

Primary bone diffuse large B-cell lymphoma is a rare variant of extranodal non-Hodgkin lymphoma historically treated with induction chemotherapy followed by consolidative radiation therapy (RT). It remains unknown whether RT confers additional benefit following rituximab-based chemoimmunotherapy (CIT) induction in patients with limited stage disease. We conducted a multicenter, retrospective analysis of patients treated between 2005 and 2019 using rituximab-based CIT regimens with or without consolidative RT to discern whether consolidative RT adds benefit in patients with stage I-II disease that could be encompassed in one radiation field. A total of 112 patients were included: 78 received CIT and radiation (RT group), and 34 received CIT alone (no RT group). The overall survival at 10 years was 77.9% in the RT group and 89.0% in the no RT group (P=0.42). The relapse-free survival at 10 years was 73.5% in the RT group and 80.3% in the no RT group (P=0.88). Neither improved overall survival nor relapse-free survival was associated with the addition of consolidative RT. Subgroup analysis of patients only achieving a partial response after CIT suggests that these patients may benefit from consolidative RT.

Abstract: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Abstract: Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N = 46) and Richter transformation (N = 5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and aspartate aminotransferase and/or alanine aminotransferase elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of uMRD at 10-4 in bone marrow was 77% (30/39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for patients with relapsed/refractory CLL including those who have been previously treated with covalent BTK inhibitors. This trial was registered on www.clinicaltrials.gov as #NCT03379051., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes., Methods: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases., Results: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort., Conclusions: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL., (© 2023. The Author(s).)

Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) have poor responses to salvage therapy. Nivolumab and brentuximab vedotin (BV) showed promising early efficacy in patients with R/R PMBL in the phase 1/2 open-label, multicenter CheckMate 436 study; we report safety and efficacy findings from the 3-year follow-up. Patients who were eligible were aged ≥15 years with R/R PMBL previously treated with either high-dose chemotherapy plus autologous hematopoietic cell transplantation (HCT) or ≥2 prior multiagent chemotherapies, and had Eastern Cooperative Oncology Group performance status scores of 0 to 1 and CD30 expression of ≥1%. Patients were treated with nivolumab 240 mg and BV 1.8 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points included complete response rate, duration of response, progression-free survival (PFS), and overall survival (OS). Safety was monitored throughout. At final database lock (30 March 2022), 29 patients had received nivolumab plus BV; median follow-up was 39.6 months. Investigator-assessed ORR was 73.3%; median time to response was 1.3 months (range, 1.1-4.8). Median PFS was 26.0 months; median OS was not reached. PFS and OS rates at 24 months were 55.5% (95% confidence interval [CI], 32.0-73.8) and 75.5% (95% CI, 55.4-87.5), respectively. The most frequently occurring grade 3/4 treatment-related adverse event was neutropenia. Consolidative HCT was received by 12 patients, with a 100-day complete response rate of 100.0%. This 3-year follow-up showed long-term efficacy for nivolumab plus BV in R/R PMBL, with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT02581631., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Adolescent and Young Adults (AYAs) are an underserved, high-risk population. Identifying health care utilization patterns, and particularly acute care visits, is important as these are high-intensity, expensive services. We investigated whether differences exist in health care utilization between the AYA lymphoma population compared to their older adult counterparts., Materials and Methods: Two correlated outcomes were used to measure health care utilization: 4 or more acute visits (emergency department or urgent care) and number of nonacute visits (office or telephone visits). We studied 442 patients with aggressive lymphoma patients 15 years or older at time of diagnosis managed at our cancer center within 2 years of their diagnosis. A multivariate generalized linear mixed model simultaneously estimated the effect of baseline predictors on 4 or more acute care visit with robust Poisson regression and nonacute visit counts with negative binomial regression allowing for a within-subject random effect., Results: AYAs had increased risk of having ≥4 acute visits (RR = 1.96; P = .047) compared to their older counterparts. Obesity (RR = 2.04, P = .015) and living less than 50 miles from the cancer center (RR = 3.48, P = .015) were independently associated with higher risk of acute care usage. Acute care visits for psychiatric or substance use related reasons were significantly higher (P = .0001) among AYA (10/114, 8.8%) vs. non-AYA (3/328, 0.9%)., Conclusion: Disease-targeted interventions to address high acute health care utilization is needed amongst AYAs. Additionally, early multidisciplinary involvement after cancer diagnosis particularly with psychiatric expertise amongst AYAs and palliative care involvement in both groups is needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: This study assessed treatment discontinuation patterns and reasons among chronic lymphocytic leukemia (CLL) patients initiating first-line (1L) and second-line (2L) treatments in real-world settings., Materials and Methods: Using deidentified electronic medical records from the CLL Collaborative Study of Real-World Evidence, premature treatment discontinuation was assessed among FCR, BR, BTKi-based, and BCL-2-based regimen cohorts., Results: Of 1364 1L patients (initiated in 1997-2021), 190/13.9% received FCR (23.7% discontinued prematurely); 255/18.7% received BR (34.5% discontinued prematurely); 473/34.7% received BTKi-based regimens, of whom 28.1% discontinued prematurely; and 43/3.2% received venetoclax-based regimens, of whom 16.3% discontinued prematurely (venetoclax monotherapy: 7/0.5%, of whom 42.9% discontinued; VG/VR: 36/2.6%, of whom 11.1% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 25/13.2%; BR: 36/14.1%; BTKi-based regimens: 75/15.9%) and disease progression (venetoclax-based: 3/7.0%). Of 626 2L patients, 20/3.2% received FCR (50.0% discontinued); 62/9.9% received BR (35.5% discontinued); 303/48.4% received BTKi-based regimens, of whom 38.0% discontinued; and 73/11.7% received venetoclax-based regimens, of whom 30.1% discontinued (venetoclax monotherapy: 27/4.3%, of whom 29.6% discontinued; VG/VR: 43/6.9%, of whom 27.9% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 6/30.0%; BR: 11/17.7%; BTKi-based regimens: 60/19.8%; venetoclax-based: 6/8.2%)., Conclusion: The findings of this study highlight the continued need for tolerable therapies in CLL, with finite therapy offering a better tolerated option for patients who are newly diagnosed or relapsed/refractory to prior treatments., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bruton tyrosine kinase inhibitors are an effective therapeutic agent for previously untreated patients with chronic lymphocytic leukemia but require indefinite treatment that can result in cumulative toxicities. Novel combinations of agents that provide deep remissions could allow for fixed duration therapy. Acalabrutinib, unlike ibrutinib, does not inhibit anti-CD20 monoclonal antibody-dependent cellular phagocytosis, making it a suitable partner drug to rituximab. Using standard dosing (375 mg/m2) of rituximab causes loss of target membrane CD20 cells and exhaustion of the finite cytotoxic capacity of the innate immune system. Alternatively, using high-frequency, low-dose (HFLD), subcutaneous rituximab limits loss of CD20 and allows for self-administration at home. The combination of HFLD rituximab 50 mg administered twice a week for 6 cycles of 28 days with the addition of acalabrutinib starting in week 2 was evaluated in a phase II study of 38 patients with treatment naive chronic lymphocytic leukemia. Patients achieving a complete response with undetectable minimal residual disease after 12 or 24 cycles of acalabrutinib could stop therapy. All patient responded, including one with a complete response with undetectable minimal residual disease in the peripheral blood and bone marrow at 12 months who stopped therapy. At a median follow-up of 2.3 years 2 patients with high-risk features have progressed while on acalabrutinib monotherapy. We conclude that HFLD rituximab in combination with acalabrutinib is an effective and tolerable self-administered home combination that provides a platform to build upon regimens that may more reliably allow for fixed-duration therapy. This trial was registered at www.clinicaltrials.gov #NCT03788291., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Monoclonal antibody induced infusion reactions (IRs) can be serious and even fatal. We used clinical data and blood samples from 37 treatment naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) initiating therapy for progressive disease with a single 50 mg dose of intravenous (IV) rituximab at 25 mg/h. Twenty-four (65 %) patients had IRs at a median of 78 min (range 35-128) and rituximab dose of 32 mg (range 15-50). IR risk did not correlate with patient or CLL characteristics, CLL counts or CD20 levels, or serum rituximab or complement concentrations. Thirty-five (95 %) patients had cytokine release response with a ≥ 4-fold increase in serum concentration of ≥ 1 inflammatory cytokine. IRs were associated with significantly higher post-infusion serum concentrations of gamma interferon induced cytokines IP-10, IL-6 and IL-8. IP-10 concentrations increased ≥ 4-fold in all patients with an IR and were above the upper limit of detection (40,000 pg/ml) in 17 (71 %). In contrast, to only three (23 %) patients without an IR had an ≥ 4-fold increase in serum concentrations of IP-10 (highest 22,013 pg/ml). Our data suggest that cytokine release could be initiated by activation of effector cells responsible for clearance of circulating CLL cells with IRs occurring in those with higher levels of gamma interferon induced cytokines. These novel insights could inform future research to better understand and manage IRs and understand the role of cytokines in the control of cytotoxic immune responses to mAb., Competing Interests: Declaration of Competing Interest PBM and CSZ report funding for research through the University of Rochester from AstraZeneca and TG Therapeutics, CSZ reports funding for research through the University of Rochester from GenMab, and PMB reports serving as a consultant for Pharmacyclics, AbbVie, Genentech and Seattle Genetics. The other authors report no potential conflicts of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded. Grade 4 hematologic toxicity was uncommon, and notable all-grade non-hematologic toxicities included bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), transaminitis (35%), atrial fibrillation (21%), and serious infection (17%). Best overall response rate was 96% (including 40% CR and 56% PR). Best rates of undetectable minimal residual disease in peripheral blood and bone marrow were 27% and 19%, respectively. With a median follow-up of 41.5 months, four-year progression-free and overall survival rates are 74% and 93%, respectively. Correlative studies demonstrated that serum CCL4 and CXCL13 levels were associated with clinical response, and BH3 profiling revealed increased BCL-2 and BCL-xL dependence in CLL cells from patients on treatment. Overall, ibrutinib plus obinutuzumab was highly active, with a manageable safety profile, supporting further investigation of this type of approach in relapsed/refractory CLL., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Primary results from the phase 3 RESONATE-2 study demonstrated superior efficacy and tolerability with ibrutinib versus chlorambucil in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Here, we describe characteristics and outcomes of patients who received ibrutinib treatment for ≥5 years in RESONATE-2. Patients aged ≥65 years with previously untreated CLL/SLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5−0.8 mg/kg for ≤12 cycles (n = 133). Baseline characteristics in ibrutinib-randomized patients (n = 136) were generally similar between patients on ibrutinib treatment for ≥5 years (n = 79) versus those on treatment for <5 years (n = 57). In patients on ibrutinib treatment for ≥5 years, complete response rates improved over time, reaching 42% by 5 years. Estimated 7-year progression-free survival and overall survival rates were 82% and 94%, respectively. Adverse events (AEs) led to dose reductions in 16/79 patients (20%); these AEs were resolved for 13/16 patients (81%). AEs led to dose holds (≥7 days) in 45/79 patients (57%); these AEs were resolved for 43/45 patients (96%). More than half (58%) of ibrutinib-randomized patients benefitted from ibrutinib treatment for ≥5 years regardless of baseline characteristics. Dose modification resolved AEs for most patients, thereby facilitating continued treatment.

Purpose: Bone marrow biopsies (BMB) are performed before/after therapy to confirm complete response (CR) in patients with lymphoma on clinical trials. We sought to establish whether BMB add value in assessing response or predict progression-free survival (PFS) or overall survival (OS) outcomes in follicular lymphoma (FL) subjects in a large, multicenter, multitrial cohort., Methods: Data were pooled from seven trials of 580 subjects with previously untreated FL through Alliance for Clinical Trials in Oncology (Alliance) and SWOG Cancer Research Network (SWOG) completing enrollment from 2008 to 2016., Results: Only 5/580 (0.9%) had positive baseline BMB, CR on imaging, and subsequent positive BMB ( P < .0001). Therefore, BMB were irrelevant to response in 99% of subjects. A sensitivity analysis of 385 FL subjects treated on an Eastern Cooperative Oncology Group study was included. In the Eastern Cooperative Oncology Group cohort, 5/385 (1.3%) had BMB that affected response assessment. Since some subjects do not undergo confirmatory BMB, we performed a landmark survival analysis from first radiologic CR with data from 580 subjects from Alliance and SWOG. Of subjects with CR on imaging (n = 187), PFS and OS were not significantly different among those with negative BMB to confirm CR (n = 47) versus those without repeat BMB (n = 140; PFS: adjusted hazard ratio, 1.10, 95% CI, 0.62 to 1.94, log-rank P = .686; OS: hazard ratio, 0.59, 95% CI, 0.23 to 1.53, log-rank P = .276)., Conclusion: We conclude that BMB add little value to response assessment in subjects with FL treated on clinical trials and we recommend eliminating BMB from clinical trial requirements. BMB should also be removed from diagnostic guidelines for FL except in scenarios in which it may change management including confirmation of limited stage and assessment of cytopenias. This would reduce cost, patient discomfort, resource utilization, and potentially remove a barrier to trial enrollment.

What Is This Summary About?: This is a plain language summary of a publication describing long-term results from the RESONATE-2 study with up to 8 years of follow-up. The original paper was published in Blood Advances in June 2022., What Were the Results?: Researchers looked at 269 adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not received any treatment for their CLL/SLL. Study participants were randomly divided into two groups: 136 participants received treatment with a drug called ibrutinib, and 133 participants received treatment with a drug called chlorambucil. Participants in the study were treated and followed for up to 8 years, with results showing that more participants who took ibrutinib (59%) were alive without worsening of their disease at 7 years after starting treatment than participants who took chlorambucil (9%). Almost half of the participants (42%) were able to stay on ibrutinib treatment for up to 8 years., What Do the Results of the Study Mean?: In people with CLL or SLL, more participants who were taking ibrutinib were alive without worsening of their disease after 7 years compared with participants who took chlorambucil. Clinical Trial Registration : NCT01722487 (ClinicalTrials.gov) Clinical Trial Registration : NCT01724346 (ClinicalTrials.gov).

Purpose: The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts., Patients and Methods: In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day)., Results: In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance <80 mL/minute) from 43% to 18%. Laboratory TLS per Howard criteria occurred in one patient; no clinical TLS was observed., Conclusions: Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS., (©2022 The Authors; Published by the American Association for Cancer Research.)

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib-rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813., (© 2022 by The American Society of Hematology.)

Joint and muscle pain, including arthralgia, myalgia, and musculoskeletal pain, are among the common adverse events (AEs) reported for ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor approved for the treatment of various B-cell malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). This pooled analysis from nine clinical trials of ibrutinib in CLL and MCL ( N  = 1178) evaluated patterns of these AEs. Any grade arthralgia, myalgia, and musculoskeletal pain occurred in 18%, 10%, and 6% of patients, respectively. AEs were primarily low-grade (grade 1/2: 97‒99%) and occurred during the first year of treatment; most resolved (67%-80%) at first occurrence. Few (<5%) patients required ibrutinib dose modification; no patients discontinued ibrutinib due to these AEs. Among patients evaluated for concomitant medication use, all those receiving concomitant medications after the first AE occurrence experienced AE resolution. These data suggest that these AEs were not treatment-limiting during ibrutinib therapy.

We report long-term follow-up from the RESONATE-2 phase 3 study of the once-daily Bruton's tyrosine kinase inhibitor ibrutinib, which is the only targeted therapy with significant progression-free survival (PFS) and overall survival (OS) benefit in multiple randomized chronic lymphocytic leukemia (CLL) studies. Patients (≥65 years) with previously untreated CLL, without del(17p), were randomly assigned 1:1 to once-daily ibrutinib 420 mg until disease progression/unacceptable toxicity (n = 136) or chlorambucil 0.5-0.8 mg/kg ≤12 cycles (n = 133). With up to 8 years of follow-up (range, 0.1-96.6 months; median, 82.7 months), significant PFS benefit was sustained for ibrutinib vs chlorambucil (hazard ratio [HR], 0.154; 95% confidence interval [CI], 0.108-0.220). At 7 years, PFS was 59% for ibrutinib vs 9% for chlorambucil. PFS benefit was also observed for ibrutinib- vs chlorambucil-randomized patients with high-risk genomic features: del(11q) (HR, 0.033; 95% CI, 0.010-0.107) or unmutated immunoglobulin heavy chain variable region (HR, 0.112; 95% CI, 0.065-0.192). OS at 7 years was 78% with ibrutinib. Prevalence of adverse events (AEs) was consistent with previous 5-year follow-up. Ibrutinib dosing was held (≥7 days) for 79 patients and reduced for 31 patients because of AEs; these AEs resolved or improved in 85% (67 of 79) and 90% (28 of 31) of patients, respectively. With up to 8 years of follow-up, 42% of patients remain on ibrutinib. Long-term RESONATE-2 data demonstrate sustained benefit with first-line ibrutinib treatment for CLL, including for patients with high-risk genomic features. These trials were registered at www.clinicaltrials.gov as #NCT01722487 and #NCT01724346., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features., (© 2022 by The American Society of Hematology.)

BACKGROUND: Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein present on many cancers. Zilovertamab vedotin (ZV) is an antibody–drug conjugate comprising a monoclonal antibody recognizing extracellular ROR1, a cleavable linker, and the anti-microtubule cytotoxin monomethyl auristatin E. METHODS: In this phase 1, first-in-human, dose-escalation study, we accrued patients with previously treated lymphoid cancers to receive ZV every 3 weeks until the occurrence of cancer progression or unacceptable toxicity had occurred. RESULTS: We enrolled 32 patients with tumor histologies of mantle cell lymphoma (MCL) (n=15), chronic lymphocytic leukemia (n=7), diffuse large B-cell lymphoma (DLBCL) (n=5), follicular lymphoma (n=3), Richter transformation lymphoma (n=1), or marginal zone lymphoma (n=1). Patients had received a median of four previous drug and/or cellular therapies. Starting dose levels were 0.5 (n=1), 1.0 (n=3), 1.5 (n=3), 2.25 (n=11), and 2.5 (n=14) mg per kg of body weight (mg/kg). Pharmacokinetic and pharmacodynamic data documented systemic ZV exposure and exposure-dependent ZV targeting of ROR1 on circulating tumor cells. As expected with an monomethyl auristatin E-containing antibody–drug conjugate, adverse events (AEs) included acute neutropenia and cumulative neuropathy resulting in a recommended ZV dosing regimen of 2.5 mg/kg every 3 weeks. No clinically concerning AEs occurred to suggest ROR1-mediated toxicities or nonspecific ZV binding to normal tissues. ZV induced objective tumor responses in 7 of 15 patients with MCL (47%; 4 partial and 3 complete) and in 3 of 5 patients with DLBCL (60%; 1 partial and 2 complete); objective tumor responses were not observed among patients with other tumor types. CONCLUSIONS: In heavily pretreated patients, ZV demonstrated no unexpected toxicities and showed evidence of antitumor activity, providing clinical proof of concept for selective targeting of ROR1 as a potential new approach to cancer therapy. (ClinicalTrials.gov number, NCT03833180.)

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10-1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10-1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy., (© 2021 by The American Society of Hematology.)

Purpose: To improve curability and limit long-term adverse effects for newly diagnosed early-stage (ES), unfavorable-risk Hodgkin lymphoma., Methods: In this multicenter study with four sequential cohorts, patients received four cycles of brentuximab vedotin (BV) and doxorubicin, vinblastine, and dacarbazine (AVD). If positron emission tomography (PET)-4-negative, patients received 30-Gy involved-site radiotherapy in cohort 1, 20-Gy involved-site radiotherapy in cohort 2, 30-Gy consolidation-volume radiotherapy in cohort 3, and no radiotherapy in cohort 4. Eligible patients had ES, unfavorable-risk disease. Bulk disease defined by Memorial Sloan Kettering criteria (> 7 cm in maximal transverse or coronal diameter on computed tomography) was not required for cohorts 1 and 2 but was for cohorts 3 and 4. The primary end point was to evaluate safety for cohort 1 and to evaluate complete response rate by PET for cohorts 2-4., Results: Of the 117 patients enrolled, 116 completed chemotherapy, with the median age of 32 years: 50% men, 98% stage II, 86% Memorial Sloan Kettering-defined disease bulk, 27% traditional bulk (> 10 cm), 52% elevated erythrocyte sedimentation rate, 21% extranodal involvement, and 56% > 2 involved lymph node sites. The complete response rate in cohorts 1-4 was 93%, 100%, 93%, and 97%, respectively. With median follow-up of 3.8 years (5.9, 4.5, 2.5, and 2.2 years for cohorts 1-4), the overall 2-year progression-free and overall survival were 94% and 99%, respectively. In cohorts 1-4, the 2-year progression-free survival was 93%, 97%, 90%, and 97%, respectively. Adverse events included neutropenia (44%), febrile neutropenia (8%), and peripheral neuropathy (54%), which was largely reversible., Conclusion: BV + AVD × four cycles is a highly active and well-tolerated treatment program for ES, unfavorable-risk Hodgkin lymphoma, including bulky disease. The efficacy of BV + AVD supports the safe reduction or elimination of consolidative radiation among PET-4-negative patients., Competing Interests: Anita KumarStock and Other Ownership Interests: BridgebioConsulting or Advisory Role: Celgene, Kite, a Gilead company, AstraZenecaResearch Funding: AbbVie/Genentech, Adaptive Biotechnologies, Celgene, Seattle Genetics, AstraZeneca, Pharmacyclics Carla CasuloHonoraria: Gilead SciencesResearch Funding: Celgene, Verastem, Gilead SciencesTravel, Accommodations, Expenses: Gilead Sciences, Roche Ranjana H. AdvaniConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Takeda, Portola Pharmaceuticals, Celgene, Sanofi, Kura Oncology, Merck, Karyopharm Therapeutics, ADC Therapeutics, Daiichi Sankyo, Bristol Myers Squibb/Celgene, Epizyme, IncyteResearch Funding: Millennium, Seattle Genetics, Genentech/Roche, Pharmacyclics, Janssen, Merck, Kura Oncology, Regeneron, Forty Seven, Cyteir Elizabeth BuddeHonoraria: AstraZenecaConsulting or Advisory Role: Roche/Genentech, Kite/Gilead, NovartisSpeakers' Bureau: Kite, a Gilead company, AstraZenecaResearch Funding: Merck, Amgen, MustangBio, AstraZenecaPatents, Royalties, Other Intellectual Property: CCR4 CAR T cells for treatment of patients with CCR4 positive cancer, CD33CAR for treatment of patients with CD33+ acute myeloid leukemiaTravel, Accommodations, Expenses: Roche/Genentech, Kite/Gilead, AstraZeneca Paul M. BarrConsulting or Advisory Role: Pharmacyclics, AbbVie, Seattle Genetics, Genentech, Novartis, Infinity Pharmaceuticals, Janssen, Merck, TG Therapeutics, MorphoSys, AstraZeneca, BeiGene, MEI Pharma, Bristol Myers Squibb/Celgene, BayerResearch Funding: Pharmacyclics, AstraZeneca Connie L. BatleviStock and Other Ownership Interests: Moderna Therapeutics, Novavax, Pfizer, Bristol Myers Squibb, Regeneron, ViatrisHonoraria: DAVAOncologyConsulting or Advisory Role: Lifesci Capital, GLG, Juno Therapeutics, Celgene, Seattle Genetics, Kite, a Gilead company, TG Therapeutics, Karyopharm TherapeuticsResearch Funding: Janssen Biotech, Novartis, Epizyme, Xynomic Pharma, Bayer, Roche, AutolusOpen Payments Link: https://openpaymentsdata.cms.gov/physician/2778694 Philip CaronStock and Other Ownership Interests: AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Johnson & Johnson/Janssen, Novartis, Pfizer, Teva Louis S. ConstineHonoraria: UpToDate, Springer, Lippincott Savita V. DandapaniResearch Funding: Bayer Pamela DrullinskyResearch Funding: Novartis Jonathan W. FriedbergConsulting or Advisory Role: Astellas Pharma, NovartisResearch Funding: Seattle GeneticsPatents, Royalties, Other Intellectual Property: Patent on bone marrow microenvironment signals Paul A. HamlinConsulting or Advisory Role: Juno Therapeutics, Karyopharm Therapeutics, Celgene, Sandoz, AstraZeneca/MerckResearch Funding: Spectrum Pharmaceuticals, Seattle Genetics, Janssen, Portola Pharmaceuticals, GlaxoSmithKline, Molecular Templates, Incyte Richard T. HoppeStock and Other Ownership Interests: Johnson & Johnson, Pfizer Steven M. HorwitzConsulting or Advisory Role: Celgene, Millennium, Kyowa Hakko Kirin, Seattle Genetics, ADC Therapeutics, Portola Pharmaceuticals, Verastem, Takeda, Astex Pharmaceuticals, Kura Oncology, Acrotech Biopharma, C4 Therapeutics, Janssen Oncology, Trillium Therapeutics, Vividion Therapeutics, Myeloid Therapeutics, Ono PharmaceuticalResearch Funding: Celgene, Seattle Genetics, Takeda, Kyowa Hakko Kirin, Aileron Therapeutics, ADC Therapeutics, Verastem, Forty Seven, Trillium Therapeutics, Daiichi Sankyo, Affimed Therapeutics, Corvus Pharmaceuticals Niloufer KhanResearch Funding: Seattle Genetics Matthew J. MatasarStock and Other Ownership Interests: MerckHonoraria: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Seattle Genetics, Takeda, IGM Biosciences, ImmunovaccineConsulting or Advisory Role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, TakedaResearch Funding: Genentech, Roche, GlaxoSmithKline, Bayer, Pharmacyclics, Janssen, Rocket Medical, Seattle Genetics, Immunovaccine, IGM BiosciencesTravel, Accommodations, Expenses: Genentech, Roche, Seattle Genetics, Bayer Alison J. MoskowitzHonoraria: Seattle GeneticsConsulting or Advisory Role: Seattle Genetics, Takeda, Imbrium Therapeutics, Merck, Janpix, Kyowa Kirin International, miRagen, ADC Therapeutics, Bristol Myers SquibbResearch Funding: Incyte, Seattle Genetics, Merck, Bristol Myers Squibb, miRagen, ADC Therapeutics Ariela NoyConsulting or Advisory Role: MorphoSys, Janssen Biotech, Prime OncologyResearch Funding: Pharmacyclics, Rafael PharmaceuticalsTravel, Accommodations, Expenses: Pharmacyclics, Janssen Oncology Maria Lia PalombaStock and Other Ownership Interests: Seres TherapeuticsHonoraria: Merck, Celgene, Pharmacyclics, Flagship Biosciences, Novartis, Evelo Therapeutics, Jazz Pharmaceuticals, Therakos, Amgen, Seres TherapeuticsConsulting or Advisory Role: Merck, Celgene, Flagship Biosciences, Novartis, Evelo Therapeutics, Jazz Pharmaceuticals, Therakos, Amgen, Seres Therapeutics, Kite, Gilead Company, NovartisResearch Funding: Seres TherapeuticsPatents, Royalties, Other Intellectual Property: Intellectual Property Rights, Juno intellectual property rights David J. StrausConsulting or Advisory Role: Takeda, Seattle Genetics Anas YounesEmployment: AstraZenecaStock and Other Ownership Interests: AstraZenecaHonoraria: Merck, Roche, Takeda, Janssen, AbbVie, Curis, EpizymeConsulting or Advisory Role: Bio-Path Holdings Inc, Xynomic Pharma, Epizyme, Roche, Celgene, HCMResearch Funding: Janssen, Curis, Roche, Genentech, Merck, Bristol Myers Squibb, SyndaxOther Relationship: AstraZeneca Andrew D. ZelenetzHonoraria: NCCN, Clinical Care Options, Oncology Information Group, PER, PlexusConsulting or Advisory Role: Gilead Sciences, Amgen, Genentech/Roche, Celgene, AstraZeneca, DAVAOncology, MorphoSys, BeiGene, MEI Pharma, Vaniam Group, Verastem, Pharmacyclics, Karyopharm Therapeutics, Debiopharm Group, Seattle Genetics, Quant Health Ltd, Kite, Gilead Company, Curis, Coherus Biosciences, Juno/Celgene/Bristol Myers Squibb, Curio ScienceResearch Funding: Genentech/Roche, Gilead Sciences, MEI Pharma, BeiGene Craig H. MoskowitzConsulting or Advisory Role: Merck Sharp & Dohme, Molecular Templates, Takeda, AstraZeneca, IncyteResearch Funding: AstraZeneca, Merck Sharp & DohmeNo other potential conflicts of interest were reported.

Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in chronic lymphocytic leukemia (CLL). Umbralisib, a novel highly selective phosphatidylinositol 3-kinase δ (PI3Kδ)/CK1ε inhibitor, is active and well tolerated in CLL patients. In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg/d in CLL patients requiring therapy, who were intolerant to prior BTK inhibitor (BTKi) or PI3K inhibitor (PI3Ki) therapy, until progression or toxicity. Primary end point was progression-free survival (PFS). Secondary end points included time to treatment failure and safety. DNA was genotyped for CYP3A4, CYP3A5, and CYP2D6 polymorphisms. Fifty-one patients were enrolled (44 BTKi intolerant and 7 PI3Kδi intolerant); median age was 70 years (range, 48-96), with a median of 2 prior lines of therapy (range, 1-7), 24% had del17p and/or TP53 mutation, and 65% had unmutated IGHV. Most common adverse events (AEs) leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median PFS was 23.5 months (95% CI, 13.1-not estimable), with 58% of patients on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib because of an AE. Eight patients (16%) had dose reductions and were successfully rechallenged. These are the first prospective data to confirm that switching from a BTKi or alternate PI3Ki to umbralisib in this BTKi- and PI3Ki-intolerant CLL population can result in durable well-tolerated responses., (© 2021 by The American Society of Hematology.)