Abstract Background: Richter transformation (RT) represents transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma histology, most commonly DLBCL. Traditionally, RT is treated with DLBCL-directed chemoimmunotherapy regimens such as R-CHOP, and more recently, clinical trials have reported efficacy of targeted therapies including BTK, PD-1, and BCL2 inhibitors. We report first results of an investigator-initiated Phase II trial of combined therapy with pirtobrutinib, a non-covalent BTKi, venetoclax, and obinutuzumab as treatment for patients (pts) with RT (NCT05536349). Methods: Pts with previously untreated or relapsed/refractory RT (DLBCL histology) arising from CLL were enrolled. Previously untreated RT were required to have received prior therapy for CLL. Pts received pirtobrutinib 200mg daily starting Cycle 1 Day 1 (C1D1) continuously daily. Obinutuzumab was given as standard 6 cycles starting C1D1. Venetoclax standard ramp-up was initiated C2D1 to the target dose of 400mg daily. Combined pirtobrutinib and venetoclax was given until end of C25. Pts in ongoing response (PR or better) after cycle 25, could continue pirtobrutinib for an additional 12 cycles. Each cycle was 28 days. Response evaluations by Lugano criteria were done by PET/CT imaging and bone marrow (BM) assessment at the end of C1, C4, C7, C10, C13, C19 and C25. Results: Between February 2023 and April 2025, 12 pts (male, n=9; female, n=3) were enrolled. Median age was 70 years (range, 48-81 years). 8/9 (89%) pts with available data had IGHV-unmutated CLL. 7/10 (70%) had del(17p)/TP53 mutated CLL. Median prior lines of therapy for CLL and RT were 2 (range, 1-4); median prior lines of treatment for CLL were 1 (range, 0-2) and for RT were 1 (range, 0-4). Prior therapy for CLL (4 pts had no prior therapy for CLL) included BTKi (n=6), BCL2i (n=2), CD20 antibody (n=3), and conventional chemotherapy (n=1). Prior therapy for RT included conventional chemotherapy (n=9), BCL2i (n=5), CD20 antibody (n=8), checkpoint inhibitor (n=4), allo-SCT (n=1), and CD19 CAR T (n=1). Three pts were previously untreated for RT (all 3 had received prior CLL therapy). Median time from CLL diagnosis to treatment was 58 months (range, 24-211) and from RT diagnosis to treatment was 6 months (range, 0.3-28). The median follow-up is 15.3 months (range, 1.8-26.8). Seven out of 12 pts achieved complete metabolic response (CMR) and 1/12 achieved partial metabolic response (PMR) giving an ORR of 8/12 (67%). One pt has stable disease after 4 cycles of therapy and remains on treatment. Three pts had no response (1 pt with previously untreated RT who received venetoclax + obinutuzumab for CLL; 1 pt with prior BR and Ibrutinib + obinutuzumab for CLL, and prior atezolizumab + venetoclax + obinutuzumab, and R-CHOP + venetoclax for RT; 1 pt with no prior CLL therapy and R-EPOCH for RT). Two of the responding pts underwent consolidative allo-SCT. 1 pt with 4 prior therapies for RT in PMR after C6; pt is alive in remission 17.5 months post allo-SCT. 1 pt who previously received R-CHOP + venetoclax followed by allo-SCT and then had relapsed RT prior to enrollment on the current trial; pt went to second allo-SCT in CMR after C12 on the trial but died 5.3 months after the second allo-SCT from transplant-related complications. Among the 3 previously untreated RT, 2 achieved a CMR and are continuing to receive treatment 13.9 and 14.7 months since treatment initiation; 1 pt had worsening disease while receiving venetoclax dose escalation in C2 and elected to go to hospice. Among the 8 responding pts, 1 pt went to allo-SCT in C6. Among the remaining 7 pts who reached end of C7, 6/7 achieved U-MRD4 remission in BM by flow-cytometry. 6 pts reached end of C13 (1 pt went to allo-SCT in C12); all 6 were U-MRD4 in BM by flow-cytometry. The 12-month EFS and OS for the whole cohort (n=12) was 73% and 82%, respectively. The 12-month EFS and OS for the R/R RT (n=9) was 75% and 88%, respectively. There have been no relapses among the responders to date. There were 4 deaths which included 3 non-responders and 1 death in a pt in remission with post-transplant complications. Conclusions: We report results of combined pirtobrutinib, venetoclax, and obinutuzumab in pts with untreated or R/R RT. We observed an ORR rate of 67% and a 12-month EFS and OS rates of 73% and 82%, respectively.
Jain et al. (Mon,) studied this question.