Acalabrutinib treatment for older (≥80 years old) and/or frail patients with CLL: primary end point analysis of the CLL-Frail trial Open Access

• In older and/or frail CLL patients treatment with acalabrutinib is highly efficacious and can improve underlying frailty

• No unexpected safety signals occurred, with infections accounting for most of high-grade adverse events and three of five deaths.

Because frail and patients ≥80 years with CLL are still underrepresented in clinical trials, the CLL-Frail trial aimed to evaluate the efficacy and safety of acalabrutinib in these patients. The primary endpoint was the overall response rate (ORR) after 6 cycles of treatment to test the null hypothesis of ORR ≤ 65%.53 patients were included into the trial and 34 patients are still on therapy. Adverse events (AEs) were the most frequent reason for early discontinuation (ten patients), whereas five patients stopped treatment because of death. Median age was 81 years and 47.2% of patients were frail. The ORR for the 46 patients receiving ≥3 cycles of treatment was 93.5% (95% confidence interval 82.1 - 98.6) meeting the primary endpoint of this trial (p < 0.001). The estimated 12-month progression-free and overall survival rates were 93.3% and 95.7%, respectively, after a median follow-up of 19 months. 53.5% of patients reported an improvement in their self-perceived frailty. Although all patients experienced AEs and severe (CTC° ≥ 3) events were reported in 63.5% of patients, there were no events of severe bleeding and atrial fibrillation was rare (two cases of CTC° 2 and 3). Five patients died, of which four deaths happened during or <28 days after treatment. Infections/COVID-19 were the cause of death in three cases. This is the first prospective trial in older and/or frail CLL patients demonstrating a high efficacy and safe treatment with acalabrutinib monotherapy. ClinicalTrials.gov ID: NCT04883749 EUDRA-CT: 2020-002142-17