Authored by Ann Liu, PhD
Medically Reviewed by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Limiting acalabrutinib therapy to 18 months significantly reduced progression-free survival for the elderly and frail with CLL compared to continuous use.
Who Performed the Research and Where Was it Presented:
Dr. Romain Guieze from the University Hospital of Clermont-Ferrand and colleagues presented the results at the American Society for Hematology (ASH) Annual Meeting in 2025.
Background:
Covalent Bruton tyrosine kinase inhibitors (BTKi) are commonly used to treat patients with chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). While they are very effective for controlling CLL / SLL, they are not curative and must be taken continuously. Over time, patients can develop resistance to covalent BTKi, or they may develop intolerable side effects that cause them to discontinue treatment. This is especially concerning for elderly patients who are considered “frail”, meaning that they are more vulnerable to injuries and illnesses and have a harder time recovering from these things. This study looked at whether second-generation covalent BTKi acalabrutinib could be used in a time-limited manner for frail patients with CLL in the hope of providing similar efficacy but better tolerability to continuous therapy.
Methods and Participants:
This phase 2 clinical trial is evaluating the impact of time-limited acalabrutinib on progression-free survival in elderly and frail patients with untreated CLL. Patients were >70 years of age and were randomly assigned to receive either 1) continuous acalabrutinib or 2) time-limited acalabrutinib, which was discontinued after 18 months. Patients in the time-limited acalabrutinib group could restart acalabrutinib if they experienced disease progression.
Results:
- A total of 121 patients were randomized to receive either continuous acalabrutinib (n=41) or time-limited acalabrutinib (n=80).
- The median age was 77 years.
- Sixty-five percent of patients had unmutated IGHV.
- In the continuous acalabrutinib group, six patients discontinued treatment due to side effects.
- In the continuous acalabrutinib group, one year after randomization, the progression-free survival was 96%, and the overall survival was 100%.
- In the time-limited acalabrutinib group, one year after randomization, the progression-free survival was 53% and overall survival was 96% with two deaths.
- In the time-limited acalabrutinib group, 37 patients had their disease progress after acalabrutinib discontinuation, and 25 (68%) of these patients required treatment.
- Twenty-four patients restarted acalabrutinib, and of these, 78% responded to acalabrutinib and 22% had stable disease.
- Patients with mutated IGHV had a significantly higher 1-year progression-free survival rate (90%) than those with unmutated IGHV (34%).
- Serious adverse events were seen in approximately in 1 in 4 on continuous therapy but only 1 in seven on the limited duration protocol.
Conclusions:
Limiting acalabrutinib therapy to 18 months significantly reduced time in remission for elderly and frail patients with CLL. Progression-free survival after one year was much lower in the group that discontinued acalabrutinib after 18 months (53%) than in the group that stayed on continuous acalabrutinib (96%). This result indicates that time-limited covalent BTKi therapy is not a great option for most patients, though the results were better in the group with the slower-growing mutated IGHV status. Fortunately, most patients did respond when acalabrutinib therapy was restarted.
The research did answer an important question, namely that most CLL patients who are considering a limited duration therapy using a BTKi will need more than one drug to maintain a durable remission after stopping treatment.
Links and Resources:
You can read the actual ASH abstract here: Time-limited acalabrutinib monotherapy in frail patients with previously untreated chronic lymphocytic leukemia: Primary endpoint analysis of the randomized STAIR trial
Take care of yourself first.
Ann Liu, PhD
