Acalabrutinib a Safe Treatment Avenue for Older, Frail Patients With CLL

Acalabrutinib (Calquence) yielded high efficacy and a manageable safety profile for the treatment of chronic lymphocytic leukemia (CLL) in older and/or frail patients, according to findings from the phase 2 CLL-Frail trial (NCT04883749).¹

This underrepresented patient group has historically been excluded from large-scale clinical trials, leaving a significant gap in evidence-based treatment guidance. CLL-Frail marks the first prospective trial of acalabrutinib monotherapy in this population.

The study met its primary end point with an overall response rate of 93.5% (95% CI, 82.1%-98.6%; P < .001) in patients who completed at least 3 cycles of therapy, significantly exceeding the predefined efficacy threshold of 65%. With a median follow-up of 19 months, the estimated 12-month progression-free survival and overall survival rates were 93.3% and 95.7%, respectively.

A critical finding of the trial is the positive impact of treatment on patient frailty. Over half of the patients (53.5%) reported an improvement in their frailty scores after 6 months, suggesting that effectively treating the underlying malignancy can partially reverse the frailty syndrome.

All 52 patients in the safety-evaluable population experienced an adverse event (AE), with grade ≥3 AEs reported in 63% of patients. Forty-nine patients (94%) experienced an AE requiring treatment or supportive care, and 46% received inpatient therapy for an AE, with a median of 9 days (IQR, 5-15) until resolution of these events.

The most common AEs were COVID-19 infection (n = 21; 40%) and hematoma (n = 19; 37%). The most common hematological AEs were anemia (n = 9; 17%) and thrombocytopenia (n = 6; 12%). A total of 40 serious AEs were reported in 50% of patients (n = 26); COVID-19 infection was the most common serious AE, occurring in 10% of patients (n = 5).

Regarding cardiac toxicity, 25% of patients experienced a cardiac AE of any grade, and 10% of patients (n = 5) experienced a grade ≥3 cardiac AE. These included 2 patients (4%) with grades 2 and 3 atrial fibrillation. The most common grade ≥3 cardiac AE was cardiac failure, which occurred in 3 patients (6%).

While continuous treatment with Bruton tyrosine kinase (BTK) inhibitors is a mainstay of first-line and relapse CLL treatment, first-generation BTK inhibitors like ibrutinib (Imbruvica) are associated with an increased risk of cardiac AEs, which limit their use in patients with comorbidities. Acalabrutinib was approved for the treatment of CLL and small lymphocytic lymphoma in November 2019.²

“Second-generation BTKis such as acalabrutinib and zanubrutinib [Brukinsa] were subsequently shown to have a superior tolerability with at least sustained efficacy,” study authors explained.¹

“Although being influenced by a high degree of preexisting cardiac diseases and age-related AEs such as valvular diseases, cardiac [adverse] effects in older patients under treatment with BTK [inhibitors] remain a concern. Notably, severe cardiac [adverse] effects in this trial only occurred in 30 patients with previously existing cardiac conditions, underscoring the need for a thorough risk-benefit assessment prior to treatment initiation,” study authors wrote.

REFERENCES

1. Simon F, Ligtvoet R, Bohn JP, et al. Acalabrutinib treatment for older (≥80 years old) and/or frail patients with CLL: primary end point analysis of the CLL-Frail trial. Blood. Published online September 5, 2025. doi:10.1182/blood.2025028550

2. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed October 15, 2025. https://tinyurl.com/598bjsy4