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236 Addition or Substitution of Acalabrutinib in Intensive Frontline Chemoimmunotherapy for Patients ≤ 70 Years Old with Mantle Cell Lymphoma: Outcomes of the 3-Arm Randomized Phase II Intergroup Trial ECOG-ACRIN EA4181

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, Waldenstrom’s, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Therapies for Mantle Cell Lymphoma
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Measurable Residual Disease
Saturday, December 7, 2024: 2:15 PM

Nina D. Wagner-Johnston, MD1, Opeyemi Jegede2*, Stephen E Spurgeon, MD3, Kami J. Maddocks, MD4, David T Yang, MD5, Justin Romanoff6*, Jonas Paludo, MD7, Paolo F. Caimi, MD8, Nancy L. Bartlett, MD9*, Patrick M. Reagan, MD10, Yazeed Sawalha, MD11, Marc Hoffmann, MD12, Boyu Hu, MD13, Ashraf R Aziz14*, Helga Marques6*, Lale Kosakoglu Shields15*, John P. Leonard, MD16, Jonathan W. Friedberg, MD17 and Brad S. Kahl, MD18

1Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD
2Dana Farber Cancer Institute, Boston, MA
3Knight Cancer Institute, Oregon Health & Science University, Portland, OR
4The James Cancer Center, The Ohio State University, Columbus, OH
5Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI
6Brown University, Providence
7Division of Hematology, Mayo Clinic, Rochester, MN
8Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
9Washington University School of Medicine, St. Louis, MO
10University of Rochester School, Fairport, NY
11Division of Hematology, The Ohio State University, Columbus, OH
12University of Kansas Cancer Center, Kansas City, KS
13Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
14Kaiser Permanente, Anaheim
15NYU Langone, New York
16Weill Cornell Medicine, New York, NY
17Wilmot Cancer Center, University of Rochester, Rochester, NY
18Washington University School of Medicine in St. Louis, St. Louis, MO

Introduction: The optimal induction for younger fit patients (pts) with mantle cell lymphoma (MCL) is unknown; though intensive chemoimmunotherapy (CIT) containing high dose cytarabine has been shown to prolong remission. Achieving molecular remission is an independent predictor of outcomes post induction therapy in patients with MCL. Incorporating undetectable measurable residual disease (uMRD) status into the primary endpoint may be preferable to progression-free survival (PFS), particularly when approaches following induction are varied (e.g., ASCT, maintenance treatment, observation). Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton’s tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439). In 2019, the US Intergroup activated EA4181 to explore the efficacy with the addition of fixed duration BTKi, to BR or BR/CR for patients with MCL ≤ 70 years old.

Patients and methods: Patients were randomized 1:1:1 (stratified by MIPI risk status) to 6 cycles of BR/CR (control arm), BR/CR-A, or BR-A. Cytarabine was dosed at 2 g/m2 Q12 hours x 4, with dose reductions based on age and creatinine clearance. Acalabrutinib was dosed at 100 mg BID continuously on BR cycles with the BR/CR-A and BR-A arms and at 100 mg BID on days 1-7 and 22-28 with CR cycles on the BR/CR-A arm to mitigate hematologic toxicity. Consolidation approaches following induction were at the discretion of the treating physician. The primary endpoint was a composite of PET/CT CMR and peripheral blood uMRD rate (< 1 in 105). ClonoSEQ (Adaptive Biotechnologies) was performed at baseline and MRD testing was obtained at the end of induction. Secondary clinical objectives included PFS and overall survival (OS) at 36 months (mo), objective response rates (ORR), and toxicity rates. With 108 patients per arm expected, there was 86% power to detect an increase in PET/CT CMR/uMRD rate from 60% in the control arm to 75% in either BR/CR-A or BR-A arms using a Z-test with a 10% alpha (1-sided).

Results: Between October 2019 and March 2023, 359 participants were randomized to BR/CR (n = 128), BR/CR-A (n = 129), and BR-A (n = 102). BR-A was closed to further accrual by the DSMC based on interim futility analysis for superiority in Fall 2022. The median (range) age was 61 (25, 70), 30% were ≥ 65 years, 77% were male, 89% were white, 89% were non-Hispanic, 18%/43%/39% were low/intermediate/high risk MIPI. Baseline clonal sequence was identified in 308/326 (95%) among samples received. 281/308 were eligible and treated and 260/281 had an end of treatment MRD test result (BR/CR = 85, BR/CR-A = 98, BR-A = 77). This subset (n = 260) is the focus of the primary analysis; sensitivity analysis included 281 eligible and treated pts with trackable clonal marker. In the primary analysis subset, 94%, 91%, and 90% in BR/CR, BR/CR-A, and BR-A arms, respectively, completed 6 cycles of protocol therapy. The PET/CT CMR/uMRD rates were 82% (BR/CR), 82% (BR/CR-A; p = 0.55 vs BR/CR), and 78% (BR-A; p = 0.76 vs BR/CR). In the sensitivity analysis set, PET/CT CMR/uMRD rates were 74% with BR/CR (n = 94), 76% (p = 0.44) with BR/CR-A (n = 106), and 74% (p = 0.52) with BR-A (n = 81). ORR (CMR) rates were 94% (91%), 99% (90%), and 94% (91%) with BR/CR, BR/CR-A, and BR-A, respectively. At a median follow-up of 27.9 mo, estimated 12-mo PFS/OS were 86%/94% (BR/CR), 89%/98% (BR/CR-A) and 87%/95% (BR-A). The proportion of treatment-related grade 3 or higher adverse events (AE) was 78%/88%/73%, with neutropenia in 52%/58%/27%, anemia in 23%/32%/3%, thrombocytopenia in 55%/66%/6%, and febrile neutropenia in 11%/12%/4%; treatment discontinuation due to AE occurred in 5%/7%/8% in BR/CR, BR/CR-A, and BR-A arms, respectively.

Conclusion: High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles. BR-A was found not superior and closed early by the DSMC; however, it is the least toxic arm with similar efficacy, and represents an appealing option to avoid high dose cytarabine.

Disclosures: Wagner-Johnston: Genentech: Research Funding; Merck: Research Funding; AstraZeneca: Research Funding; Beigene: Consultancy. Maddocks: Gilead/KITE: Consultancy; Genentech: Consultancy; ADC Therapeutics: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Lilly: Consultancy; Incyte: Consultancy; Genmab: Consultancy; AstraZeneca: Consultancy; MorphoSys: Consultancy. Paludo: Biofourmis: Research Funding; AstraZeneca: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding. Caimi: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Other: Avisory Board, Research Funding; Novartis: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Synthekine: Other: Advisory Board, Research Funding; Sobi: Honoraria; Recordati: Honoraria, Research Funding; Abcon: Research Funding; Luminary Therapeutics: Other: Scientific Advisory Board, Research Funding; Genmab: Research Funding; Profound Bio: Research Funding; Arvinas: Honoraria, Research Funding. Reagan: Kite, a Gilead Company: Consultancy, Honoraria; Seagen: Research Funding; Caribou Biosciences: Consultancy; Genentech: Research Funding. Sawalha: Genmab: Honoraria, Research Funding; ADC: Consultancy; AbbVie: Research Funding; Beigene: Research Funding. Hoffmann: Bristol Myers Squibb: Other: Travel; ADC, Janssen, Pharmacyclics, BeiGene, Novartis, Astra-Zeneca, Abbvie, Kite, TG: Consultancy, Honoraria; Genentech: Consultancy, Research Funding. Hu: ImmPACT Bio, Caribou Biosciences, Genentech, CRISPR Therapeutics, Morphosys AG, Repare Therapeutics, Artiva Biosciences, Newave, Astrazeneca: Research Funding; Eli Lilly, Genmab, ADC Therapeutics, ImmPACT Bio, SeaGen, Regeneron, Caribou Biosciences, Abbvie, Kite Pharma, Bristol-Myers Squibb: Consultancy, Honoraria. Leonard: AbbVie, AstraZeneca, Astellas, Bayer, BeiGene,BMS, Calithera, Caribou Bioscences, Constellation, Eisai, Epizyme,GenMab, Grail, Incyte, Janssen, Karyopharm, Lilly, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro, Treelin: Consultancy, Honoraria. Kahl: Lilly: Consultancy, Honoraria; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADCT: Consultancy; Roche: Consultancy, Research Funding; AbbVie: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Honoraria.

OffLabel Disclosure: Acalabrutinib with chemoimmunotherapy in the front line setting for mantle cell lymphoma

*signifies non-member of ASH