Acalabrutinib in treatment-naive chronic lymphocytic leukemia

Abstract

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.

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

“…Long-term data from the phase 2 ACE-CL-001 study reaffirmed that acalabrutinib monotherapy for patients with treatment-naïve and R/R CLL provided durable responses with a favorable safety profile, with no new safety concerns reported (14,15). Several clinically relevant AEs considered to be associated with BTK inhibition in the clinical setting appear to be present at a low frequency in patients treated with acalabrutinib.…”

“…The median age of the patients with treatment-naïve CLL in this study was 64 years (range, 33-85) (14); and 66 years (range, 42-85) for patients with R/R CLL (20% of whom were aged ≥75 years) (15). In treatment-naïve patients, the most common AEs of any grade were diarrhea (51%), headache (45%), upper respiratory tract infection (44%), arthralgia (42%), and contusion (42%) (14). Any-grade and grade ≥3 severity AEs of clinical interest included infection (84% and 15%, respectively), bleeding event (66%/3%), and hypertension (22%/11%) (14).…”

“…This review will discuss the mechanisms of BTK inhibition, review AEs associated with ibrutinib therapy, together with their possible underlying molecular basis, and AEs reported with acalabrutinib therapy in patients with CLL, including recommendations for the management of acalabrutinib-related AEs. Acalabrutinib-associated AEs will be described using data from the phase 3 ASCEND ( 12 ) and ELEVATE-TN ( 13 ) trials, long-term safety data from the phase 2 ACE-CL-001 study in patients with CLL who were either treatment naïve or who became R/R ( 14 , 15 ), and from reports of the most common acalabrutinib-related AEs observed in clinical practice. AEs associated with the use of zanubrutinib in the treatment of patients with treatment-naïve or R/R CLL will also be presented ( 10 , 11 ).…”

Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial

“…6,7 Treatment discontinuations because of adverse events in longer-term analyses of a phase II clinical trial of acalabrutinib monotherapy in previously untreated or relapsed or refractory CLL were reported in 6% and 11% of patients, respectively, at the median follow-up of 53 and 41 months, respectively. 22,23 Acalabrutinib has also demonstrated efficacy and tolerability in ibrutinib-intolerant patients with CLL. 24 This phase III trial prospectively compared the efficacy and safety of acalabrutinib with ibrutinib in patients with previously treated CLL to test the hypothesis that acalabrutinib was noninferior to ibrutinib in PFS with improved tolerability.…”

Chemoimmunotherapy in the First-Line Treatment of Chronic Lymphocytic Leukaemia: Dead Yet, or Alive and Kicking?

“…There were more discontinuations due to AEs with ibrutinib (21%) than acalabrutinib (15%) [83]. Finally, the long-term results of the phase I/II study in the untreated CLL population confirmed a very good safety profile, with less than 10% of patients discontinuing treatment due to an adverse event [84].…”