Emerging Therapies in CLL, CAR-T, Richter's Transformation, and Closing Remarks

The panel addresses two important areas not fully covered earlier. Dr. Hoffmann highlights a real-world dataset examining pirtobrutinib as bridge therapy to CAR-T in CLL, noting that the TRANSCEND CLL004 CAR-T study showed only 20% complete response rates in an extremely heavily pretreated population with median 5 prior lines of therapy. However, disease bulk represents a significant negative predictor of CAR-T outcomes, and effective bridging with pirtobrutinib to de-bulk patients before apheresis and infusion may improve outcomes in real-world practice compared to the challenging clinical trial population.

Dr. Parikh highlights Richter's transformation as the most significant unmet need in CLL, noting updated data from the RTE1 trial combining tislelizumab (PD-1 inhibitor) with zanubrutinib showed median PFS of approximately 10 to 12 months, which was improved over historical RCHOP outcomes. A subsequent cohort adds sonrotoclax to this combination. The SWOG study randomizing patients to R-CHOP versus R-CHOP plus pirtobrutinib represents another cooperative group approach. The RT2 study comparing RCHOP/mini-R-CHOP against pirtobrutinib-epcoritamab (without chemotherapy) tests whether T-cell redirecting therapy plus BTK inhibition could replace chemoimmunotherapy entirely in Richter's.

Closing thoughts from each panelist: Dr. Coombs celebrates improvements across the full disease spectrum including hints of progress in Richter's. Dr. Lipsky notes multiply relapsed patients can now access genuinely helpful emerging therapies while earlier lines continue advancing. Dr. Parikh emphasizes the luxury of multiple excellent options requiring individualized selection, with emerging data suggesting patient survival increasingly approaches age-matched general population outcomes. Dr. Shadman calls for the field to develop novel trial endpoints that capture combined efficacy, safety, and quality-of-life considerations rather than relying solely on traditional PFS and overall survival metrics, which may inadequately compare continuous versus time-limited strategies.