According to research published in Blood, treatment of patients with Richter syndrome (RS) using venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) demonstrated the highest complete remission (CR) rate of any published study in RS.
The researchers hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS, which typically has a poor prognosis, to chemoimmunotherapy and improve outcomes. They conducted a single-arm, investigator-sponsored, phase 2 trial to determine the CR rate with the VR-EPOCH combination therapy (ClinicalTrials.gov Identifier: NCT03054896).
Patients were administered R-EPOCH for 1 cycle, followed by accelerated daily venetoclax ramp-up to 400 mg after count recovery, then VR-EPOCH for up to 5 cycles. Off-study venetoclax maintenance or cellular therapy were given to responding participants.
The study enrolled 27 patients, with a median age of 63 years (range, 49-77). Clonal relatedness of RS to prior chronic lymphocytic leukemia (CLL) was determined in 11 patients; among them, 82% were clonally related. Overall, the median number of prior therapies for CLL was 1 (range, 0-7). Only 2 patients had received prior treatment of RS, and 6 patients (22%) were previously untreated for CLL.
Of those enrolled, 26 patients were treated. CR was achieved in 50% of treated patients. Of those achieving CR, 11 of 13 achieved undetectable bone marrow minimal residual disease for CLL. The overall response rate was 62% (including 3 partial responses). The median progression-free survival and overall survival were 10.1 months and 19.6 months, respectively.
All treated patients were evaluable for safety. The most common adverse events were hematologic toxicities, including neutropenia (65% ≥grade 3; 58% grade 4), febrile neutropenia (26% ≥grade 3; 12% grade 4), anemia (62%, all grade 3), and thrombocytopenia (50% ≥grade 3; 42% grade 4). During daily venetoclax ramp-up, no patients experienced tumor lysis syndrome. Deaths of 12 patients were reported (8 of disease progression, 2 of post-allogeneic transplantation nonrelapse mortality, 1 of sepsis during cycle 1 before venetoclax, and 1 of sudden death).
“In summary, VR-EPOCH led, to our knowledge, to the highest CR rate and longest median OS reported in a study of patients with RS,” wrote the authors. “Given that no effective standard therapy exists for RS, our data support consideration of using VR-EPOCH in clinical practice in appropriate patients with close monitoring.”
They suggest that future studies comparing venetoclax + chemoimmunotherapy to chemoimmunotherapy alone in RS are warranted.
Disclosure: This research was supported by Genentech/AbbVie. Please see the original reference for a full list of disclosures.
Davids MS, Rogers KA, Tyekucheva S, et al. Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome. Blood. 2022;139(5):686-689. doi:10.1182/blood.2021011386