Acalabrutinib in Chinese Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: 24-Month Efficacy and Safety Results from an Open-Label, Multicenter Phase 1/2 Trial
Authors: Yang Shenmiao , Huang Haiwen , Zhou Keshu , Zhao Xielan , Han Yanqiu , Li Lindong , Wang Yujie , Liu Xiaofeng , Li Jianyong 
Published: December 2024

Background: Chronic lymphocytic leukemia (CLL) is an incurable, relapsing disease with an increasing incidence in East Asia reported in approximately 0.3/100,000 individuals in China. Acalabrutinib (acala) is a highly selective Bruton tyrosine kinase inhibitor approved in the US, Europe, and China for treatment of CLL. Pivotal studies of acala had limited inclusion of Asian populations. In the first phase 1/2 trial (NCT03932331) in Chinese patients (pts) with relapsed/refractory (R/R) CLL, acala demonstrated high response rates and acceptable tolerability at follow-up durations of 6 months (Yang S et al. HemaSphere. 2023;7(S3):3716) and 12 months (Yang S et al. Blood. 2023;142:6537-8). Here, we present 24-mo results from the final analysis of this trial.
Methods: Adults (≥18 years) with active CLL and Eastern Cooperative Oncology Group performance status ≤2 who received ≥1 prior systemic therapy for CLL were enrolled to receive acala 100 mg twice daily in 28-day cycles until disease progression or treatment discontinuation due to adverse events (AEs) presenting substantial clinical risk. The primary endpoint was overall response rate (ORR) per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria as assessed by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS) as assessed by BICR; ORR, DOR, and PFS as assessed by investigators (INV); overall survival (OS); and AEs.
Results: A total of 60 pts from China received acala (median age 62 y; 31.7% female; 20.0% with del(17p) or TP53 mutation; 51.7% with unmutated IGHV; 71.7%, 23.3%, and 5.0% with 1, 2, or ≥3 prior lines of therapy, respectively). At the updated data cutoff of December 18, 2023, 45 pts (75.0%) were receiving acala; reasons for acala discontinuation were progressive disease (15.0%; n=9), AEs (6.7%; n=4), pt decision (1.7%; n=1), and other (1.7%; n=1). Median duration of treatment was 28.4 mo (range 0.6-40.0). BICR-assessed ORR (95% CI) was 86.7% (75.4, 94.1); no pt had complete response (CR). Median DOR by BICR was not reached (NR). At a median follow-up of 32.0 mo, median PFS by BICR was NR; the estimated 30-mo PFS rate (95% CI) was 62.3% (44.6, 75.9). When assessed by INV, ORR (95% CI) was 85.0% (73.4, 92.9) with 2 pts having CR, median DOR was NR, and median PFS was NR; the estimated 30-mo PFS rate (95% CI) was 75.8% (59.2, 86.4). Median OS was also NR; the estimated 30-mo OS rate (95% CI) was 96.7% (87.3, 99.2). AEs of any grade were reported in 59 pts (98.3%); 30 pts (50.0%) had grade ≥3 AEs, most commonly decreased neutrophil count (18.3%, n=11), COVID-19 (11.7%, n=7), pneumonia (10.0%, n=6), decreased platelet count (8.3%, n=5), and upper respiratory tract infection (6.7%, n=4). AEs leading to treatment discontinuation included COVID-19, decreased neutrophil count, paraneoplastic pemphigus, pneumonia, rectal neoplasm, and decreased white blood cell count (n=1 each). AEs leading to dose interruption were reported in 39 pts (65.0%), most commonly COVID-19 (31.7%), COVID-19 pneumonia (13.3%), and decreased neutrophil count (5.0%). Twenty-one pts (35.0%) had serious AEs; the most common were COVID-19 (10.0%), COVID-19 pneumonia (8.3%), and pneumonia (6.7%). Fatal AEs (occurring ≤30 d after last dose) were reported in 1 pt (cardiac arrest in a 73-y-old pt with multiple cardiorespiratory comorbidities on study day 34). Among events of clinical interest, neutropenia was reported in 28 pts (46.7%) and hypertension was reported in 3 pts (5.0%). No cases of atrial fibrillation/flutter, major hemorrhage, second primary malignancies, or tumor lysis syndrome were reported.
Conclusions: The 24-mo data from this study in Chinese pts with R/R CLL treated with acala demonstrated a high ORR, with durable, clinically meaningful responses. In addition, continuous treatment with acala was well tolerated with manageable toxicities; no unexpected safety observations were observed in Chinese pts with R/R CLL.