Acalabrutinib Demonstrates Improved Safety, Survival to Chemoimmunotherapy in CLL

Acalabrutinib (Calquence, AstraZeneca) in patients with chronic lymphocytic leukemia (CLL) was associated with a substantially improved safety profile, with lesser risk of mortality, bleeding events, and atrial fibrillation, according to a retrospective cohort study presented at the 2025 American Society of Clinical Oncology Annual Meeting.¹

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CLL is a cancer of the blood and bone marrow that affects lymphocytes, leading to complications such as frequent infections and fatigue. A cornerstone of the treatment landscape for CLL are Bruton tyrosine kinase (BTK) inhibitors, which have greatly improved response rates and survival outcomes. Acalabrutinib is a second-generation BTK inhibitor that received initial FDA approval in 2017 for treatment of patients with mantle cell lymphoma. Two years later in 2019, the agent was approved for CLL, supported by data from the ELEVATE-TN (NCT02475681) and ASCEND (NCT02970318) trials.^2-4

Acalabrutinib demonstrates promising potential as a targeted therapy alternative to chemoimmunotherapy for patients with CLL. In a retrospective cohort analysis, researchers leveraged the TriNetX platform to compare the safety and efficacy of acalabrutinib and chemoimmunotherapy.¹

The analysis included patient data from January 2000 through January 2025, examining outcomes for individuals diagnosed with CLL who received either acalabrutinib or chemoimmunotherapy. Patients were divided into 2 cohorts based on treatment type, clinical characteristics, and demographic data (eg, age [≥18 years], sex, race, and ethnicity). The primary outcomes measured included all-cause mortality, atrial fibrillation, hypertension, acute heart failure, ventricular arrhythmias, and bleeding events. Kaplan-Meier survival analysis was used to assess mortality risk.¹

Out of a total of 4006 patients, 847 received acalabrutinib and 3172 underwent chemoimmunotherapy. The mean age was about 70 ± 11 years in the acalabrutinib group and 69 ± 14 years in the chemoimmunotherapy group. Both groups were predominantly male, and most patients were non-Hispanic White. The median follow-up periods were about 578 and 925 days in the acalabrutinib and chemoimmunotherapy groups, respectively.¹

The analysis revealed a substantially lower risk of mortality in patients treated with acalabrutinib (relative risk [RR]: 0.407; 95% CI: 0.32–0.51; P < .0001). Cardiovascular safety outcomes also favored acalabrutinib. Atrial fibrillation occurred in fewer than 10 patients in the acalabrutinib group, translating to significantly lower odds compared with chemoimmunotherapy (odds ratio [OR]: 0.3; 95% CI: 0.16–0.58; P = .001), where 120 patients experienced the condition. Hypertension incidence was also significantly lower among patients receiving acalabrutinib, reinforcing its more favorable cardiovascular profile.¹

Bleeding events occurred less frequently in the acalabrutinib cohort. However, there were no statistically significant differences observed in the risk of acute heart failure (OR: 1.25; 95% CI: 0.61–2.57; p = 0.54) or ventricular arrhythmias (OR: 1.5; 95% CI: 0.72–3.14; p = 0.2) between the 2 treatment groups.¹

These findings underscore acalabrutinib’s potential as a safer and more effective therapeutic option for CLL. In addition to prolonging survival, the drug appears to reduce the likelihood of serious adverse events such as atrial fibrillation and bleeding, which are notable concerns with traditional chemoimmunotherapy regimens.¹

“The data highlight acalabrutinib’s favorable safety profile, particularly in reducing cardiovascular complications and bleeding risks,” the authors noted. “Given the statistically significant survival benefit, clinicians may consider incorporating acalabrutinib as a preferred treatment approach for appropriate patients with CLL.”¹

REFERENCES

1. Qadeer A, Aslam R, Khan A, et al. Differential cardiotoxicity of acalabrutinib versus chemoimmunotherapy in chronic lymphocytic leukemia: A retrospective cohort study from 2000-2025 using TriNetX database. 2025 American Society of Clinical Oncology Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL. Abstract e19022

2. Gerlach A. Zanubrutinib Outperforms Acalabrutinib in Adjusted Head-to-Head Analysis. Pharmacy Times. July 16, 2025. Accessed August 14, 2025. https://www.pharmacytimes.com/view/zanubrutinib-outperforms-acalabrutinib-in-adjusted-head-to-head-analysis

3. Calquence FDA approval history. Drugs.com. Updated January 18, 2025. Accessed August 14, 2025. https://www.drugs.com/history/calquence.html

4. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed August 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll