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Clinical Trial
. 2024 Sep 10;8(17):4539-4548.
doi: 10.1182/bloodadvances.2023012424.

Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis

Michael Wang  1 , Tadeusz Robak  2 , Kami J Maddocks  3 , Tycel Phillips  4 , Stephen D Smith  5 , David Gallinson  6 , Roser Calvo  7 , Chuan-Chuan Wun  8 , Veerendra Munugalavadla  8 , Wojciech Jurczak  9
Affiliations
Clinical Trial

Acalabrutinib plus venetoclax and rituximab in treatment-naive mantle cell lymphoma: 2-year safety and efficacy analysis

Michael Wang et al. Blood Adv. .

Abstract

This phase 1b study evaluated safety and efficacy of acalabrutinib, venetoclax, and rituximab (AVR) in treatment-naive mantle cell lymphoma (TN MCL). Patients received acalabrutinib from cycle 1 until progressive disease (PD) or undue toxicity, rituximab for 6 cycles with maintenance every other cycle through cycle 24 or until PD, and venetoclax, beginning at cycle 2, for 24 cycles. Twenty-one patients were enrolled; 95.2% completed induction (6 AVR cycles) and 47.6% continued acalabrutinib maintenance. Thirteen (61.9%) patients had grade 3-4 adverse events (AEs), most commonly neutropenia (33.3%). Seven (33.3%) patients had COVID-19 infection (6 [28.6%] serious AEs and 5 [23.8%] deaths, all among unvaccinated patients). There was no grade ≥3 atrial fibrillation, ventricular tachyarrhythmias, major hemorrhages, or tumor lysis syndrome. Overall response rate (ORR) was 100% (95% CI, 83.9-100.0) with 71.4% complete response. With median follow-up of 27.8 months, median progression-free survival (PFS) and overall survival (OS) were not reached. PFS rates at 1 and 2 years were 90.5% (95% CI, 67.0-97.5) and 63.2% (95% CI, 34.7-82.0), respectively; both were 95% after censoring COVID-19 deaths. OS rates at 1 and 2 years were 95.2% (95% CI, 70.7-99.3) and 75.2% (95% CI, 50.3-88.9), respectively; both were 100% after censoring COVID-19 deaths. Overall, 87.5% of patients with available minimal residual disease (MRD) data achieved MRD negativity (10-6; next-generation sequencing) during treatment. AVR represents a chemotherapy-free regimen for TN MCL and resulted in high ORR and high rates of MRD negativity. The trial was registered at www.ClinicalTrials.gov as #NCT02717624.

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Conflict of interest statement

Conflict-of-interest disclosure: M.W. reports consultancy from AbbVie, Acerta Pharma, ADC Therapeutics America, Amphista Therapeutics Limited, AstraZeneca, Be Biopharma, BeiGene, BioInvent, Bristol Myers Squibb (BMS), Deciphera, DTRM Biopharma (Cayman) Limited, Genentech, InnoCare, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Lilly, Merck, Miltenyi Biomedicine, Milken Institute, Oncternal, Parexel, Pepromene Bio, Pharmacyclics, and VelosBio; research funding from Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genmab, Genentech, InnoCare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics, VelosBio, and Vincerx; and honoraria from AbbVie, Acerta Pharma, AstraZeneca, Bantam Pharmaceutical, BeiGene, BioInvent, BMS, CAHON, Catamount Medical Education, Dava Oncology, Eastern Virginia Medical School, Genmab, i3 Health, IDEOlogy Health, Janssen, Kite Pharma, Leukemia & Lymphoma Society, Medscape, Meeting Minds Experts, MD Education, MJH Life Sciences, Merck, Moffit Cancer Center, MSC National Research Institute of Oncology, National Institutes of Health, Nurix, Oncology Specialty Group, OncLive, Pharmacyclics, Physicians Education Resources, Practice Point Communications, Research To Practice, Scripps, Syneos Health, Studio ER Congressi, South African Clinical Hematology Society, and WebMD. T.R. reports research funding from Acerta, Roche, Janssen, AbbVie, Novartis, BioGene, AstraZeneca, Pharmacyclics, Pfizer, MorphoSys, UTX-TGR, GlaxoSmithKline, and BMS; travel, accommodation, and expenses from Roche, Janssen, and AbbVie; honoraria from Sandoz, Novartis, Octapharma, BioGene, AstraZeneca, and Pharmacyclics; and consultancy from Sandoz, Takeda, and Momenta. K.J.M. reports research funding from Pharmacyclics, Pfizer, and BMS; and consulting/advisory for AbbVie, ADC, Acerta, AstraZeneca, BeiGene, BMS, Celgene, Genmab, Genentech, Gilead, Incyte, Janssen, Kite, Lilly, MorphoSys, and Pharmacyclics. T.P. reports consultancy from AbbVie, ADCT, AstraZeneca, Bayer, BeiGene, BMS, Genmab, Genentech, Epizyme, Eli Lilly, Incyte, Janssen, Kite Pharma, MorphoSys, Pharmacyclics, Seattle Genetics, Regeneron, and Xencor; research funding from AbbVie, Bayer, Genentech, and Sobi; served as scientific committee member for Genmab, Genentech, and Merck. S.D.S. reports research funding from ADC Therapeutics, AstraZeneca, Ayala (spouse), Bayer, BeiGene, BMS (spouse), De Novo Biopharma, Enterome, Genentech, Ignyta (spouse), Incyte Corporation, Kymera Therapeutics, Merck Sharp and Dohme Corp, MorphoSys, Nanjing Pharmaceuticals Co, Ltd, and Viracta Therapeutics; consultancy/advisory board roles for ADC Therapeutics, BeiGene, Kite Pharma, Incyte, Numab Therapeutics AG, AbbVie, and Coherus BioSciences; and advisory board (spouse) for Genentech. R.C. is employed by and holds stock ownership of AstraZeneca. C.-C.W. is employed by AstraZeneca. V.M. is employed by and holds stock ownership of AstraZeneca. A family member is an employee and stockholder of Gilead Sciences. W.J. reports research funding and advisory boards for AstraZeneca. D.G. declares no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Impact of COVID-19 vaccine on patient outcomes.aAmong 17 patients who did not receive a COVID-19 vaccine, 7 contracted COVID-19. The dates of onset of COVID-19 infection were between 21 July 2020 and 9 April 2022, and the end dates of COVID-19 infection were between 5 August 2020 and 29 April 2022. Of the 7 patients who did not receive a COVID-19 vaccine and contracted COVID-19, 1 patient experienced grade 3 COVID; this patient received cefepime IV transfusion for 7 days and remdesivir IV transfusion for 4 days, and their COVID-19 resolved. The 6 other patients who did not receive a COVID-19 vaccine and contracted COVID-19 died; 5 deaths were due to COVID-19 and 1 death was due to disease progression. bAmong the 4 patients who received the COVID-19 vaccine, 1 patient received 3 doses of the Pfizer messenger RNA vaccine on 5 March 2021, 9 June 2021, and 7 January 2022, and then contracted grade 2 COVID-19 on 9 March 2022, which resolved on 20 March 2022. The other 3 patients did not contract COVID-19. Gr, grade; VAX, vaccination.
Figure 2.
Figure 2.
ORR per Lugano criteria and by PET/CT alone with corresponding 95% CI based on the Clopper-Pearson exact binomial test. Four of the 6 patients had PR per Lugano and were counted as CR by PET/CT because BM biopsy was missing to confirm CR per Lugano.
Figure 3.
Figure 3.
Maximum change from baseline in SPD, including 4 patients with missing BM biopsies reported as CR by PET/CT. Asterisks (∗) denote the missing BM biopsies reported as CR by PET/CT. Among the 4 patients with CR per PET/CT only, 1 patient had missing postscreening measurements for 2 of the 6 target lesions. Only 4 of the 6 target lesions were calculated for SPD, denoted by ∗a. SPD, sum of the products of perpendicular diameters.
Figure 4.
Figure 4.
PFS after a median follow-up of 27.8 months, with and without censoring for 5 deaths due to COVID-19 infection.
Figure 5.
Figure 5.
OS after a median follow-up of 27.8 months, with and without censoring for 5 deaths due to COVID-19 infection.
Figure 6.
Figure 6.
Longitudinal MRD analysis using NGS with clinical data. NGS, next-generation sequencing.
See this image and copyright information in PMC

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