Acalabrutinib Shows Consistent Safety in Older or Frail Patients With CLL


Patients aged 80 years or older and/or considered frail who received acalabrutinib for chronic lymphocytic leukemia experienced toxicities consistent with prior trials.

Image Credit: © Artem -

Image Credit: © Artem -

Patients who were 80 years or older and/or considered frail who received acalabrutinib (Calquence) for chronic lymphocytic leukemia (CLL) experienced toxicities consistent with prior trials, according to an interim safety analysis presented at the 2023 European Hematology Association Congress.1

At a median observation time of 8 months, 21 out of 30 patients remained on treatment. Fifteen severe adverse events (AEs) were reported, 8 of which were treatment related. Discontinuation for 5 patients was due to AEs, and 1 death was considered treatment related.

“Although representing roughly 20% of the general CLL population, older patients remain underrepresented in clinical trials,” the investigators stated in their poster.

Bruton tyrosine kinase (BTK) inhibitors such as acalabrutinib are effective in treating patients with CLL; however, older and frailer patients may not respond as well or are unable to tolerate BTK inhibitor therapy, but this has not been investigated sufficiently. For instance, in the global phase 3 ELEVATE-TN trial (NCT02475681), over 90% of patients had an ECOG performance status of 0 or 1, and the median patient age was 70.0 (interquartile range; 66.0-75.0) in the acalabrutinib monotherapy arm.2 The phase 2 CLL-FRAIL trial (NCT04883749) aimed to investigate the efficacy and safety of acalabrutinib in the older and frailer population.

Patients were eligible for this trial if they were aged at least 80 and/or had a FRAIL scale score of at least 2.1 This scale is a 5-item questionnaire correlating with Fried’s frailty phenotype. At least 50% of patients enrolled were required to have a score of 3 or higher. “Frailty is a multidimensional symptom complex and associated with worse outcomes in hematologic malignancies,” the investigators wrote.

Thirty patients were enrolled in the first 12 months of recruitment. The median age was 82.0 years, and 50.0% had a FRAIL score of 3 or higher. The median cumulative illness rating scale score was 10, with 73.3% having a score of greater than 6, which is considered to be elevated. The median ECOG performance status was 1. Most patients (76.7%) had a Binet stage of A; 11 (36.7%) had unmutated IGHV and 3 (10.0%) had a mutation/deletion of TP53. Nineteen (63.3%) were treatment-naive and 11 (36.7%) had received 1 prior line of therapy.

Patients received 100 mg of acalabrutinib twice daily until disease progression or intolerance. The primary end point was overall response rate at day 1 of cycle 7.

At the data cut-off of November 24, 2022, the preplanned interim safety analysis was performed. All patients experienced at least 1 AE and 200 total AEs were reported. AEs of grade 3 or higher occurred at a rate of 18%. There were no occurrences of grade 3 or higher bleeding. Two patients (6%) experienced atrial fibrillation; 1 patient had grade 2, and the other grade 3. Two cardiac severe AEs termed cardiac failure were reported in patients who had prior hypertension and atrial fibrillation.

Common AEs of any grade included hematoma, COVID-19 infection, anemia, headache, constipation, diarrhea, fatigue, pneumonia, weight loss, and dehydration. Four patients on the trial died, 1 due to concomitant disease (Parksinonism), 2 due to COVID-19 pneumonia, and 1 due to bacterial pneumonia.

“The first interim analysis of an ongoing phase 2 study evaluating treatment with acalabrutinib in very old and/or frail patients with CLL did not show unexpected safety signals in comparison to prior published data,” the investigators concluded in their poster.

1. Simon F, Ligtvoet R, Noesslinger T, et al. Safety and treatment adherence with acalabrutinib in very old (≥80y) and/or frail patients with chronic lymphocytic leukemia (CLL) - interim safety analysis of the ongoing phase-II CLL-FRAIL trial. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract P630.
2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
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