Real-World Data: Acalabrutinib Safety Profile Superior in CLL/SLL

A new real-world analysis of patients with chronic lymphocytic leukemia (CLL) and small cell lymphocytic leukemia (SLL) indicates that the risk of adverse events is lower with a second-generation Bruton tyrosine kinase (BTK) inhibitor, compared to a first-generation counterpart.

The results are important because despite the effectiveness of BTK inhibitors, a significant number of patients discontinue their treatment due to adverse events.¹ A study published last year based on nearly 700 Chinese patients who took BTK inhibitors, found that 30.9% of patients who discontinued therapy did so due to toxicity, and 9% of those patients stopped due to cardiac arrhythmia.² 

In that study, two-thirds of patients were taking the first-generation BTK inhibitor ibrutinib (Imbruvica). In the new report, which was published in the Annals of Hematology, corresponding author Rafael Amorim Belo Nunes, MD, PhD, of Brazil’s Hospital Alemão Oswaldo Cruz, and colleagues, wanted to see what real-world data said about the risk of adverse events for patients taking ibrutinib compared to patients taking the second-generation BTK inhibitor acalabrutinib (Calquence).¹

They noted that acalabrutinib and the more-recently approved zanubrutinib (Brukinsa) have greater selectivity than ibrutinib, raising the expectation that they will have better tolerability.

The investigators used medical records from a multinational network of more than 100 healthcare organizations around the world in order to identify adult patients with CLL or SLL who were treated with ibrutinib or acalabrutinib within the last decade. They then tracked the 3-year cumulative incidences of several adverse events, including atrial flutter or fibrillation, other arrhythmias, heart failure, ischemic stroke or peripheral embolism, acute coronary syndrome, bleeding, and sepsis.

The authors created cohorts of 2,107 patients who took acalabrutinib and the same number who took ibrutinib. The patients were matched so each group had similar demographics and comorbidity histories. For instance, 44.7% of patients in the acalabrutinib group and 42.1% of patients in the ibrutinib group had hypertension at baseline, and 13.1% of patients in the acalabrutinib group and 11.9% of patients in the ibrutinib group were overweight or obese.

Nunes and colleagues found patients taking acalabrutinib had a significantly lower risk of 3 adverse events, and that the difference in incidence in the other adverse event categories did not reach statistical significance.

Specifically, the 3-year incidence of atrial fibrillation or flutter was 7.11% in the acalabrutinib group and 14.78% in the ibrutinib group (HR 0.68; 95% CI, 0.55-0.84). The 3-year incidence of new-onset hypertension was 16.29% in the acalabrutinib group and 27.8% in the ibrutinib group (HR 0.81; 95% CI, 0.66-0.98). In the case of sepsis, the incidence was 6.49% among patients taking acalabrutinib, versus 11.37% among patients receiving ibrutinib (HR 0.77; 95% CI, 0.60-0.98).

The investigators noted that despite the lower incidence of atrial fibrillation/flutter in the acalabrutinib group, incidences of ischemic stroke and peripheral arterial embolization were similar—and low—in both groups.

“A possible explanation for these findings is that BTK inhibitors can interfere with platelet aggregation and coagulation through signaling pathways such as GP1b and GPIV platelet receptors as well as with factor VIII and von Willebrand factor, leading to a less thrombophilic environment in this setting,” they wrote.

Nunes and colleagues added that, contrary to previous studies, they did not find that ibrutinib led to higher incidences of bleeding compared to acalabrutinib.

The authors noted that their study was subject to limitations, including that it was retrospective and that it was based on diagnostic codes that involved the subjective opinions of providers.

Despite those factors, they said their real-world evidence suggests that, “patients with CLL or SLL treated with acalabrutinib have a better cardiovascular and non-cardiovascular safety profile than those treated with ibrutinib.”

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
2. Yan Y, Lv R, Wang T, et al. Real-world treatment patterns, discontinuation and clinical outcomes in patients with B-cell lymphoproliferative diseases treated with BTK inhibitors in China. Front Immunol. 2023;14:1184395. doi:10.3389/fimmu.2023.1184395