Acalabrutinib in Treatment-Naïve Chronic Lymphocytic Leukemia.

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). The efficacy and safety of acalabrutinib monotherapy was evaluated in a treatment-naïve CLL cohort of a single-arm phase 1/2 clinical trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patient demographics included a median age of 64 years and 47% with Rai stage III/IV disease. Acalabrutinib was administered orally either 200 mg once daily (QD) or 100 mg twice daily (BID) until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene (IGHV), and 12 (18%) had TP53 aberrations. After a median follow-up of 53 months, 85 patients remain on treatment; 14 patients discontinued treatment, mostly due to adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Due to improved trough BTK occupancy with BID dosing, all patients were transitioned to 100 mg BID. The median duration of response (DOR) was not reached; the 48-month DOR rate was 97% (95% confidence interval [CI], 90%, 99%). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) due to second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). The durable efficacy and long-term safety of acalabrutinib in this trial provide support for its use in clinical management of symptomatic, untreated CLL patients.