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Clinical Trial
. 2025 Mar;43(7):788-799.
doi: 10.1200/JCO-24-02503. Epub 2024 Dec 7.

Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naïve Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease

Matthew S Davids  1 , Christine E Ryan  1 , Benjamin L Lampson  1 , Yue Ren  2 , Svitlana Tyekucheva  2 , Stacey M Fernandes  1 , Jennifer L Crombie  1 , Austin I Kim  1 , Matthew Weinstock  3 , Josie Montegaard  1 , Heather A Walker  1 , Claire Greenman  1 , Victoria Patterson  1 , Caron A Jacobson  1 , Ann S LaCasce  1 , Philippe Armand  1 , David C Fisher  1 , Steve Lo  4 , Adam J Olszewski  5 , Jon E Arnason  3 , Inhye E Ahn  1 , Jennifer R Brown  1
Affiliations
Clinical Trial

Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naïve Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease

Matthew S Davids et al. J Clin Oncol. 2025 Mar.

Erratum in

Abstract

Purpose: The AMPLIFY trial recently established fixed-duration acalabrutinib, venetoclax, and obinutuzumab (AVO) as a new standard-of-care option for patients with previously untreated chronic lymphocytic leukemia (CLL) with wild-type TP53; however, due to the chemoimmunotherapy control arm, AMPLIFY excluded patients with high-risk TP53 aberration, for whom current standards of care are continuous Bruton tyrosine kinase inhibitor therapy or alternatively fixed-duration venetoclax-based doublets. AVO has not previously been evaluated in patients with CLL with TP53 aberration.

Methods: This investigator-sponsored, multicenter, phase II study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by TP53 aberration (ClinicalTrials.gov identifier: NCT03580928). Patients received acalabrutinib, obinutuzumab, and then venetoclax, with each treatment introduced sequentially and in combination, with the duration guided by measurable residual disease (MRD). Patients who achieved undetectable MRD (uMRD) after either 15 or 24 cycles could discontinue treatment. The primary end point was complete remission (CR) with bone marrow uMRD (BM-uMRD) at the start of cycle 16.

Results: Seventy-two patients were accrued, including 45 patients with TP53 aberration. The CR with BM-uMRD rates at the start of cycle 16 were 42% in patients with TP53 aberration and 42% in all-comers, and the BM-uMRD rates were 71% and 78%, respectively. Hematologic toxicities were mainly low grade, and cardiovascular toxicities and bleeding complications were infrequent. After a median follow-up of 55.2 months, 10 patients had progressed, including four with transformation, and three patients died. Four-year progression-free survival and overall survival for patients with or without TP53 aberration were 70%/96% and 88%/100%, respectively.

Conclusion: AVO was highly active and well tolerated in patients with previously untreated high-risk CLL, supporting its use as a new standard-of-care treatment option.

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Conflict of interest statement

Steve Lo is the chair of Medical Advisory Board for Breast Cancer Alliance, Greenwich, CT (received no payments).

Adam J. Olszewski has received consulting fees from Genmab, BeiGene, Blue Cross and Blue Shield of Rhode Island, Bristol-Myers Squibb, Schrodinger, ADC Therapeutics.

Phillipe Armand has received consultancy fees from Merck, Bristol Meyers Squibb/Celgene, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, Astra Zeneca, Genentech/Roche, Xencor, Foresight, ATB Therapeutics, Stelexis, research funding from Kite Pharma, institutional research funding from Merck, BMS-Celgene, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, Genentech/Roche, IGM, Astra Zeneca, and honoraria from Merck and Bristol Meyers Squibb.

Josie Montegaard has participated on a Data Safety Monitoring Board or Advisory Board for Abbvie, Beigene, Bristol Myers Squibb, AstraZeneca.

Jon Arnason has received payment for lectures, presentations, speakers bureaus, manuscript writing or educational events from the Regeneon Speakers Fee (June 2024).

Inhye Ahn has received grants or contracts from Lilly (to the institution), consulting fees from AstraZeneca, BeiGene, and Lilly, and feeds for participation on a Data Safety Monitoring Board or Advisory Board, BeiGene.

Jennifer Crombie has received consulting fees from Genentech/Roche and research support from Abbvie.

Austin Kim had received grants or contracts for the institution from AstraZeneca, Research funding to institution, honoraria for invited presentations for the Community Oncology Connections On-line CME 2024, New York Oncology Hematology.

Caron Jacobson has received consulting fees from Kite Pharma/Gilead, Novartis, Bristol Myers Squibb, Galapagos, Caribou, Appia, ADC Therapeutics, AstraZeneca, Abbvie, Miltenyi, Janssen, Sana, Synthekine, Kyverna, and has received fees from participation on a Data Safety Monitoring Board or Advisory Board from Kyverna.

Benjamin Lampson is a paid employee of Blueprint Medicines since April 2023 and has stock and stock options in Blueprint Medicines.

Ann LaCasce has received consulting fees from Genmab, Curio, Pierre Fabre, MJH Life Sciences, Ideology, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, Research to Practice.

Matthew Davids has received support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from AstraZeneca, research grants from Ascentage Pharma, MEI Pharma, and Novartis, royalties from UpToDate, Consulting fees from AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb, Eli Lilly, Genentech, Genmab, Janssen, Merck, MEI Pharma, Nuvalent, SecuraBio, Takeda, TG Therapeutics, participated on a Data Safety Monitoring (Chair, CLL17 Trial DMC).

Jennifer R. Brown has received research funding from BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, and TG Therapeutics, royalties from UpToDate, served as a consultant for Abbvie, Acerta/Astra-Zeneca, Alloplex Biotherapeutics, BeiGene, Bristol-Myers Squibb, EcoR1, Galapagos NV, Genentech/Roche, Grifols Worldwide Operations, InnoCare Pharma Inc, iOnctura, Kite Pharma, Loxo/Lilly, Magnet Biomedicine, Merck, Numab Therapeutics, Pfizer, & Pharmacyclics, and serves on the Data Safety Monitoring Board for Grifols Therapeutics.

All other authors report no disclosures.

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