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Chaitra Ujjani, 1 Anthony Mato, 2 Brian T Hill, 3 John N Allan, 4 Erick Lansigan, 5 Ryan Jacobs, 6 Hande Tuncer, 7 John Pagel, 8 Danielle Brander, 9 Bruce Cheson, 10 Paul Barr, 11 Lindsey E Roeker, 2 Jeffrey Pu, 12 Nirav N Shah, 13 Andre Goy, 14 Stephen J Schuster, 15 Nicole Lamanna, 16 Alison Sehgal, 17 Constantine S Tam, 18 Mazyar Shadman 1 1Seattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 2Division of Hematological Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA; 4Division of Hematology and Medical Oncology, New York Presbyterian & Weill Cornell, New York, NY, USA; 5Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA; 6Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Charlotte, NC, USA; 7Lowell General Hospital, Tufts Medical Center, Boston, MA, USA; 8Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA; 9Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, NC, USA; 10Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA; 11Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA; 12Division of Hematology/Oncology, SUNY Upstate Medical University, Syracuse, NY, USA; 13Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 14John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA; 15Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 16Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA; 17University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 18Peter McCallum Cancer Centre, University of Melbourne, East Melbourne, VI, AustraliaCorrespondence: Chaitra UjjaniSeattle Cancer Care Alliance, Fred Hutchinson Cancer Research Center, 825 Eastlake Ave E, Mail Stop CE3-300, Seattle, WA, USATel +1 206-606-1955Fax +1 206-606-1130Email ujjani@uw.eduIntroduction: Recent randomized trials have demonstrated the efficacy of ibrutinib-based therapy in the treatment of patients with CLL. In Alliance A041202, a higher than expected number of unexplained deaths were reported with front-line ibrutinib in a patient population aged at least 65 years compared to ECOG 1912, which included patients up to 70 years of age.Methods: Therefore, we conducted a retrospective analysis to investigate whether ibrutinib was associated with a greater mortality in older patients outside of a clinical trial setting. This multicenter analysis was performed by investigators at 20 academic and community practices.Results: Amongst the 391 patients included, there was no correlation between age and response rate, PFS, or OS. However, there was a trend to higher rate of deaths in patients > 65-years-old (8.7% vs 3.8%, p=0.097), with an increased number of early deaths (13 vs 4, p=0.3).Conclusion: These data suggest greater intolerance, and possibly mortality, with ibrutinib in an older population. Patients should be educated regarding the potential complications related to ibrutinib and symptoms of concern to report.Keywords: CLL, ibrutinib, elderly

Abstract: Venetoclax is a B-cell lymphoma 2 inhibitor used in chronic lymphocytic leukemia (CLL), which can cause tumor lysis syndrome (TLS). We aimed to determine the incidence of, and risk factors for, TLS among patients with CLL/small lymphocytic lymphoma who received treatment with venetoclax at our institution from 1 January 2016 to 31 December 2020. We included 616 venetoclax escalations among 136 patients with CLL. Overall, 74 patients (54%) underwent escalation exclusively outpatient, 35 (26%) had at least 1 planned hospitalization, and 27 (20%) were escalated exclusively inpatient. During venetoclax initiation, 86% of patients received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 7 patients (5.1%) developed laboratory TLS by modified Cairo Bishop criteria and none developed clinical TLS. Incidence of laboratory TLS was 15% for those escalated exclusively inpatient, 2.9% for those with any prophylactic hospitalization, and 2.7% for those escalated exclusively outpatient. Those who developed TLS were more likely to have higher TLS risk, and no additional risk factors were identified. In this single institution retrospective cohort study, laboratory TLS was observed, although clinical TLS was not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting., (© 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.)

Hypomethylating agents (HMA) and venetoclax (VEN) are commonly used in patients with IDH -mutated ( IDH m) acute myeloid leukemia (AML) ineligible for induction chemotherapy. While prior studies demonstrated high response and survival rates with HMA/VEN in IDH m AML, the impact of treatment modifications in real-world settings is unclear. We retrospectively reviewed 89 IDH m AML patients treated with HMA/VEN from January 2018 to June 2023. CR/CRi rates were 76% in newly diagnosed (ND) and 55% in relapsed/refractory (R/R) patients, and median overall survival was 29.2 months (ND) and 17.1 months (R/R), respectively. Treatment modifications were common. Early VEN reductions were associated with lower response rates but not worse survival. Prolonged cycles were not associated with worse response rates or survival. Significant neutropenia and ED visits or unplanned hospitalizations were considerable before and after CR/CRi, though febrile neutropenia decreased afterward. HMA/VEN is efficacious, with treatment modifications not affecting survival, though long-term toxicities are notable.

Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment of B-cell malignancies, but intolerance has often led to their discontinuation. The phase 1/2 BRUIN study evaluated pirtobrutinib, a highly selective non-covalent (reversible) BTKi, in patients with R/R B-cell malignancies (NCT03740529). Pirtobrutinib was investigated in 127 patients with intolerance to at least one prior BTKi therapy in the absence of progressive disease. The most common adverse event (AE) leading to BTKi discontinuation was cardiac disorders (n=40, 31.5%), specifically atrial fibrillation (n=30, 23.6%). The median follow-up was 17.4 months and the median time on pirtobrutinib was 15.3 months. The most common reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%), or death (5.5%). The most frequent treatment-emergent AEs were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 CLL/SLL and 21 MCL patients intolerant to prior BTKi, ORR to pirtobrutinib was 76.9% and 81.0%, respectively. Median PFS for CLL/SLL was 28.4 months and was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.

Abstract: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial. Prior covalent BTKi therapy was allowed, but not prior treatment with venetoclax. Patients were assigned to receive PV (n = 15) or PVR (n = 10) for 25 cycles. Most patients (68%) had received prior covalent BTKi therapy. At the data cutoff date, the median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% confidence interval [CI], 68.1-99.8) for PV and 100% (95% CI, 69.2-100.0) for PVR, with 10 complete responses (PV: 7; PVR: 3). After 12 cycles of treatment, 85.7% (95% CI, 57.2-98.2) of PV and 90.0% (95% CI, 55.5-99.7) of PVR patients achieved undetectable minimal residual disease (<10-4) in peripheral blood. Progression-free survival at 18 months was 92.9% (95% CI, 59.1-99.0) for PV patients and 80.0% (95% CI, 40.9-94.6) for PVR patients. No dose-limiting toxicities were observed during the 5-week assessment period. The most common grade ≥3 adverse events (AEs) for all patients included neutropenia (52%) and anemia (16%). AEs led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi. This trial was registered at www.clinicaltrials.gov as #NCT03740529., (© 2024 American Society of Hematology. Published by Elsevier Inc. 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: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study., Methods: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529)., Findings: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths., Interpretation: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor., Funding: Loxo Oncology., Competing Interests: Declaration of interests WGW reports research funding from Numab Therapeutics, Loxo Oncology–Lilly, Janssens Biotech, NIH P30 CA016672/MDACC Cancer Center Support Grant, GlaxoSmithKline, AbbVie, Cyclacel, Nurix Therapeutics, Juno Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma Miragen, Oncternal Therapeutics, Janssens Biotech, Accutar Biotechnology, Sunesis, KITE Pharma, Gilead Sciences, Genentech, Pharmacyclics, GlaxoSmithKline–Novartis; consultancy fees from AbbVie, Cyclacel Nurix Therapeutics, Bristol Myers Squibb (Juno & Celgene), AstraZeneca–Acerta Pharma; a non-relevant financial relationship with the National Comprehensive Cancer Network; support from the National Institutes of Health and National Cancer Institute under award number P30 CA016672; and use of MDACC Cancer Center Support Grant shared resources. NNS reports consultancy fees from Umoja, Janssen, Bristol Myers Squibb–Juno, LOXO Oncology–Lilly, TG therapeutic, Novartis, Seattle Genetics, Gilead–Kite, Incyte, AbbVie, Lilly Oncology, and Miltenyi Biotec; research funding from Miltenyi Biotec and Lilly Oncology; having stock options in a privately-held company with Tundra Therapeutics; and travel support from Epizyme and Miltenyi Biotec. CYC reports consultancy fees, honoraria, and having an advisory role for Roche, Janssen, Gilead, AstraZenecca, Eli Lilly, BeiGene, AbbVie, Menarini, Daizai, and Genmab, and research funding from Roche, MSD, Eli Lilly, Bristol Myers Squibb, and AbbVie. DL reports consultancy fees from Kite, BeiGene, Roche, Eli Lilly, and Janssen and membership on an entity's board of directors or advisory committees with Kite, BeiGene, Roche, Eli Lilly, and Janssen. MSH reports consultancy fees and honoraria from Pharmacyclics. CCC reports consultancy fees from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie, Octapharma, Allogene, Janssen, TG Therapeutics, MEI Pharma, and Mingsight; honoraria from LOXO Oncology–Eli Lilly, BeiGene, AstraZeneca, Genentech, AbbVie; research funding paid to an institution from LOXO Oncology–Eli Lilly, AbbVie, and CarnaBio; membership on an entity's board of directors or advisory committees with BeiGene, AstraZeneca, Genentech, and AbbVie; being an equity holder in a publicly-traded company with Bluebird Bio, Geron, and Pfizer; and receiving travel support from LOXO Oncology–Eli Lilly. NL reports consultancy fees from Genentech, Pharmacyclics, BeiGene, AstraZeneca, AbbVie, Adaptive Biotechnologies, Janssen, and research funding from Genentech, TG Therapeutics, BeiGene, AstraZeneca, AbbVie, MingSight, LOXO Oncology–Eli Lilly, Oncternal, and Octapharma. SM reports consultancy fees from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Genentech, Janssen Pharmaceuticals, BeiGene; membership on a board of directors or advisory committee with AstraZeneca, Juno–Bristol Myers Squibb, Janssen Pharmaceuticals, Eli Lilly, Loxo Oncology, and BeiGene; research funding from AstraZeneca, Juno–Bristol Myers Squibb, AbbVie, Janssen Pharmaceuticals, Eli Lilly–Loxo Oncology, BeiGene; and speakers bureau with AstraZeneca, Eli Lilly–Loxo Oncology, and BeiGene. DJ reports research funding from Seagen, Trillium Pharmaceuticals, Regeneron Pharmaceuticals, MEI Pharma, Loxo Oncology, Debio Pharma, ATARA Biotherapeutics, AstraZeneca and membership on a board of directors or advisory committees with Affimed and Daiichi Sankyo. TM reports consultancy fees from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; honoraria from BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie; membership on a board of directors or advisory committees on BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, Abbvie; research Funding from Janssen, AbbVie; and speakers bureau for BeiGene, Alexion, Sobi, Roche, AstraZeneca, Janssen, and AbbVie. YW reports research funding from Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, and AbbVie; membership on an advisory board with Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, and Genmab; consultancy fees from Innocare and AbbVie; and honoraria from Kite. TAE reports membership on an entity's Board of Directors or advisory committees from Loxo Oncology, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Roche, Gilead, Secura Bio; speakers bureau from Loxo Oncology, Eli Lilly, Incyte, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Medscape, Janssen, Gilead, PeerView; research funding from BeiGene and AstraZeneca; consultancy fees from Eli Lilly, Incyte, Beigene, Autolus, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead; and honoraria from Eli Lilly, BeiGene, AstraZeneca, KITE, AbbVie, Loxo Oncology, Roche, Janssen, and Gilead. JMR reports consultancy fees from Pharmacyclics, Jannsen, Genentech, GenMab, AstraZeneca, Morphosys, ADC Therapeutics, Epizyme, BeiGene, and AbbVie; research funding from Pharmacyclics, Velosbio, Loxo Oncology, Acerta, Oncternal Pharmaceuticals, Epizyme, and AbbVie; and honoraria from SeaGen. MM reports consultancy from Bayer, ADC therapeutics, Epizyme, Genentech, F Hoffmann-La Roche, and Incyte; research funding from BeiGene, Janssen, F Hoffmann-La Roche– Genentech, Celgene–Bristol Myers Squibb, and Incyte; and speakers bureau with ADC therapeutics, BeiGene, and Kite–Gilead. CT reports honoraria from Loxo Oncolgy. WJ reports consultancy fees from AbbVie, AstraZeneca, BeiGene, Eli Lilly, Pfizer, Roche, SOBI, and Takeda and research funding from AbbVie, AstraZeneca, Bayer, BeiGene, Celgene, Janssen, Eli Lilly, Roche, SOBIm, and Takeda. KI reports honoraria from Eli Lilly, SymBio Pharmaceuticals, Meiji Seika, Nihon Kayaku, Takeda, AstraZeneca, Janssen, Genmab, MSD, Pfizer, AbbVie, Ono Pharmaceuticals, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Chugai Pharma, and Kyowa Kirin; consultancy fees from Takeda, AstraZeneca, Genmab, AbbVie, Otsuka, Eisai, Ono Pharmaceuticals, Nippon Shinyaku, Mitsubishi Tanabe Pharma, and Zenyaku Kogyo; and research funding from AstraZeneca, Genmab, MSD, Pfizer, AbbVie, Otsuka, Eisai, Regeneron, Loxo Oncology, BeiGene, Daiichi Sankyo, Yakult, Novartis, Bristol Myers Squibb, Incyte, Astellas Amgen, Chugai Pharma, Kyowa Kirin. AA reports membership on a board of directors or advisory committees with Genentech, Eli Lilly and Company, Amgen, TG Therapeutics, Incyte, BeiGene, Epizyme, Janssen, and SeaGen; research funding from Eli Lilly, Incyte, and BeiGene; and honoraria from Dr Reddy. MP reports consulting fees from Kura, Accutar, Mitsubishi; participating on a data safety monitoring board or advisory board with lema, Nurix, Daiichi, Kura, and Janssen; leadership with ION Pharma; honoraria from Janssen Oncology; and participating in a consulting or advisory role with Olema Pharmaceuticals, Daiichi Sankyo–UCB Japan, Kura Oncology, Accutar Biotech, and Kura. JFS reports honoraria from Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; consultancy fees from Hoffmann-La Roche, TG Therapeutics, Bristol Myers Squibb; participating on a data safety monitoring board or advisory board with Genor Bio, Hoffmann-La Roche, AbbVie, AstraZeneca, Janssen, Bristol Myers Squibb, Gilead, and BeiGene; speakers bureau with Hoffmann-La Roche, AbbVie, and BeiGene; and research funding from F Hoffmann-La Roche and AbbVie. JAW reports consultancy from Newave, Loxo Oncology, BeiGene, AstraZeneca, AbbVie, Janssen, and Pharmacyclics and research funding from Schrodinger, Morphosys, Karyopharm, Janssen, and Pharmacyclics. PAT reports consultancy and honoraria from AbbVie, Adaptive Biotechnologies, Ascentage AstraZeneca, BeiGene, Genentech, Genmab, Janssen, Lilly, Merck, Pharmacyclics; speakers bureau from AbbVie, Adaptive Biotechnologies, AstraZeneca, Janssen, and Merck; research funding from AbbVie, Pharmacyclics, Genentech, Lilly, and Adaptive Biotechnologies; and travel support from Merck. PA is a current employee of and equity holder in Eli Lilly. CH reports being an equity holder in Eli Lilly and Foundation Medicine and travel support from Eli Lilly. SCM reports current employment with, being an equity holder in, and travel support from Eli Lilly. NM reports being a current equity holder in Eli Lilly and current employment with Loxo Oncology. BN, CW, BCN, and DET reports current employment with and current equity holder in Eli Lilly. ASR reports current employment with and being equity holder in Eli Lilly and consultancy work with Telios Pharma. HL reports current employment with Loxo Oncology. LER reports serving as a consultant for AbbVie, Ascentage, AstraZeneca, BeiGene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, and TG Therapeutics; membership of a data safety monitoring committee for Ascentage; serving as a CME speaker for DAVA, Curio, Medscape, and PeerView; holding minority ownership interest in Abbott Laboratories; having received travel support from LOXO Oncology; and having received research funding (paid to the institution) from Adaptive Biotechnologies, AstraZeneca, Genentech, AbbVie, Pfizer, Loxo Oncology, Aptose Biosciences, Dren Bio, and Qilu Puget Sound Biotherapeutics. PG reports consultancy, fees, honoraria, and research funding from Janssen, Eli Lilly–Loxo Oncology, MSD, Roche, AbbVie, BMS, BeiGene, and AstraZeneca., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor, has demonstrated promising efficacy in B-cell malignancies and is associated with low rates of discontinuation and dose reduction. Pirtobrutinib is administered until disease progression or toxicity, necessitating an understanding of the safety profile in patients with extended treatment., Methods: Here we report the safety of pirtobrutinib in patients with relapsed/refractory B-cell malignancies with extended (≥12 months) drug exposure from the BRUIN trial. Assessments included median time-to-first-occurrence of adverse events (AEs), dose reductions, and discontinuations due to treatment-emergent AEs (TEAEs) and select AEs of interest (AESIs)., Results: Of 773 patients enrolled, 326 (42%) received treatment for ≥12 months. In the extended exposure cohort, the median time-on-treatment was 19 months. The most common all-cause TEAEs were fatigue (32%) and diarrhea (31%). TEAEs leading to dose reduction occurred in 23 (7%) and discontinuations in 11 (3%) extended exposure patients. One patient had a fatal treatment-related AE (COVID-19 pneumonia). Infections (73.0%) were the most common AESI with a median time-to-first-occurrence of 7.4 months. Majority of TEAEs and AESIs occurred during the first year of therapy., Conclusions: Pirtobrutinib therapy continues to demonstrate an excellent safety profile amenable to long-term administration without evidence of new or worsening toxicity signals., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

AZD7442 (tixagevimab-cilgavimab) is a combination of two human monoclonal antibodies for pre-exposure prophylaxis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among high-risk patients who do not mount a reliable vaccine response. Foremost among these are hematologic malignancy patients with limited clinical trial or realworld experience to assess the effectiveness of this combination treatment since the emergence of Omicron and its subvariants. We performed a retrospective study of 892 high-risk hematologic malignancy patients who received AZD7442 at Memorial Sloan Kettering Cancer Center in New York City from January 1, 2022 to July 31, 2022. We evaluated demographic, clinical, and laboratory characteristics and performed regression analyses to evaluate risk factors for breakthrough infection. We also evaluated the impact of updated AZD7442 dosing regimens on the risk of breakthrough infection. Among 892 patients, 98 (10.9%) had a breakthrough infection during the study period. A majority received early outpatient treatment (82%) and eventually eight (8.2%) required hospitalization for management of Coronavirus Disease 2019 (COVID-19), with a single instance of severe COVID-19 and death. Patients who received a repeat dose or a higher firsttime dose of AZD7442 had a lower incidence of breakthrough infection. Univariate analyses did not reveal any significant predictors of breakthrough infection. While AZD7442 is effective at reducing SARS-CoV-2 breakthrough infection in patients with hematologic malignancies, no risk factors reliably predicted risk of infection. Patients who received updated dosing regimens as per Food and Drug Administration guidelines had better protection against breakthrough infection.

Novel agents, including Bruton tyrosine kinase inhibitors (BTKis), have become the standard of care for patients with chronic lymphocytic leukemia (CLL). We conducted a real-world retrospective analysis of patients with CLL treated with acalabrutinib vs ibrutinib using the Flatiron Health database. Patients with CLL were included if they initiated acalabrutinib or ibrutinib between 1 January 2018 and 28 February 2021. The primary outcome of interest was time to treatment discontinuation (TTD). Kaplan-Meier analysis was used to estimate unweighted and weighted median TTD. A weighted Cox proportional hazards model was used to compare the TTD between cohorts. Of the 2509 patients included in the analysis, 89.6% received ibrutinib, and 14.1% received acalabrutinib. TTD was not significantly different between cohorts in the unweighted analysis. After weighting, the cohorts were balanced on all baseline characteristics except cardiovascular risk factors and baseline medications use. The median (95% confidence interval [CI]) TTD was not reached (NR; 95% CI, 25.1 to NR) for the acalabrutinib cohort and was 23.4 months (95% CI, 18.1-28.7) for the ibrutinib cohort. The discontinuation rate at 12 months was 22% for the weighted acalabrutinib cohort vs 31% for the weighted ibrutinib cohort (P = .005). After additional adjustment for prior BTKi use, the acalabrutinib cohort had a 41% lower risk of discontinuation vs ibrutinib (hazard ratio, 0.59; 95% CI, 0.43-0.81; P = .001). In the largest available study comparing BTKis, patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs those receiving ibrutinib., (© 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.)

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.)

Somatic hypermutation status of the IGHV gene is essential for treating patients with chronic lymphocytic leukemia/small lymphocytic lymphoma. Unlike the conventional low-throughput method, assessment of somatic hypermutation by next-generation sequencing (NGS) has potential for uniformity and scalability. However, it lacks standardization or guidelines for routine clinical use. We critically assessed the performance of an amplicon-based NGS assay across 458 samples. Using a validation cohort (35 samples), the comparison of two platforms (Ion Torrent versus Illumina) and two primer sets [leader versus framework region 1 (FR1)] in their ability to identify clonotypic IGHV rearrangement(s) revealed 97% concordance. The mutation rates were identical by both platforms when using the same primer set (FR1), whereas a slight overestimation bias (+0.326%) was found when comparing FR1 with leader primers. However, for nearly all patients this did not affect the stratification into mutated or unmutated categories, suggesting that use of FR1 may provide comparable results if leader sequencing is not available and allowing for a simpler NGS laboratory workflow. In routine clinical practice (423 samples), the productive rearrangement was successfully detected by either primer set (leader, 97.7%; FR1, 94.7%), and a combination of both in problematic cases reduced the failure rate to 1.2%. Higher sensitivity of the NGS-based analysis also detected a higher frequency of double IGHV rearrangements (19.1%) compared with traditional approaches., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

This retrospective study using the nationwide de-identified Flatiron Health electronic health record-derived database was designed to evaluate clinical outcomes among patients with chronic lymphocytic leukemia (CLL) who previously received both a covalent Bruton's tyrosine kinase inhibitor (cBTKi) and B-cell lymphoma 2 inhibitor (BCL2i) in a real-world setting. Outcomes for the immediate next line of therapy following the latter of the cBTKi or BCL2i treatment included: real-world response rate of 34.4% (using methods most consistent with clinical trials); median duration of real-world response of 13.3 months; and median real-world progression-free survival of 9.2 months. Median overall survival was 25.5 months from the start of the immediate next line of therapy. There remains a need for more effective therapies after cBTKi and BCL2i therapy for patients with CLL.

Targeted therapies have largely replaced chemoimmunotherapy (CIT) in first-line treatment of chronic lymphocytic leukemia (CLL). We aimed to develop a prognostic model to determine who would benefit from first-line CIT vs target therapy. In follicular lymphoma, time from diagnosis to second treatment (TT2T) correlates better with overall survival (OS) than time from diagnosis to first treatment (TT1T). We hypothesized that TT2T is a potential surrogate for OS in CLL. In a model-building cohort ( n  = 298), we evaluated potential predictors for TT2T and derived a risk score, which we validated in an external cohort ( n  = 1141). Our data demonstrated that TT2T and OS were more strongly correlated than TT1T and OS. Our risk score model consisted of three predictors (unmutated IGHV, β 2 -microglobulin >297 nmol/L, and Rai stage I-IV), and was prognostic for TT2T and OS. TT2T is a promising surrogate for OS in CLL, but further validation is needed to establish this association.

As patients continue to live longer with chronic lymphocytic leukemia, it has become evident that there is an unmet treatment need for patients who have progressed on multiple lines of therapy. In this article, we attempt to define the "double refractory" patient as resistant to both Bruton's tyrosine kinase inhibitors (BTKi) and venetoclax for which prognosis is poor and there remains no standard of care. We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non-covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development., (© 2022 Wiley Periodicals LLC.)

Here we describe the rationale and design of MAJIC, a phase III, prospective, multicenter, randomized trial comparing the combination of the BTK inhibitor acalabrutinib plus the BCL2 inhibitor venetoclax versus the combination of venetoclax plus obinutuzumab as frontline treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. In both treatment arms, disease response (assessed by International Workshop on Chronic Lymphocytic Leukemia criteria) and minimal residual disease will be used to guide therapy duration, with all patients ultimately discontinuing treatment after a maximum of 2 years. The primary end point is progression-free survival. Key secondary end points include rates of undetectable minimal residual disease, overall response and overall survival. This study will address key unanswered questions in frontline chronic lymphocytic leukemia/small lymphocytic lymphoma therapy by investigating the optimal duration of finite treatment and identifying the optimal venetoclax doublet regimen.

Purpose: Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an "add on" approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO)., Patients and Methods: Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, <1 cell in 10-4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation., Results: Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7-67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%., Conclusions: This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up., (©2022 American Association for Cancer Research.)

Bruton's tyrosine kinase (BTK) is a critical downstream signaling element from the B-cell receptor (BCR) that has been effectively inhibited in B-cell cancers by irreversible, covalent inhibitors including ibrutinib and acalabrutinib. All FDA-approved covalent BTK inhibitors rely on binding to the cysteine 481 (C481) amino acid within the active site of BTK, thus rendering it inert. While covalent BTK inhibitors have been very successful in multiple B-cell malignancies, improving both overall survival and progression-free survival relative to chemoimmunotherapy in phase 3 trials, they can be limited by intolerance and disease progression. Pirtobrutinib is a novel, highly selective, and non-covalent BTK inhibitor that binds independently of C481, and in a recent, first-in-human phase 1/2 clinical trial was shown to be extremely well tolerated and lead to remissions in relapsed/refractory patients with multiple B-cell malignancies. Here, we review the pharmacologic rationale for pursuing non-covalent BTK inhibitors, the clinical need for such inhibitors, existing safety, and resistance mechanism data for pirtobrutinib, and the forthcoming clinical trials that seek to define the clinical utility of pirtobrutinib, which has the potential to fulfill multiple areas of unmet clinical need for patients with B-cell malignancies., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.L.J. is an AbbVie shareholder. A.R.M. receives research support from TG Therapeutics, Pharmacyclics, Abbvie, Adaptive Biotechnologies, Johnson and Johnson, Acerta / AstraZeneca, DTRM BioPharma, Sunesis, BeiGene, Genentech, Genmab, Janssen, Loxo Oncology, Nurix, and does advisory/consultancy/DSMB work with TG Therapeutics, Pharmacyclics, Adaptive Biotechnologies, Abbvie, Johnson and Johnson, Acerta / AstraZeneca, DTRM BioPharma, Sunesis, AstraZeneca, BeiGene, Genentech, Janssen, Loxo Oncology. L.E.R. has served as a consultant for AbbVie, AstraZeneca, Beigene, Janssen, Loxo Oncology, Pharmacyclics, Pfizer, TG Therapeutics, and Vaniam group, holds minority ownership interest in Abbott Laboratories, and has received research funding (paid to the institution) from Pfizer, Loxo Oncology, and Aptose Biosciences. C.C.C. has served as a consultant for AbbVie, has served on steering committees for AbbVie and Loxo Oncology, has served on independent review committees for AbbVie and Octapharma, has received honoraria from AbbVie, AstraZeneca, Beigene, Genentech, LOXO Oncology, MEI Pharma, Novartis, TG Therapeutics, and has received research funding (paid to the institution) from H3 Biomedicine, Incyte, Loxo Oncology., (© The Author(s), 2022.)

The scope of dermatologic adverse events to ibrutinib has not been systematically described. We sought to determine the incidence and severity of ibrutinib-associated dermatologic toxicities and provide management recommendations. We conducted a systematic literature search of clinical trials and cohorts investigating ibrutinib monotherapy for cancer or chronic graft-versus-host disease through June 2020. Thirty-two studies with 2258 patients were included. The incidence of all-grade toxicities included cutaneous bleeds (24.8%; 95%CI, 18.6-31.0%), mucocutaneous infections (4.9%; 95%CI, 2.9-7.0%), rash (10.8%; 95%CI. 6.1-15.5%), mucositis (6%; 95%CI, 3.6-8.5%), edema (15.9%; 95%CI, 11.1-20.6%), pruritus (4.0%; 95%CI, 0.0-7.9%), xerosis (9.2%; 95%CI, 5.5-13.0%), nail changes (17.8%; 95%CI, 4.1-31.5%), and hair changes (7.9%; 95%CI, 0.0-21.3%). The incidence of high-grade toxicities included mucocutaneous infection (1.3%; 95%CI, 0.5-2.2%), rash (0.1%; 95%CI, 0.0-0.2%), mucositis (0.1%; 95%CI, 0.0-0.3%), and edema (0.1%; 95%CI, 0.0-0.2%). It is imperative that clinicians familiarize themselves with ibrutinib-associated dermatologic toxicities to learn how to manage them, prevent discontinuation, and improve patient outcomes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL., (©2021 American Association for Cancer Research.)

In this review, we examine the literature supporting treatment decision making in the front-line and relapsed/refractory settings for patients with chronic lymphocytic leukemia (CLL). In the front-line setting, novel-agent-based approaches, including continuous Bruton tyrosine kinase (BTK) inhibitor-based therapy and time-limited venetoclax with obinutuzumab, have demonstrated survival benefit over chemoimmunotherapy. While novel-agent-based front-line approaches are appropriate for most patients, fludarabine, cyclophosphamide, and rituximab (FCR) remains a consideration for a selected population of young patients with immunoglobulin heavy chain variable region gene (IGHV)-mutated disease because of the possibility of a prolonged remission following FCR. As front-line novel-agent-based approaches have not been compared directly, decision making regarding which novel-agent-based approach to use in the front-line setting is often based on comorbidities and shared decision making. In the relapsed/refractory setting, BTK inhibitors, venetoclax-based therapy, and phosphoinositide 3-kinase (PI3K) inhibitors have demonstrated survival benefit when compared with chemoimmunotherapy regimens. Data to support various treatment sequences are limited, which highlights the need for prospective data to examine the optimal treatment sequence. Finally, we examine therapies with combinations of novel agents, and novel agents in development, including covalent and noncovalent BTK inhibitors, PI3K inhibitors, B-cell lymphoma 2 (BCL2) inhibitors, immunotherapies, and cellular therapies. With effective approved options and new agents in development, the role of chemoimmunotherapy in the management of CLL has diminished., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration., Methods: This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10 -4 ]) assessed per protocol. This trial is registered at clinicaltrials.gov (NCT03824483). The primary cohort is closed to recruitment, and recruitment continues in the TP53-mutated mantle cell lymphoma cohort., Findings: Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli., Interpretation: BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics., Funding: Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute., Competing Interests: Declaration of interests JDS reports consulting fees from Abbvie, AstraZeneca, Beigene, Bristol Myers Squibb, TG Therapeutics, and Verastem, and research funding from Adaptive Biotechnologies, Beigene, BostonGene, Genentech (Roche), GSK, Moderna, and TG Therapeutics. ARM reports consulting fees from Curio, Dava, Medscape, GenMab, PeerView, AstraZeneca, Abbvie, Adaptive, Beigene, Genentech, LOXO, Janssen, Pharmacyclics, and TG Therapeutics, research funding from DTRM, Nurix, GenMab, AstraZeneca, Abbvie, Adaptive, Beigene, Genentech, LOXO, Janssen, Pharmacyclics, and TG Therapeutics, and Data Safety Monitoring Board membership for TG Therapeutics. AD reports consulting fees from Physician's Education Resource, Seattle Genetics, Takeda, EUSA Pharma, and Abbvie, and research funding from Roche and Takeda. EJ reports consulting fees from AstraZeneca and Epizyme. EH reports consulting fees from Leuko and Intervention Insights. JSA reports consulting fees from Abbvie, Bayer, Celgene, Gilead, Juno Therapeutics, Kite Pharma, Genentech, Amgen, Novartis, Karyopharm, Verastem, Janssen, Merck, and Seattle Genetics. CLB reports consulting fees from Life Sci, GLG, Juno (Celgene), Seattle Genetics, Kite, Karyopharm, TG Therapeutics, and ADC Therapeutics, honoraria from Dava Oncology, TouchIME, and Medscape, stock ownership in BMS, Pfizer, Viatris, Regeneron, Moderna, and Novavax, and research funding from Autolus, Bayer, Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, and Genentech (Roche). MJM reports consulting fees from Genentech (Roche), Merck, Bayer, Juno, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, Takeda, honoraria from Genentech (Roche), GSK, Bayer, Pharmacyclics, Janssen, Seattle Genetics, Immunovaccine Technologies, and Takeda, travel, accommodation, or other expenses from Genentech (Roche), Bayer, and Seattle Genetics, and research funding from Genentech (Roche), Bayer, GlaxoSmithKline, IGM Biosciences, Rocket Medical, Seattle Genetics, Janssen, Pharmacyclics, and Immunovaccine Technologies, and minority ownership interest in Merck. AN reports consulting fees from Epizyme, Janssen, Pharmacyclics, Medscape, Targeted Oncology, and Morphosys, and research funding from Pharmacyclics and Rafael Pharma. MLP reports consulting fees from Beigene, Celgene, Novartis, Merck, and Synthekine, research funding from Pharmacyclics, Genentech, Juno, and Regeneron, and an immediate family member who receives royalties from Juno and Seres. AK reports consulting fees from Kite Pharmaceuticals, AstraZeneca, and Janssen, and research funding from Abbvie, Adaptive, Celgene, Pharmacyclics, Seattle Genetics, and AstraZeneca, and serves on a steering committee for mantle cell lymphoma Registry for AstraZeneca. LER reports consulting fees from Abbvie, AstraZeneca, Beigene, Janssen, Loxo Oncology, Pfizer, Pharmacyclics, TG Therapeutics, and Vaniam Group, minority ownership interest in Abbott Laboratories and Abbvie, and research funding from Pfizer. MT reports honoraria from the Massachusetts Medical Society, the Brazilian Association of Haematology, MJH Life Sciences, Curio Science, and VJHemeOnc. MR reports consulting fees from Celgene, Auron Therapeutics, and Physician's Education Resource, research funding from Cellularity, NGM, Genentech, and Beat AML, and ownership or equity interest in Auron Therapeutics. JH reports employment from Beigene. JB reports employment from Genentech. QW reports employment from Genentech. AJ reports employment from Adaptive Biotechnologies. OA-W reports consulting fees from H3 Biomedicine, Envisagenics, Janssen, and Merck. ADZ reports consulting fees from Adaptive Biotechnologies, Abbvie, Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, Celgene, Genentech (Roche), Gilead, MEI Pharma, MorphoSys, NCCN, Novartis, and Verastem, data safety monitoring committee membership for BMS, Celgene, and Juno, data safety monitoring committee membership chair for Beigene, and research funding from MEI Pharma, Gilead, Beigene, and Roche. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Coronavirus disease-19 (COVID-19) vaccine response data for patients with hematologic malignancy, who carry high risk for severe COVID-19 illness, are incomplete. In a study of 551 hematologic malignancy patients with leukemia, lymphoma, and multiple myeloma, anti-SARS-CoV-2 spike IgG titers and neutralizing activity were measured at 1 and 3 months from initial vaccination. Compared with healthy controls, patients with hematologic malignancy had attenuated antibody titers at 1 and 3 months. Furthermore, patients with hematologic malignancy had markedly diminished neutralizing capacity of 26.3% at 1 month and 43.6% at 3 months, despite positive seroconversion rates of 51.5% and 68.9% at the respective time points. Healthy controls had 93.2% and 100% neutralizing capacity at 1 and 3 months, respectively. Patients with leukemia, lymphoma, and multiple myeloma on observation had uniformly blunted responses. Treatment with Bruton tyrosine kinase inhibitors, venetoclax, phosphoinositide 3-kinase inhibitors, anti-CD19/CD20-directed therapies, and anti-CD38/B-cell maturation antigen-directed therapies substantially hindered responses, but single-agent immunomodulatory agents did not., Significance: Patients with hematologic malignancy have compromised COVID-19 vaccine responses at baseline that are further suppressed by active therapy, with many patients having insufficient neutralizing capacity despite positive antibody titers. Refining vaccine response parameters is critical to guiding clinical care, including the indication for booster vaccines, for this vulnerable population. See related article by Tamari et al., p. 577 . This article is highlighted in the In This Issue feature, p. 549 ., (©2021 American Association for Cancer Research.)

Patients with hematological malignancies are at risk for poor outcomes when diagnosed with coronavirus disease 2019 (COVID-19). It remains unclear whether cytopenias and specific leukemia subtypes play a role in the clinical course of COVID-19 infection. Here, we report outcomes and their clinical/laboratory predictors for 65 patients with acute and chronic leukemias diagnosed with COVID-19 between 8 March 2020 and 19 May 2020 at Memorial Sloan Kettering Cancer Center in New York City. Most patients had CLL (38%) or AML (26%). A total of 14 (22%) patients required high flow nasal cannula or were intubated for mechanical ventilation and 11 patients (17%) died. A diagnosis of AML (OR 4.7, p =.028), active treatment within the last 3 months (OR 5.22, p =.047), neutropenia within seven days prior and up to 28 days after SARS-CoV-2 diagnosis (11.75, p =.001) and ≥3 comorbidities (OR 6.55, p =.019) were associated with increased odds of death.

Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution., (© 2021 by The American Society of Hematology.)

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients., Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529., Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date., Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients., Funding: Loxo Oncology., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Novel agents, including Bruton's tyrosine kinase inhibitors (BTKi; ibrutinib, acalabrutinib), venetoclax, and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idelalisib, duvelisib), have fundamentally changed the chronic lymphocytic leukemia (CLL) treatment landscape, allowing for a chemotherapy-free paradigm for many. Randomized trials that demonstrated efficacy of these agents in the relapsed/refractory setting rarely included patients with prior novel agent exposure. Herein, we review available data, including single-arm prospective studies and retrospective cohorts, on outcomes for novel agent approaches after novel agent exposure. We examine data for subsequent treatment options in 3 specific scenarios: (1) progression of disease while receiving BTKi, (2) progression of disease after discontinuation of BTKi for intolerance, and (3) after treatment with venetoclax. Data are most robust for venetoclax-based regimens after progression on BTKi. For patients who experience progression of disease after discontinuation of BTKi for intolerance, venetoclax-based regimens and retreatment with BTKi (depending on severity of initial intolerance) are 2 data-driven options. After frontline venetoclax/obinutuzumab, subsequent treatment approaches depend on whether patients experience progression of disease during or after discontinuation of their fixed duration frontline regimen and whether venetoclax/obinutuzumab was discontinued for intolerance. After progression of disease while on venetoclax, we recommend BTKi as second-line therapy. For patients who experience progression after completion or premature discontinuation (because of intolerance) of fixed duration venetoclax/obinutuzumab, either BTKi or retreatment with venetoclax (with aggressive supportive care if prior intolerance) are reasonable considerations. Subsequent lines of therapy in these scenarios include PI3Ki and consideration of cellular therapies. Finally, clinical trial enrollment for interested patients in any line of therapy is recommended., Competing Interests: Conflict-of-interest disclosure: L.R. receives grant support from American Society of Hematology and has minority ownership interest in AbbVie and Abbott Laboratories. A.R.M. has received grants, personal fees, and other from TG Therapeutics; grants and personal fees from Pharmacyclics, Genetech, AbbVie, Janssen, Adaptive, and AstraZeneca; grants and other from Celgene; grants from Loxo, Sunesis, Regeneron, and DTRM; and personal fees from Beigene., (© 2020 by The American Society of Hematology.)

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.

Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options., (© 2020 by The American Society of Hematology.)

As the SARS-CoV-2 (COVID-19) pandemic spreads and the number of Bruton's tyrosine kinase inhibitor (BTKi)-treated COVID-19-affected patients grows, we must consider the pros and cons of BTKi discontinuation for our patients. In favor of BTKi continuation, BTK plays an active role in macrophage polarization. By modulating key transcription factors, BTK may regulate macrophage polarization downstream of classic M1 and M2 polarizing stimuli and mitigate the hyperinflammatory state associated with COVID-19. In favor of BTKi discontinuation, we note a potentially increased risk of secondary infections and impaired humoral immunity. We hypothesize that the potential benefit of blunting a hyperinflammatory response to SARS-CoV-2 through attenuation of M1 polarization outweighs the potential risk of impaired humoral immunity, not to mention the risk of rapid progression of B-cell malignancy following BTKi interruption. On the basis of this, we suggest continuing BTKi in patients with COVID-19., (©2020 American Association for Cancer Research.)

Purpose: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood., Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]., Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve ( n = 130), and 81% were idelalisib naïve ( n = 263). ORR to BTKi was 84% ( n = 44) in BTKi-naïve patients versus 54% ( n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons., Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies. See related commentary by Rogers, p. 3501 ., (©2020 American Association for Cancer Research.)

fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P = .006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P = .0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P = .06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P = .002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P < .001) or other (HR, 32; 95% CI, 3.9 to 257; P = .001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT., (Copyright © 2019. Published by Elsevier Inc.)

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice., Experimental Design: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected., Results: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV , 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose., Conclusions: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety., (©2019 American Association for Cancer Research.)

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; P = .7) and HR 1.2 (95% CI, 0.6-2.3; P = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; P = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; P = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings., (© 2019 by The American Society of Hematology.)