A phase 1/2 study of duvelisib plus venetoclax in patients with relapsed/refractory CLL/SLL or Richter transformation.

In this phase 1/2 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). Venetoclax was added after 1 week of duvelisib. After 1 year of therapy, patients with a complete response (CR) and undetectable minimal residual disease (uMRD) could discontinue therapy; patients with detectable MRD continued venetoclax monotherapy until 2 separate occasions of uMRD. Thirty five patients with CLL/SLL and 9 with RT enrolled. Among patients with CLL, 77% had unmutated immunoglobulin heavy chain variable region, 46% had TP53 aberrancy, and patients had a median of 2 prior therapies, including 60% with prior Bruton tyrosine kinase inhibitor. In phase 1 the maximum tolerated dose was not reached, and the recommended phase 2 dose was 25mg twice daily duvelisib plus 400mg daily venetoclax. 91% of patients experienced ≥grade 3 neutropenia, with febrile neutropenia in 6%. Common nonhematologic toxicities were diarrhea (63%, 14% ≥grade 3) and elevated aspartate aminotransferase (51%, 9% ≥grade 3). The best CR and overall response rates were 60% and 91%, respectively. At cycle 13, peripheral blood and bone marrow uMRD at 10-4 were 43% and 40%, respectively. The median progression-free survival (PFS) for patients with CLL/SLL was 46 months, and the 3-year PFS was 67% (95% confidence interval, 0.51-0.86). Four patients with RS achieved a response (3 CRs). Overall, duvelisib plus venetoclax was active in R/R CLL/SLL and RT, although serious adverse events occurred, including immune-mediated toxicities. This trial was registered at www.clinicaltrials.gov as NCT03534323.