Comparative safety profiles of frontline BTK inhibitor–containing regimens in mantle cell lymphoma: A cross-trial analysis of phase III studies.

e19049 Background: Bruton tyrosine kinase inhibitors (BTKis) are increasingly incorporated into frontline mantle cell lymphoma (MCL) regimens, either combined with chemoimmunotherapy or as chemotherapy-free approaches. Given differences in BTKi selectivity and treatment backbone intensity, comparative safety data are needed to inform regimen selection. Methods: We performed a structured safety extraction from published phase III frontline MCL trials incorporating a BTKi: SHINE (ibrutinib + bendamustine-rituximab [BR]), ECHO (acalabrutinib + BR), TRIANGLE (ibrutinib integrated with cytarabine-based induction ± autologous stem cell transplantation [ASCT]), and ENRICH (ibrutinib-rituximab vs immunochemotherapy). Outcomes included grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, adverse events of special interest (atrial fibrillation, infections, cytopenias), and TEAEs leading to treatment discontinuation. Analyses were descriptive, based on published trial reports. Results: In SHINE, grade 3–4 TEAEs occurred in 81.5% with ibrutinib + BR versus 77.3% with placebo + BR. Atrial fibrillation was more frequent with ibrutinib (13.9% vs 6.5%), as was grade 3–4 pneumonia (20.1% vs 14.2%). Study-drug discontinuation due to adverse events occurred in 10.5% versus 9.1%, respectively. In ECHO, grade ≥3 TEAEs were comparable between acalabrutinib + BR and placebo + BR (88.9% vs 88.2%), while serious TEAEs were more frequent with acalabrutinib (69.0% vs 62.0%). TEAEs leading to discontinuation were higher with acalabrutinib (42.8% vs 31.0%), though atrial fibrillation rates remained low (~6–7%). In TRIANGLE, incorporation of ibrutinib into intensive induction and ASCT was associated with higher grade 3–5 infections (25% vs 13%) and neutropenia (44% vs 17%) compared with ASCT alone. In ENRICH, grade ≥3 adverse events occurred in 67% with chemo-free ibrutinib-rituximab versus 70% with immunochemotherapy. Grade ≥3 neutropenia was lower with ibrutinib-rituximab (9%) compared with R-CHOP (21%) and BR (19%). Conclusions: Frontline BTKi-containing regimens in MCL are associated with high but regimen-dependent toxicity burdens. Chemo-based BTKi combinations demonstrate moderately increased infections and cytopenias, while ibrutinib-containing regimens show moderately higher cardiovascular event rates. Chemo-free ibrutinib-rituximab offers a favorable cytopenia profile. These findings highlight the importance of individualized treatment selection and proactive toxicity monitoring when incorporating BTK inhibitors into frontline MCL therapy.