Kriachok, Iryna

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract Background: BCL-2 inhibition with venetoclax has proved to be highly effective treatment for patients with CLL. However, when administered to patients with CLL who have a high tumor burden, venetoclax is associated with an elevated risk of tumor lysis syndrome (TLS). Because of this risk, venetoclax is initiated with a gradual, 5-week dose ramp-up, requiring close laboratory monitoring over an extended period. Lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor under clinical development for hematologic malignancies (HMs). Preliminary data in 18 patients with CLL treated in a first-in-human study suggested the feasibility of an abbreviated ramp-up of lisaftoclax that might also result in a lower incidence of neutropenia (Ailawadhi et al, J Clin Oncol 39, 2021; abstr 7502). Methods: This new study is a global, open-label, multicenter, two-part phase 1b dose escalation and dose expansion study to assess the safety and tolerability of lisaftoclax (Part 1) and lisaftoclax combined with rituximab or acalabrutinib (Part 2), including dose-limiting toxicity (DLT) and maximum tolerated dose (MTD). The trial is enrolling adults with (1) histologically confirmed CLL/SLL (by 2018 iwCLL criteria) that is relapsed or refractory to ≥ 1 prior therapy and requires treatment (also by 2018 iwCLL criteria); (2) adequate bone marrow function (in the absence of growth factors), including absolute neutrophils ≥ 1.0 × 10 9/L in patients without bone marrow involvement (not required in CLL/SLL patients with bone marrow involvement); and (3) adequate renal and hepatic function. Exclusion criteria: (1) recent history of allogeneic stem cell transplantation or CAR T-cell therapy (< 90 days); (2) prior treatment with a BCL-2 inhibitor (unless patient discontinued such therapy without disease progression); (3) treatment with vitamin K anticoagulants or previous discontinuation of treatment due to acalabrutinib toxicity (in acalabrutinib plus lisaftoclax cohort); (4) active Richter's syndrome; (5) infection (e.g. HIV, hepatitis); (6) CNS involvement; (7) prior cancer that has recurred within 2 years of screening and requires treatment (apart from adequately treated cervical or breast carcinoma in situ); (8) uncontrolled and other serious concomitant illnesses, including cardiovascular disease and diabetes; (9) failure to recover adequately after surgical procedures; and (10) active graft-vs-host disease or a requirement for immunosuppressive treatment. In a standard "3+3" dose escalation design (Part 1), lisaftoclax is being administered orally once daily in a 28-day cycle, with full doses of 200 to 1,200 mg (by 200-mg increments at 4 dose levels (400, 600, 800, and 1,000 mg) in parallel. The ramp-up is performed in the hospital with close monitoring for TLS and consists of the following doses and days of lisaftoclax treatment: 20 mg on Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 600 mg on Day 6, 800 mg on Day 7, and 1,000 mg on Day 8. Patients who experience TLS on any of these days have their dose held until resolution of TLS before proceeding to the next dose. Part 2 includes a further standard 3+3 dose escalation of lisaftoclax combined with rituximab or acalabrutinib (in separate cohorts), with a further planned dose expansion at recommended phase 2 doses of these combination regimens. Primary outcome measures are (1) DLTs observed during cycle 1; and (2) MTD (measured over the same interval). DLT criteria are defined as grade 4 thrombocytopenia or neutropenia lasting > 7 days, grade 3 ≥ thrombocytopenia with bleeding, grade 4 febrile neutropenia, or grade 3 ≥ non-hematologic toxicities. As of July 19, 2021, 71 patients have been enrolled (of 144 planned). Clinicaltrial.gov identifier: NCT04215809. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Siddiqi: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Juno therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Other: DSM Member, Speakers Bureau; PCYC: Speakers Bureau; Jannsen: Speakers Bureau; Dava Oncology: Honoraria; ResearchToPractice: Honoraria. Pagel: Gilead: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Incyte/MorphoSys: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy; Actinium Pharmaceuticals: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Kriachok: Takeda, Roche, Abbivie, Janssen, MSD: Consultancy; Takeda, Roche, Abbvie, Janssen, MSD, Pfizer: Honoraria, Speakers Bureau. Usenko: Abbvie: Honoraria; Acerta: Honoraria; Ascentage: Honoraria; AstraZeneca: Honoraria; Celgene: Honoraria; Il Yang: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Oncopeptides: Honoraria; Rigel: Honoraria; Takeda: Honoraria; UCB: Honoraria. Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Huang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Ahmad: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Mudenda: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.