Two trials: acalabrutinib in CLL

Results from both the phase 2 ACE-CL-001 trial and the pivotal phase 3 ASCEND trial demonstrated the long-term efficacy and tolerability of acalabrutinib in chronic lymphocytic leukaemia (CLL) patients, in both treatment-naïve as well as in relapsed/refractory (R/R) disease.

Because CLL patients often require treatment over long periods of time, the sustained safety and efficacy profile of a given therapy is highly relevant to their quality of life. In the single-arm ACE-CL-001 trial, previously untreated patients with CLL (mean age 64 years) were randomised to either 100 mg of acalabrutinib twice daily (n=62) or 200 mg once daily (n=37).

The final results of ACE-CL-001 were presented by Prof. John Byrd (Ohio State University Comprehensive Cancer Centre, USA). With a median follow-up of >4 years, 86% of patients with CLL who were treated with acalabrutinib as a first-line monotherapy remained on treatment. There was an overall response rate (ORR) of 97%, with 7% having a complete response (CR), and 90% a partial response (PR).

Remarkably, in patients with high-risk disease characteristics, a 100% ORR was observed, including patients with pre-specified stratification for wildtype IGHV (n=57), 17p deletion (n=9), TP53 mutation (n=9), and/or a complex karyotype (n=12). In addition, a reduction in lymph node disease was noted in all patients tested (n=97).

The safety findings of ACE-CL-001 were consistent with previous reports. Adverse events (AEs) were attributed for the discontinuation of 6 patients, and 3 discontinued because of progressive disease. The most common AEs (≥40%) of any grade in the trial were diarrhoea (52%), headache (45%), upper respiratory tract infection (44%), arthralgia (42%), and contusion (42%). Atrial fibrillation of all grades occurred in 5% of patients, with grade ≥3 occurring in 2%. Second primary malignancies excluding non-melanoma skin tumours occurred in 11% of patients. Serious AEs were reported in 38% of patients.

Prof. Paolo Ghia (Università Vita-Salute San Raffaele, Milan, Italy) presented the global, randomised, open-label phase 3 ASCEND trial, in which patients with R/R CLL were given either 100 mg twice daily of acalabrutinib (n=155) with the comparator arm being the investigator’s choice of rituximab with either idelalisib or bendamustine (n=155). The median number of prior therapies was 1 (range 1-8) in the acalabrutinib arm and 2 (range 1-10) with the investigator’s choice arm.The trial met the primary endpoint of independent review committee-assessed progression-free survival at the interim analysis and was recently published [3]. In the final analysis of the trial, approximately 82% of patients with R/R CLL who were treated with acalabrutinib were alive and free from disease progression at 18 months compared with 48% of those who were given rituximab combined with idelalisib or bendamustine.

In total, 16% of patients on acalabrutinib, 56% of patients on idelalisib, and 17% of patients on bendamustine discontinued treatment due to AEs. AEs of clinical interest for acalabrutinib versus controls included atrial fibrillation, major haemorrhage, infections, and second primary tumours excluding non-melanoma skin cancer. Serious AEs of any grade occurred in 33% of patients receiving acalabrutinib, 56% of those receiving idelalisib, and 26% of those receiving bendamustine.

Collectively, these data argue for a reasonable safety profile for acalabrutinib, for any line of CLL treatment, and initial efficacy data is promising.

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   1. Byrd JC, et al. Acalabrutinib in treatment-naïve chronic lymphocytic leukemia: mature results from phase 2 study demonstrating durable remissions and long-term tolerability. EHA25 Virtual, 11-21 June 2020, Abstract S163.
   2. Ghia P, et al. Acalabrutinib vs idelalisib plus rituximab (IDR) or bendamustine plus rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): ASCEND final results. EHA25 Virtual, 11-21 June 2020, Abstract S159.
   3. Ghia P, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia [published online ahead of print, 2020 May 27]. J Clin Oncol. 2020;JCO1903355.

Posted on 9 September 202019 November 2021