Background: Maintenance therapy with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib following ibrutinib-containing chemoimmunotherapy with or without high-dose chemotherapy and autologous stem cell rescue (HDT/ASCR) in younger patients (pts) with mantle cell lymphoma (MCL) has demonstrated superior efficacy over standard chemoimmunotherapy with ASCR (Dreyling et al. 2024). Even without the addition of a BTKi during induction therapy, BTKi as maintenance therapy post-HDT/ASCR is often used. However, ibrutinib is no longer approved in the US for MCL, and there are no data on other BTKi, such as acalabrutinib, for post-ASCR maintenance. Therefore, this single-arm, Phase II study investigated the safety and efficacy of post-HDT/ASCR acalabrutinib maintenance in pts with MCL (NCT04402138).

Methods: Participants were adults (≥18 years) with confirmed MCL who had completed induction chemotherapy and eligible to receive HDT/ASCR. Pts who had disease relapse or progression before or after HDT/ASCR or who received anticancer therapy after HDT/ASCR and before starting study treatment were excluded. Starting on Day 100 following standard-of-care HDT/ASCR, pts received 100 mg acalabrutinib twice daily in 28-day cycles until 2 years post-HDT/ASCR. Concurrent maintenance with rituximab was not used. Bone marrow (BM) aspirate and blood were collected at 6-month intervals for measurable residual disease (MRD) analysis using the clonoSEQ next-generation sequencing assay (Adaptive Biotechnologies, Seattle, WA). MRD-detectable (MRD+) was defined as any measurable disease activity identified by analysis (10-6 to 10-7). The primary endpoint was progression-free survival (PFS) rate at 2 years post-HDT/ASCR; secondary endpoints were conversion rate from MRD+ to MRD-undetectable (MRD-U) during therapy and incidence of adverse events (AEs).

Results: A total of 15 pts were enrolled: median age 66y (range: 48, 73); 73.3% male, 26.7% female; 80% white, 20% race not reported; 100% with ECOG performance status of 0-1. At initial diagnosis, 86.6% of pts had Stage III/IV disease. MCL International Prognostic Index results were as follows: low risk, 33.3%; intermediate risk, 46.7%; high risk, 20%. One pt had a known positive TP53 mutation. MRD results at screening (Day 100) were MRD+, 3 pts (BM) and 2 pts (blood), and MRD-U, 11 pts (BM) and 12 pts (blood).

Twelve pts completed treatment, with 3 pts (20%) discontinued from treatment: 1 pt due to treatment-emergent AEs (Grade 3 diarrhea, Grade 3 headache, and Grade 1 dyspnea) and 2 pts due to disease progression. A total of 53.3% of pts had dose interruptions due to AEs, with 40% having 2 or more dose interruptions; 13.3% of pts had dose reductions due to AEs. All pts (100%) had at least 1 treatment-related AE (TRAE). Six pts (40%) had Grade 3 or 4 TRAEs: fatigue (20%) and diarrhea, headache, neutropenia, neutrophil count decreased, dyspnea, lymphocyte count decreased, and pneumonia (each 6.7%). There were no pt deaths on study. Median duration of study treatment was 20.4 months (range: 2.8, 22.3), and median duration on study was 35.2 months (range: 12.3, 41.1). Due to early study termination, 6 pts were not followed up after end-of-treatment.

All pts were evaluable for morphologic response before starting maintenance, with all pts (100%) being in a complete response per RECIL 2017. From screening to 1 year (BM) and 2 years (blood) post-HDT/ASCR, 2 pts (BM) and 1 pt (blood) remained MRD+, 8 pts (BM) and 5 pts (blood) remained MRD-U, 1 pt (BM and blood) converted from MRD+ to MRD-U, and 1 pt (BM) and 4 pts (blood) converted from MRD-U to MRD+. Of the 3 pts who experienced disease progression during treatment or follow-up, 2 had persistent MRD+ by 6 months after HDT/ASCR. Median PFS was not reached. At 2 years, the PFS rate (95% confidence interval) was 73.5% (35.9, 91.1) in the overall study population, 37.5% (1.1, 80.8) in pts with MRD+, and 88.9% (43.3, 98.4) in pts with MRD-U (MRD based on status at Day 100).

Conclusions: Acalabrutinib demonstrated a tolerable safety profile and promising results in maintaining MRD-U, supporting the use of acalabrutinib as maintenance therapy post-HDT/ASCR in pts with MCL. Given the early study closure, the limited sample size, and the need for longer follow-up for PFS, additional investigations may provide further insights into the role of BTKi maintenance in the post-HDT/ASCR setting.

Disclosures

Tees:Merck&Co./Arqule: Research Funding; NKarta: Research Funding; Kite: Research Funding; Allogene: Research Funding; Syneos: Research Funding; Juno: Research Funding; Nurix: Research Funding; 2seventy: Research Funding; STEP: Research Funding; Accutar: Research Funding; Cargo: Research Funding. Saba:ADC Therapeutics: Consultancy, Honoraria; Seagen Inc: Consultancy, Research Funding; MorphoSys AG: Consultancy, Research Funding; Merck: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Eli Lilly and Company: Consultancy, Research Funding, Speakers Bureau; Incyte Corporation: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; BeiGene USA: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding. Flinn:Nurix: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Portola Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Research Funding; Seattle Genetics: Research Funding; Step Pharma: Research Funding; Tessa Therapeutics: Research Funding; TG Therapeutics: Research Funding; Vincerx Pharma, 2seventybio: Research Funding; Vincerx Advisory Committee: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Myeloid Therapeutics: Research Funding; MorphoSys: Research Funding; Millennium Pharmaceuticals: Research Funding; Merck: Research Funding; Marker Therapeutics: Research Funding; Loxo: Research Funding; Kite, a Gilead Company: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Infinity Pharmaceuticals: Research Funding; IGM Biosciences: Research Funding; InnoCare Pharma: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Epizyme: Research Funding; Fate Therapeutics: Research Funding; Biopharma: Research Funding; CTI: Research Funding; Curis: Research Funding; Constellation Pharmaceuticals: Research Funding; City of Hope Medical Center: Research Funding; Celgene: Research Funding; CALGB: Research Funding; BMS: Research Funding; CALIBR: Research Funding; BioPath: Research Funding; AstraZeneca: Research Funding; ArQule: Research Funding; Agios: Research Funding; Vincerx: Consultancy; Acerta: Research Funding; Roche: Consultancy; Kite, a Gilead Company: Consultancy; Genmab: Consultancy; Genentech: Consultancy; Tennessee Oncology & OneOncology: Current Employment; Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding.

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2024
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