The Bottom Line:
Duvelisib plus venetoclax is a time-limited, all-oral regimen active in relapsed/refractory chronic lymphocytic leukemia (CLL) and Richter’s Syndrome.
Who Performed the Research and Where Was it Presented:
Dr. Christine Ryan from Dana-Farber Cancer Institute and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2022. The principal investigators were Dr. Matt Davids and Dr. Jennifer Crombie.
Both relapsed/refractory CLL / small lymphocytic lymphoma (SLL) and Richter’s Syndrome can be difficult to treat. Therefore, scientists are investigating combination therapies, hypothesizing that they will produce higher response rates and deeper remissions. The PI3K inhibitor duvelisib and the BCL2 inhibitor venetoclax have been shown to work synergistically in preclinical models, so investigators decided to test the combination in a phase 1/2 clinical trial.
In this interview, Dr. Brian Koffman interviewed Dr. Christine Ryan, a clinical fellow in hematology/oncology at Dana-Farber Cancer Institute. They discussed the most recent results from the phase 1/2 clinical trial, which we previously covered here and here.
Methods and Participants:
This phase 1/2 clinical trial enrolled patients with relapsed/refractory CLL or Richter’s Syndrome. Patients received oral duvelisib and venetoclax for a maximum of 12 cycles (~1 year). Venetoclax was continued beyond 12 cycles based on MRD status.
- These latest results are from 35 patients with CLL and 8 patients with Richter’s Syndrome and are based on the most recently updated data presented in the poster.
- Many of the patients had been previously treated with a BTK inhibitor.
- Non-hematologic toxicity results were as follows: Diarrhea: 55%, nausea: 50%, fatigue: 67%.
- Diarrhea is one of the characteristic side effects of PI3K inhibitors.
- Most of the nausea and fatigue were mild.
- Low blood counts were also common with low neutrophil counts in 93%, low platelet counts in 64%, and low red blood cell counts (anemia) in 62%, but this was manageable with growth factor support.
- The best overall response rate in patients with CLL was 94% (60% complete response, 34% partial response).
- 44% of patients with CLL achieved undetectable measurable residual disease (uMRD) in the bone marrow.
- Two out of eight patients with Richter’s Syndrome had a complete response, and one successfully underwent an allogeneic stem cell transplant.
- The 2-year progression-free survival for patients with CLL was 78%, and the 2-year overall survival was 90%.
Duvelisib plus venetoclax is a time-limited, all-oral regimen active in relapsed/refractory CLL and Richter’s Syndrome. Most side effects were manageable with supportive therapy.
This research suggests a possible role for PI3K inhibitors in combination therapies. However, as noted at the end of the interview, the future of PI3K inhibitors is very much in question since the FDA raised safety concerns last year about the toxicities of this drug class. Nevertheless, we at the CLL Society and many doctors would like to keep PI3K inhibitors available as a treatment option, especially for hard-to-treat cases. Last year, the CLL Society sent a letter requesting the FDA to allow the continued use of approved PI3K Inhibitors in CLL / SLL patients with no other approved treatment options. Stay tuned to see what happens.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia (CLL) or Richter’s Syndrome (RS)
Take care of yourself first.
Ann Liu, PhD