ASH 2025 Highlights Reinforce Durability, Safety, and Strategic Sequencing in MCL Therapy

EP: 1.Sonrotoclax Shows Promising Efficacy, Improved Tolerability in Heavily Pretreated MCL

EP: 2.Duration of Response With Sonrotoclax Vs Current Therapies for MCL

EP: 3.Ushering in a New Combination-Driven Era in MCL

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EP: 4.ASH 2025 Highlights Reinforce Durability, Safety, and Strategic Sequencing in MCL Therapy

Michael Wang, MD, highlights several notable abstracts from ASH 2025 that collectively underscore continued progress in mantle cell lymphoma (MCL), spanning long-term safety, emerging targeted therapies, cellular therapy durability, and treatment sequencing strategies.

Wang first discusses 5-year follow-up data for pirtobrutinib, a third-generation, noncovalent BTK inhibitor. Even with prolonged exposure, the therapy demonstrated a favorable safety profile, with only isolated, manageable cardiac events and no new cardiovascular safety signals. Importantly, there was no cumulative increase in adverse events over time, reinforcing the drug’s tolerability as a long-term oral therapy. Wang emphasizes that pirtobrutinib maintains strong efficacy and complete response rates while offering improved tolerability compared with covalent BTK inhibitors, positioning it as one of the safest oral agents currently available in MCL.

He also highlights emerging targeted therapies presented at the meeting. One abstract described a novel BTK inhibitor with both covalent and noncovalent properties, showing single-agent response rates exceeding 60%, suggesting meaningful activity with a potentially differentiated resistance profile. Another study introduced a next-generation BCL2 inhibitor with a single-agent overall response rate above 70%, adding to a growing pipeline of alternatives beyond venetoclax.

Wang then turns to cellular therapy, noting updated 2-year follow-up data from the ZUMA-2 trial of brexucabtagene autoleucel, a CD19-directed CAR T-cell therapy. The data confirmed durable responses without unexpected late toxicities, supporting the long-term benefit and safety of CAR T-cell therapy in relapsed/refractory MCL.

Finally, Wang discusses a post hoc phase 3 analysis from the ECHO trial comparing concurrent versus sequential therapy. The analysis showed that upfront triplet therapy with bendamustine, rituximab, and acalabrutinib significantly prolonged time to third-line treatment compared with sequential approaches, supporting early intensification rather than reserving BTK inhibition for relapse.

Together, these findings highlight how durability, safety, and strategic combination therapy continue to reshape MCL management.