Acalabrutinib Approved in Japan for Relapsed/Refractory CLL

January 25, 2021 - The Japanese Ministry of Health, Labour and Welfare approved the BTK inhibitor acalabrutinib for use in adult patients with relapsed/refractory chronic lymphocytic leukemia, including small lymphocytic lymphoma

The Japanese Ministry of Health, Labour and Welfare approved the BTK inhibitor acalabrutinib (Calquence) for use in adult patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including small lymphocytic lymphoma (SLL).1

The regulatory decision was based on findings from the pivotal phase 3 ASCEND trial (NCT02970318), as well as findings from a phase 1 trial that examined the agent specifically in Japanese patients. In these efforts, single-agent acalabrutinib was found to result in a statistically significant improvement in progression-free survival (PFS) compared with standard-of-care treatment comprised of rituximab (Rituxan) plus physician’s choice of either idelalisib (Zydelig; RI) or bendamustine (BR).2

Specifically, findings from ASCEND revealed that the median PFS with the BTK inhibitor had not been reached versus 16.5 months with rituximab plus idelalisib or bendamustine, translating to a 69% reduction in the risk of disease progression or death (HR, 0.31; 95% CI, 0.20-0.49; P <.0001).2

“Today’s news marks great progress for patients with CLL in Japan. As the ASCEND trial showed, [acalabrutinib] provides a significant improvement in PFS compared with current standard therapies,” Dai Maruyama, MD, PhD, director of the Department of Hematology and Oncology at the Cancer Institute Hospital of Japanese Foundation for Cancer Research, stated in a press release. “Treatment with a safe and tolerable regimen remains paramount for these patients who often require ongoing therapy for many years.”

The international, multicenter, open-label ASCEND trial enrolled a total of 310 patients with previously treated CLL. Participant were randomized in a 1:1 fashion to receive acalabrutinib monotherapy at a twice-daily dose of 100 mg until progressive disease or unacceptable toxicity (n = 155) or physician’s choice of RI (n = 119) or BR (n = 36). Rituximab was administered intravenously (IV) at 375 mg/m2 or 500 mg/m2 for up to 8 treatment cycles, while idelalisib was given at a twice-daily dose of 150 mg and IV bendamustine was delivered at 70 mg/m2 for 6 treatment cycles.

The median age of patients enrolled to the trial was 67 years and just under half, or 42%, had Rai stage III/IV disease. Moreover, 16% of participants had del(17p). In the acalabrutinib arm, the median number of previous therapies received was 1 (range, 1-8) versus 2 in the RI or BR arm (range, 1-10). The most common prior treatment received were alkylating drugs (85%), followed by CD20-directed strategies (80%), and purine analogues (69%).

Patients were stratified based on ECOG performance status (0-1 vs 2), del(17p) status (yes vs no), and number of previous lines of treatment received (1-2 vs 4 or more). Notably, crossover from the IR/BR arms to the acalabrutinib arm was allowed once a patient experienced disease progression.

The primary end point of the trial was PFS via independent review committee (IRC) assessment. Secondary end points comprised PFS per physician evaluation, overall response rate (ORR) per both IRC and physician assessment, as well as duration of response (DOR). Investigators also evaluated time to next treatment, overall survival (OS), and patient-reported outcomes.

Final results from ASCEND presented during the 2020 ASCO Virtual Scientific Program showed that the BTK inhibitor significantly extended PFS compared with IR/BR in patients with high-risk features such as those with del(17p)/TP53 mutations and unmutated immunoglobulin heavy chain variable.3 Specifically, the estimated 18-month PFS rate with acalabrutinib monotherapy was 82% versus just 48% with either of the standard approaches. The estimated 18-month OS rates were 88% in both treatment arms, with the median OS not reached with either approach.

Moreover, the ORRs between the treatment arms proved to be comparable. The DOR with the BTK inhibitor, however, was longer than that observed with IR or BR. The median DOR in the investigative arm had not yet been reached compared with 18.0 months in the control arm.

Twenty-nine percent of patients who received the BTK inhibitor experienced serious toxicities compared with 56% of those who received IR and 26% of those who were given BR. Ten percent of patients in the investigative arm died compared with 14% of those who received BR and 11% of those given IR. The estimated DOR rate at 18 months with acalabrutinib was 85.4% versus 49.4% with the control.

Regarding safety, toxicity was the most frequently reported reason for treatment discontinuation in all arms. Notably, more participants enrolled to the IR arm discontinued compared with the BTK inhibitor and BR arms. In the investigative arm, the most common any-grade toxicities comprised headache, neutropenia, diarrhea, and upper-respiratory tract infection; most of these effects were found to be grade 1 or 2 in severity.

Acalabrutinib was approved by the FDA in November 2019 for the treatment of adult patients with CLL or SLL based on data from the phase 3 ELEVATE-TN (NCT02475681) and ASCEND trials. A year later, in November 2020, the BTK inhibitor also gained approval by the European Union for patients with CLL based on the same trials.


  1. Calquence approved in Japan for the treatment of relapsed or refractory chronic lymphocytic leukemia. News release. AstraZeneca. January 25, 2021. Accessed January 25, 2021.
  2. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355
  3. Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed/refractory chronic lymphocytic leukemia: ASCEND final results. J Clin Oncol. 2020;38(suppl 15):8015. 10.1200/JCO.2020.38.15_suppl.8015