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Long-term data with more than 6 years of follow-up, solidify the efficacy and safety of acalabrutinib in newly-diagnosed CLL patients

Final results of the phase 1/2 ACE-CL-001 study further support the use of acalabrutinib in the first line treatment of patients with chronic lymphocytic leukemia (CLL). The overall response rate (ORR) with first-line acalabrutinib was reported at 97% and after a median follow-up of more than 6 years, both the median duration of response (DoR) and the median progression-free survival (PFS) were still not reached. Importantly, similar efficacy results were obtained in the subgroup of patients with high-risk cytogenetic features. Finally, long-term use of acalabrutinib did not reveal any new safety signals.


Over the last decade, the introduction of Bruton tyrosine kinase inhibitors (BTKi) has revolutionized the treatment of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Acalabrutinib is a second-generation BTKi that is currently approved for the treatment of both treatment naïve (TN) as relapsed/refractory (R/R) CLL/SLL patients. Previously, results of the phase 1/2, multicenter ACE-CL-001 study (NCT02029443) after a median follow-up of 53 months, demonstrated durable responses and a good long-term tolerability with acalabrutinib in the first-line treatment of patients with CLL. During the 2022 annual ASH meeting, final results were presented for the TN cohort of this trial with a follow-up of more than 6 years.

Study design

The ACE-CL-001 study enrolled adult patients with TN CLL/SLL who met the 2008 iwCLL criteria for treatment, had an ECOG performance status 0–2 and were unfit or unwilling to undergo standard chemoimmunotherapy. In the expansion phase of this study, patients in the TN CLL cohort were treated with acalabrutinib at a dose of 100 mg BID or 200 mg QD until disease progression, or unacceptable toxicity. After an amendment of the study, all patients were switched to a 100 mg BID dose. Of note, patients with a need for warfarin or a proton pump inhibitor were excluded from the study as were patients with significant cardiovascular disease; any New York Heart Association class III/IV cardiac disease, or a left ventricular ejection fraction ≤40%. The primary endpoint of the trial was safety, while secondary objectives included investigator-assessed ORR, time to response (TTR), DoR and PFS.

High rates of durable response with acalabrutinib in TN CLL

The TN cohort of this study included a total of 99 patients with a median age of 64 years. About half of the patients (47%) had a Rai stage III or IV, with 10% and 17% of patients harboring a deletion 17p, or a deletion 11q, respectively. Furthermore, 62% of patients had an unmutated IGHV status and 18% presented with a complex karyotype. At data cut-off, the median study follow-up was 73.7 months (range 0.92–82.4), and at that time 70 (71%) patients remained on treatment with acalabrutinib. The most common reasons for acalabrutinib discontinuation consisted of adverse events (AEs) (10%) and progressive disease (6%).

The most common adverse events were consistent with what has been reported in the 53-month update. The only grade ≥3 adverse events with a ≥50% increase in incidence since the prior update were pneumonia (4% in prior update vs. 8% now) and syncope (4% in prior update vs. 6% now). Interestingly, the incidence of adverse events generally decreased over time. In total, two on-study grade 5 adverse events were reported: 1 cardiac failure and 1 patient with multiple organ dysfunction syndrome. Adverse events of particular clinical interest included infections (all grade: 87%; grade ≥3: 19%), bleeding events (all grade: 74%; grade ≥3: 7%), major bleeding events (all grade: 8%; grade ≥3:  7%), and hypertension (all grade: 29%, grade ≥3: 13%). Atrial fibrillation was reported in 6% of patients (grade ≥3: 3%), while second primary malignancies (excluding non-melanoma skin cancer) occurred in 14% of patients.

The ORR in this TN cohort was 97%, including 9% of patients with a complete response and 88% with a partial response. Responses to acalabrutinib also occurred rapidly, with a median TTR of 3.7 months, ranging from 1.7 to 22.1 months. Responses proved to be very durable, with a median DoR that was still not reached after more than 6 years of follow-up. The response durability is further reflected by an estimated 66-month DoR rate of 89%. Interestingly, a 100% ORR was observed across different high-risk subgroups, including patients with a del(17p) (9/9), a del(11q) (15/15), an unmutated IGHV status (57/57), and a complex karyotype (12/12). At the time of the final analysis, the median PFS was still not reached, with an estimated 72-month PFS rate of 87%. In patients with a del(17p), unmutated IGHV, or a complex karyotype, this rate was reported at 50%, 85% and 68%, respectively. The estimated 72-month EFS was 78%, with EFS events consisting of adverse events (N=10/99, 10%), disease progression (N=9/99, 9%), and new anticancer therapy (N=3/99, 3%).


The final data from ACE-CL-001 further support the long-term efficacy and safety of acalabrutinib monotherapy, with high response rates and rapid, durable responses in patients with TN CLL, regardless of high-risk genomic features. With over 6 years of follow-up, this study firmly establishes the tolerability and safety profile of acalabrutinib seen consistently in subsequent studies, with a low incidence of atrial fibrillation/flutter seen and no new long-term safety issues identified.


J. Byrd, et al. Final Results of the Phase 1/2 Study of Acalabrutinib Monotherapy in Treatment-Naive Chronic Lymphocytic Leukemia with >6 Years of Follow-up. Presented at ASH 2022; Abstract 4431.

Speaker John Byrd

John Byrd

John Byrd, MD, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA


See: Keyslides


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