Zanubrutinib maintenance post-autologous stem cell transplantation in Mantle Cell Lymphoma: A prospective multicenter Phase II trial

Abstract Introduction Autologous stem cell transplantation (ASCT) is a potent treatment to improve the prognosis of mantle cell lymphoma (MCL), but relapse is still the main cause of death post-transplantation. Previous studies showed maintenance therapy post-ASCT could reduce the relapse rate of MCL and improve survival. The addition of zanubrutinib to chemotherapy has significantly improved survival outcomes in MCL. This trial aimed to investigate the safety and efficacy of zanubrutinib maintenance post-ASCT in MCL. Methods This investigator-initiated, prospective, multicenter, phase II trial (ChiCTR2100054731) enrolled patients aged 18-65 years with histologically confirmed stage III/IV MCL who were ASCT-eligible across five transplant centers in China. Participants received oral zanubrutinib (160 mg twice daily) as post-transplant maintenance therapy for 2 years. The primary endpoint was event-free survival (EFS); secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety assessments. Additionally, a retrospective analysis used 11 ASCT-treated MCL patients as controls: seven received alternative maintenance regimens (three with anti-CD20 monoclonal antibody; four with thalidomide; one with anti-CD20 antibody combined with lenalidomide; one with ibrutinib who transitioned to anti-CD20 antibody), while four received no maintenance. Results From January 2022 to April 2025, 13 patients receiving post-transplant zanubrutinib maintenance were enrolled, with a median age of 52 years (range 44-62). After a median follow-up of 1017 days (range 94-1298), all patients were alive; only one patient relapsed, and the median EFS, OS and PFS were not reached. Between February 2017 and March 2025, eleven control patients who underwent ASCT and received either alternative maintenance regimens or no maintenance had a median age of 53 years (range 44-66). After a median follow-up of 1505 days (range 132-2351), five patients relapsed and three died. At last follow-up, the 3-year EFS was 100% in the zanubrutinib maintenance group and 87.5% (95% CI 67.3-100%) in the control group (p = 0.317). The 3-year OS was also 100% in the zanubrutinib maintenance group and 87.5% (95% CI 67.3-100%) in the control group (p = 0.317). Moreover, the 3-year PFS was 100% in the zanubrutinib maintenance group and 62.5% (95% CI 36.5-100%) in the control group (p = 0.230). Zanubrutinib maintenance was well-tolerated in all 13 patients, with no treatment discontinuations due to serious adverse events (AEs). The most common AEs were hematologic toxicities. Neutropenia occurred in 4 (30.8%) patients, with grade 3-4 severity observed in 2 (15.4%). Thrombocytopenia developed in 3 (23.1%) patients, and grade 3-4 severity occurred in 1 (7.7%) patient without treatment-related bleeding complications. Anemia occurred in 1 (7.7%) patient without grade ≥3 events. For nonhematologic toxicities, nausea and vomiting were reported in 1 (7.7%) patient without grade ≥3 occurrences. Infection occurred in 1 (7.7%) patient, with no serious infections documented. Conclusion Our preliminary findings indicate that zanubrutinib maintenance demonstrates promising efficacy and a manageable safety profile in post-ASCT MCL patients, supporting its potential as a viable therapeutic option for this population. Keywords Mantle cell lymphoma, autologous hematopoietic stem cell transplantation, maintenance therapy, zanubrutinib