Acalabrutinib vs Ibrutinib: Real-World Insights Into Safety Differences for Patients With CLL

A recent real-world study comparing Bruton tyrosine kinase (BTK) inhibitors for treating chronic lymphocytic leukemia (CLL) and small cell lymphocytic lymphoma (SLL) has found that the second-generation drug acalabrutinib offers a safer adverse effect profile than the first-generation ibrutinib. The study, published in the Annals of Hematology, looked at the incidence of cardiovascular and noncardiovascular adverse events over a 3-year period.¹

The study looked at 4214 patients using data from the TriNetX network, which includes over 100 health care organizations worldwide. A total of 2107 patients were included in each group after propensity score matching to balance baseline characteristics such as age, sex, race, and comorbidities.

A calabrutinib may be a safer option than ibrutinib for CLL, offering a lower risk of serious cardiovascular and infection-related adverse events. | Image Credit: © Pana Studio - stock.adobe.com

The study's results showed a significant difference in the incidence of atrial fibrillation or flutter. During the 3-year follow-up period, 7.1% of patients treated with acalabrutinib experienced these events compared with 14.7% of those treated with ibrutinib (HR, 0.68; 95% CI, 0.55-0.84), indicating a 32% lower risk for patients on acalabrutinib. The study also found that 16.3% of patients on acalabrutinib developed new-onset hypertension compared with 27.7% on ibrutinib (HR, 0.81; 95% CI 0.66-0.98).

Despite these differences, the study noted no significant variance between acalabrutinib and ibrutinib concerning other cardiovascular events, such as ischemic stroke with an incidence of 2.5% vs 2.7% (HR, 1.41; 95% CI, 0.954-2.09), heart failure ​with 6.6% vs 10.4% (HR, 0.88; 95% CI, 0.69-1.11) and acute coronary syndrome with 4.1% vs 4.11% (HR, 1.37, 95% CI, 0.99-1.88), respectively.

The study also highlighted differences in noncardiovascular adverse events, particularly the incidence of sepsis. "An interesting finding in our study was a lower incidence of sepsis in patients in the acalabrutinib than in the ibrutinib group," the authors note. Sepsis was diagnosed in 6.5% of patients receiving acalabrutinib vs 11.3% of those on ibrutinib (HR, 0.77; 95% CI, 0.60-0.98). This is particularly important given the high incidence of infections and sepsis in this population.

In contrast, the rates of bleeding events, which included gastrointestinal and intracranial hemorrhages, did not show a significant difference between the acalabrutinib and ibrutinib groups. The study found that 3.5% of acalabrutinib patients and 5.1% of ibrutinib patients experienced bleeding (HR, 1.019; 95% CI, 0.73=1.41), indicating that both drugs present a similar risk. "The mechanisms behind this adverse effect involve platelet dysfunction as well as coagulation pathway disturbances related to the on-target and off-target actions of BTK inhibitors," the authors added.

The researchers also note “the incidences of the study cardiovascular and non-cardiovascular outcomes, such as atrial fibrillation, new-onset hypertension, and sepsis, observed in acalabrutinib and ibrutinib groups were higher than those observed in the general population. This suggests that both drugs influence these adverse events, although acalabrutinib had a better safety profile." These results align with previous studies suggesting that second-generation BTK inhibitors like acalabrutinib, which have greater selectivity, may lead to fewer off-target effects​.^2-4 While the mechanisms behind these adverse events are currently unclear, the authors add, "Still, the hypothesis that they could be related to inhibiting off-target pathways leads to the search for next-generation BTK inhibitors."

References:

1. Nunes RAB, Avezum Á, de Oliveira Marques M, Baiocchi OCCG, Bachour P. Three-year cardiovascular and non-cardiovascular adverse events in patients with chronic lymphocytic leukemia or small cell lymphocytic lymphoma treated with Bruton tyrosine kinase inhibitors acalabrutinib or ibrutinib: a real-world analysis. Ann Hematol. Published online August 17, 2024. doi:10.1007/s00277-024-05921-7

• Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210
• Htut TW, Han MM, Thein KZ. Acalabrutinib-related cardiac toxicities in patients with chronic lymphocytic leukemia: a meta-analysis of randomized controlled trials. J Immunother Precis Oncol. 2021;5(2):43-47. doi:10.36401/JIPO-21-12
• Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210