Research Summary:
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are B-cell malignancies that frequently affect older adults and often require prolonged use of Bruton tyrosine kinase inhibitor (BTKi) therapy in the relapsed or refractory (R/R) setting. Ibrutinib and acalabrutinib are both recommended BTKis for R/R CLL/SLL, but ibrutinib is associated with atrial fibrillation, hypertension (HTN), bleeding, and other cardiovascular (CV) toxicities that can compromise long-term tolerability, lead to treatment discontinuation, and increase healthcare resource use (HCRU). Randomized trial data, including ELEVATE-RR, previously showed similar progression-free survival but fewer CV events with acalabrutinib vs ibrutinib, and emerging real-world analyses further suggest a more favorable safety profile with acalabrutinib. However, the impact of CV medical events of interest (MEOIs) on HCRU in the R/R population had not been fully characterized. This retrospective, real-world study by Dranitsaris et al1 evaluated CV safety, treatment discontinuation, and HCRU associated with acalabrutinib vs ibrutinib monotherapy in patients with R/R CLL/SLL.
The analysis included patients with R/R CLL/SLL who received at least 1 prior systemic therapy and were treated with acalabrutinib or ibrutinib monotherapy. The primary endpoint was development of new or worsening HTN during BTKi therapy, defined as addition or dose escalation of an antihypertensive drug, BTKi dose modification or discontinuation attributed to elevated blood pressure, or a provider statement documenting new or worsening HTN. The key secondary endpoint was development of a CV MEOI. HCRU related to CV MEOIs included emergency department visits, hospital admissions, length of stay, specialist consultations, and CV-related procedures, such as echocardiograms, cardiac catheterizations, and cardioversions.
The analysis included 270 patients; 90 were treated with acalabrutinib and 180 with ibrutinib. Median follow-up was 26 months in the acalabrutinib group and 42 months in the ibrutinib group, for an overall median of 33 months. Dosing patterns reflected label-recommended regimens, with median starting and final daily doses of 200 mg for acalabrutinib and 420 mg for ibrutinib. Dose decreases were more frequent with ibrutinib than with acalabrutinib (31.1% vs 22.2%). Overall, 51.1% of acalabrutinib-treated patients and 27.8% of ibrutinib-treated patients remained on therapy at the end of data collection. Disease progression accounted for a similar proportion of discontinuations in both groups, whereas CV-related MEOIs and other adverse events were more frequent reasons for discontinuation with ibrutinib. The risk of treatment discontinuation due to CV MEOIs or other adverse events was approximately 2.5-fold higher with ibrutinib (odds ratio [OR]: 2.54; 95% confidence interval [CI]: 1.36–4.91; p=0.002). Median time to treatment discontinuation was 29.7 months with acalabrutinib and 24.8 months with ibrutinib.
New or worsening HTN occurred in 5 patients (5.6%) receiving acalabrutinib and 25 patients (13.9%) receiving ibrutinib. In propensity score–weighted multivariable analysis, treatment with acalabrutinib was associated with a significantly lower risk of new or worsening HTN than ibrutinib (OR: 0.27; 95% CI: 0.074–0.98; p=0.046), indicating a 73% relative risk reduction. Higher baseline systolic blood pressure modestly increased HTN risk (OR: 1.03 per mm Hg; 95% CI: 1.01–1.06; p=0.002). Other CV MEOIs, including atrial fibrillation and clinically significant bleeding, were numerically less frequent with acalabrutinib, and patients treated with ibrutinib developed CV MEOIs more rapidly. In weighted multivariable analysis with any CV MEOI as the dependent variable, acalabrutinib was associated with a numerically lower risk (OR: 0.54; 95% CI: 0.28–1.04; p=0.067). Age of at least 65 years, history of atrial fibrillation, and baseline lymphadenopathy increased the likelihood of developing a CV MEOI, with ORs of 2.32, 3.46, and 2.14, respectively.
HCRU analyses showed that patients in the ibrutinib group more frequently required angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics, and some other antihypertensive drugs, whereas use of most other supportive drugs, including beta blockers, calcium channel blockers, vasodilators, and antithrombotics, was similar between groups. Emergency department visits for CV MEOIs were infrequent in both cohorts, but hospitalizations differed meaningfully, as 18 hospital admissions for CV MEOIs occurred among 90 acalabrutinib-treated patients vs 43 among 180 ibrutinib-treated patients, corresponding to approximately 0.20 vs 0.24 admissions per patient. Total hospital days for CV MEOIs were 77 with acalabrutinib and 266 with ibrutinib, and the median length of stay per admission was 3.0 days vs 6.0 days, respectively. Specialist consultations and CV-related procedures were also more frequent in the ibrutinib cohort (10 vs 40 consultations and 10 vs 33 procedures).
Acalabrutinib was associated with a lower incidence of new or worsening HTN, fewer CV MEOIs, reduced risk of toxicity-related treatment discontinuation, and decreased HCRU compared with ibrutinib. These results supported acalabrutinib as a more tolerable BTKi option for long-term management in patients with CLL.
References
- Dranitsaris G, Peevyhouse A, Neuhalfen H, et al. A real-world study evaluating drug tolerability and health care resource use with acalabrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. J Med Econ. 2026;29(1):30–40.