A phase I/II Study of Duvelisib plus Venetoclax in Patients with Relapsed/Refractory CLL/SLL or Richter Transformation

In this phase I/II study, we evaluated duvelisib plus venetoclax in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and Richter Transformation (RT). Patients received duvelisib monotherapy for 1 week prior to addition of venetoclax. After 1 year of combination therapy patients with a complete response (CR) and undetectable minimal residual disease (uMRD) could discontinue therapy; patients with detectable MRD continued venetoclax monotherapy until two separate occasions of uMRD were achieved. 44 patients were enrolled: 35 with CLL/SLL and 9 with RT. CLL patient characteristics included 77% with unmutated IGHV, 46% with TP53 aberrancy, and a median of 2 prior therapies, including prior BTK inhibitor in 60%. In phase I, the maximum tolerated dose was not reached, and the recommended phase II dose was 25 mg BID duvelisib plus 400 mg daily venetoclax. 91% of patients experienced ≥grade 3 neutropenia, with febrile neutropenia in 6%. Common non-hematologic toxicities were diarrhea (63%, 14% ³grade 3), elevated aspartate aminotransferase (51%, 9% ³grade 3), and nausea (49%, 3% grade 3). The best CR and overall response rates were 60% and 91%, respectively. At cycle 13, peripheral blood and bone marrow uMRD by flow cytometry at 10-4 were 43% and 40%, respectively. The median PFS for patients with CLL/SLL was 46 months, and the 3-year PFS was 67% (95% CI: 0.51-0.86). 4 patients with RS achieved a response (3 CRs). Overall, duvelisib plus venetoclax was active in high-risk R/R CLL/SLL and RT, though serious adverse events occurred, including immune-mediated toxicities. NCT03534323.