Venetoclax plus dose-adjusted R-EPOCH for Richter syndrome

Abstract

Richter's Syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. (Funded by Genentech/AbbVie; ClinicalTrials.gov number, NCT03054896).

Biology and Treatment of Richter Transformation

“…Main adverse events were related to grade 3–4 neutropenia (65%), thrombocytopenia (50%) and febrile neutropenia (38%). No tumor lysis syndrome (TLS) occurred with daily venetoclax ramp‐up after 1 lead in cycle of R‐EPOCH ( 91 ).…”

Long-term effect of venetoclax therapy in a patient with the transformation of chronic lymphocytic leukemia into Richter’s syndrome

“…Higher intensity chemotherapy does not improve outcomes. The treatment of CLL and RS dramatically changed with the emergence of several novel targeted agents, such as ibrutinib, acalabrutinib, idelalisib, duvelisib and venetoclax [ 1 , 2 , 3 , 5–8 ]. In our case, the disease progression associated with transformation into DLCDL determined the necessity of decision regarding further treatment.…”

Emerging Therapies for the Management of Richter Transformation

“…78 However, in combination with DA-R-EPOCH, deeper, more durable responses were obtained. Davids et al 79 performed a phase II study of DA-EPOCH-R + venetoclax in 26 patients with RT: the ORR of 61.5% (CR 50%) and the median OS 19.6 months compared favorably with historic controls. However, toxicity was substantial with more than 50% of patients developing ≥ grade 3 cytopenias (38% febrile neutropenia).…”