Acalabrutinib in Patients with Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Subjected to Allogeneic Hematopoietic Stem Cell Transplantation. a Phase 2 Study By the Polish Lymphoma Research Group

Background Allogeneic hematopoietic cell transplantation (allo-HCT) Is a potentially curative option for patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). The aim of this clinical trial was to evaluate safety and efficacy of acalabrutinib used to reduce tumor burden prior to allo-HCT and as a maintenance after transplantation in order to prevent relapse. Methods This was a phase 2, prospective, open label, multicenter study conducted by the Polish Lymphoma Research Group (clinicaltrials.gov: NCT04716075). Patients with R/R MCL and CLL, intended for allo-HCT were treated with acalabrutinib 100 mg BID for 3-6 months. Those achieving complete or partial response (CR, PR) and having appropriate donor were referred for allo-HCT. Acalabrutinib was restarted 30-90 days after allo-HCT and administered for subsequent 9 months. Remaining patients continued acalabrutinib until progression or unacceptable toxicity. Results Twenty-nine patients with MCL (n=28) and CLL (n=1) were included. For the purpose of this report the efficacy analysis was restricted to subjects with MCL. Median age was 61 (43-68) years. Median number of preceding lines of therapy was 1 (1-5), including autologous HCT in 11 cases. Twelve patients (43%) were refractory to last line of treatment. ECOG performance score was 1 (n=14) or 2 (n=14). Sixteen patients (57%) responded to initial acalabrutinib treatment, including CR in 14 cases (50%) and PR in 2 cases (7%). Six patients (23%) achieved CR with negative status of minimal residual disease. Fifteen subjects (54%) underwent allo-HCT, from either matched sibling (n=3), unrelated (n=10) or haploidentical (n=2) donor. With the median follow-up of 24 months, the probabilities of overall and progression-free survival (PFS) at 2 years were 60% (95%CI, 40-79) and 41.5% (23-60), respectively. Cumulative incidence of relapse and non-relapse mortality was 36% (18-55) and 22% (6-38), respectively. PFS rate for patients treated with allo-HCT was 67% (44-92) at 18 months. No events (progression or death in remission) were observed after 12 months. The grade ≥3 adverse events were observed in 23 subjects, including neutropenia (n=10), anemia (n=3), thrombocytopenia (n=2), infections (n=6), gastrointestinal disorders (n=4) and neurological events (n=3). Five patients died of treatment-related complications, most frequently due to infections (n=4), including 2 cases of COVID-19 (the study was conducted during SARS-Cov-2 pandemia). Among allo-HCT recipients there were no cases of grade 3 or 4 acute graft-versus-host disease (GVHD). One patient experienced severe chronic GVHD. Conclusions Acalabrutinib generates high response rates in patients with R/R MCL. It may serve as a “bridge” to allo-HCT and maintenance after transplantation, offering a chance of cure for selected patients having available donor. Infections are the most frequent life-threating complications.