Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
In patients with CLL and high-risk genetic factors, specific mutations affect response duration to acalabrutinib-venetoclax combination therapies.
Who Performed the Research and Where Was it Presented:
Dr. Paolo Ghia from Università Vita-Salute San Raffaele and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Chronic lymphocytic leukemia (CLL) / small lymphocytic leukemia is a complex disease that can change and mutate over time, and genetic changes can alter the way cancer cells grow and spread. Certain genetic factors can affect how quickly CLL / SLL will worsen and how it will respond to different treatments. For instance, CLL / SLL with unmutated IGHV or mutated TP53 tends to grow quickly and does not respond well to traditional chemoimmunotherapy. Researchers are interested in learning about how patients with high-risk genetic factors respond to treatment with the new targeted therapies that are available. In this study, researchers looked at how certain genetic factors influenced outcomes for patients treated with acalabrutinib plus venetoclax, acalabrutinib plus venetoclax and obinutuzumab, or chemoimmunotherapy.
Methods and Participants:
This study is a subgroup analysis of the AMPLIFY trial, an ongoing phase 3 clinical trial in patients with treatment-naïve CLL. Patients were randomly assigned to receive:
- Acalabrutinib plus venetoclax (AV)
- Acalabrutinib, venetoclax, and obinutuzumab (AVO)
- Chemoimmunotherapy (either fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab)
Blood samples were collected at baseline and analyzed for genetic factors, including umutated IGHV and six mutations (ATM, CARD11, NOTCH1, BIRC3, MYD88, SF3B1). Researchers analyzed how mutation status affected patient outcomes, including progression-free survival and time to next treatment.
Results:
- A total of 867 patients were enrolled in the AMPLIFY trial.
- 59% of patients had unmutated IGHV.
- Mutations were most commonly seen in ATM (20-24%), NOTCH1 (14-17%), and SF3B1 (15-16%)
- Mutations in ATM, NOTCH1, and SF3B1 occurred more frequently in patients with unmutated IGHV.
- After three years, the proportion of patients who were progression-free was
- 77% for AV
- 83% for AVO
- 67% for chemoimmunotherapy
- Patients with unmutated IGHV had longer progression-free survival on AV and AVO than on chemoimmunotherapy.
- AV and AVO also improved progression-free survival compared with chemoimmunotherapy in patients with mutated ATM, mutated NOTCH1, or mutated SF3B1.
- AV and AVO improved time to next treatment compared with chemoimmunotherapy in patients with unmutated IGHV, mutated ATM, mutated NOTCH1, or mutated SF3B1.
- After three years, 85-90% of patients treated with AV or AVO have not needed a next therapy.
Some high-risk markers were associated with shorter average time to next treatment with AV than others. Conclusions:
As for others, patients with CLL and high-risk genetic factors had better outcomes on acalabrutinib-venetoclax combination therapies than on chemoimmunotherapy. High-risk genetic factors are associated with good, but variably response to AV and AVO depending upon the type of mutation. Detailed genetic analysis before treatment, especially among those with unmutated IGHV, may impact the choice of treatment. Three-drug treatment may be more appropriate for those with certain markers, especially if healthy enough to tolerate increased risks of infection and other side effects.
Links and Resources:
Watch the interview on the abstract here:
You can read the actual ASH abstract here: Impact of prognostic mutations on outcomes with fixed-duration acalabrutinib-venetoclax combinations versus chemoimmunotherapy: An exploratory analysis from AMPLIFY
