Background
Phase 1/2, open-label, single-arm study (BRUIN), Richter transformation (RT) cohort. N=82 patients with biopsy-confirmed Richter transformation (DLBCL histology) arising from CLL. Pirtobrutinib, a noncovalent (reversible) BTK inhibitor, was administered as monotherapy. Richter transformation is the most aggressive complication of CLL with very poor prognosis (historical mOS ~5–8 months) and no established standard of care. Published Lancet Haematology 2024.
Interventions and follow up
Regimen: Pirtobrutinib 200 mg orally once daily continuously — Richter transformation cohort of BRUIN
Primary endpoint: ORR (per Lugano 2014 criteria, independent review)
mFollow up: ~12 months
Primary endpoint: ORR (per Lugano 2014 criteria, independent review)
mFollow up: ~12 months
Results
ORR (Richter transformation): 50%
CR: 13%
mDOR: 7.4 months
mPFS: 4.8 months
mOS: 10.7 months
CR: 13%
mDOR: 7.4 months
mPFS: 4.8 months
mOS: 10.7 months
Adverse events
Hematologic: Neutropenia grade ≥3 34%; anemia grade ≥3 24%; thrombocytopenia grade ≥3 18%
Infections: Grade ≥3 infections 24%; one treatment-related death (infection)
Other: Grade ≥3 AEs 60%; fatigue any grade 29%; atrial fibrillation any grade 3%; discontinuation due to AEs 15%
Infections: Grade ≥3 infections 24%; one treatment-related death (infection)
Other: Grade ≥3 AEs 60%; fatigue any grade 29%; atrial fibrillation any grade 3%; discontinuation due to AEs 15%
Conclusions
Pirtobrutinib achieved a 50% ORR in BTKi-pretreated Richter transformation — a notable response rate in this historically treatment-refractory population. An mOS of 10.7 months and mDOR of 7.4 months represent meaningful, if not durable, benefit and a potential bridge to consolidative cellular therapy.
Key Limitations
Single-arm design: No comparator; ORR benchmarked against historical controls
Short durability: mPFS of only 4.8 months and mDOR 7.4 months indicate responses are not durable as monotherapy
Heterogeneous prior therapy: Variable prior BTKi exposure and lines of therapy
Short durability: mPFS of only 4.8 months and mDOR 7.4 months indicate responses are not durable as monotherapy
Heterogeneous prior therapy: Variable prior BTKi exposure and lines of therapy
Clinical Context
Pirtobrutinib is FDA-approved for R/R CLL/SLL and R/R mantle cell lymphoma after a prior BTKi; the Richter cohort is not a labeled indication but supports off-label use as a bridge. Richter transformation has no ELN/iwCLL-endorsed standard regimen; chemoimmunotherapy (e.g., R-EPOCH) and clinical-trial cellular therapies (CAR-T, alloSCT) are pursued. Pirtobrutinib monotherapy offers a tolerable cytoreductive option to enable transplant or CAR-T consolidation.