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

Clinical Snapshot

Key Findings

• P Value: Not reported for primary endpoints

• Effect Size: Complete response rate 60%, median PFS 46 months

• Primary Outcome: Overall response rate 91% in CLL/SLL patients

• Nnt Or Sensitivity: uMRD achievement: 43% peripheral blood, 40% bone marrow at cycle 13

• Confidence Interval: 3-year PFS 67% (95% CI: 0.51-0.86)

Clinical Application

Requires careful monitoring for neutropenia and immune-mediated toxicities; specialist haematology setting essential Both duvelisib and venetoclax available through PBS Special Access Scheme; aligns with RACGP referral guidelines for complex haematological malignancies Patients with R/R CLL/SLL, particularly those with high-risk features (TP53 aberrancy, unmutated IGHV) or prior BTK inhibitor exposure

Abstract

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.

References

1. 1.Crombie, J. L., Ryan, C. E., Ren, Y., Tyekucheva, S., Carey, C., Zou, A., Normilus, S., Montegaard, J., Bhandari, S., Alencar, A., Soumerai, J. D., Arnason, J. E., Kim, A. I., Parry, E. M., Armand, P., Fisher, D. C., Brown, J. R., & Davids, M. S. (2026). A phase 1/2 study of duvelisib plus venetoclax in patients with relapsed/refractory CLL/SLL or Richter transformation. Blood Advances. https://doi.org/10.1182/bloodadvances.2025018878