A Single-Arm, Phase II Study of Acalabrutinib As Post-Autologous Stem Cell Transplant Maintenance Therapy in Patients with Mantle Cell Lymphoma
Authors: Tees Michael T. , Saba Nakhle S , Kambhampati Suman , Flinn Ian W. 
Published: December 2024

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.