Data from a systematic review highlight a significantly higher risk of any bleeding and major bleeding in patients with treatment-naïve chronic lymphocytic leukemia treated with a second generation Bruton tyrosine kinase inhibitors.
Treatment with second-generation Bruton tyrosine kinase (BTK) inhibitors acalabrutinib (Calquence) and zanubrutinib (Brukinsa) produced no significant differences in all-cause mortality and cardiovascular mortality among patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). However, investigators noted that BTK inhibitors significantly reduced cardiovascular mortality in those with relapsed/refractory disease and led to a significantly higher risk of bleeding in patients with treatment-naïve disease, according to findings from a systematic review and meta-analysis.
Investigators highlighted no significant differences in all-cause mortality with second-generation BTK inhibitors in the relapsed/refractory group (odds ratio [OR], 0.83; 95% CI, 0.62-1.10; I2 = 0.0%) and the treatment naïve group (OR, 0.84; 95% CI, 0.52-1.36; I2 = 33.0%). The OR for all-cause mortality across all patients was 0.83 (95% CI, 0.65-1.06; I2 = 0.0%).
Patients with relapsed/refractory CLL experienced a significant decrease in cardiovascular events leading to mortality (OR, 0.16; 95% CI, 0.03-0.78; I2 = 0.0%). Additionally, the OR for cardiovascular mortality was reported to be 1.02 (95% CI, 0.06-16.44; I2 = 67.0%) in the treatment naïve population and 0.36 (95% CI, 0.08-1.65; I2 = 45.0%) among all patients.
Treatment with BTK inhibitors yielded a significantly higher risk of any bleeding (OR, 6.18; 95% CI, 4.38-8.71; I2 = 0.0%) in the treatment-naïve population compared with the relapsed/refractory group (OR, 1.31; 95% CI, 0.55-3.15; I2 = 93.0%). Additionally, the risk of major bleeding appeared to be significantly increased among patients with treatment-naïve disease (OR, 2.84; 95% CI, 1.16-6.90; I2 = 0.0%) compared with those with relapsed/refractory disease (OR, 0.84; 95% CI, 0.50-1.41; I2 = 0.0%).
There were no significant differences in hypertension and stroke among the treatment-naïve and relapsed/refractory disease groups. According to the investigators, it may be necessary to conduct additional large-scale controlled trials to affirm the safety and tolerability of second-generation BTK inhibitors in this patient population.
Investigators of this meta-analysis conducted a systematic search of studies evaluating BTK inhibitors for CLL via databases including PubMed, Cochrane, Scopus, and Embase up to January 14, 2023. Phase 2 or 3 randomized clinical trials assessing acalabrutinib or zanubrutinib among patients with CLL in any clinical setting were eligible to be part of the meta-analysis. Investigators used the I2 to measure heterogeneity.
End points of the analysis included cardiovascular AEs such as bleeding, major hemorrhage, acute coronary syndrome, atrioventricular block, hypotension, atrial fibrillation, and cardiac arrest. Investigators also assessed cardiovascular AEs resulting in death and all-cause mortality. As part of a subgroup analysis, outcomes with second-generation BTK inhibitors were compared with those achieved with ibrutinib (Imbruvica).
Investigators initially retrieved a total of 1774 eligible studies following their database search. Of these studies, 5 were used as part of the meta-analysis, which included 3 evaluating patients with relapsed/refractory CLL and 2 assessing those with treatment-naïve disease.
Overall, data from 2588 patients with CLL were assessed in the meta-analysis. Of these patients, 1484 had relapsed/refractory disease, and 1104 had treatment-naïve disease.
Investigators presented these findings as part of a poster session at the 2023 Society of Hematologic Oncology (SOHO) Annual Meeting.
Proskuriakova E, Shrestha D, Jasaraj R, et al. Cardiovascular adverse events associated with second generation Bruton tyrosine kinase inhibitor therapy in patients with chronic lymphocytic leukemia: a systematic review and meta-analysis. Presented at: 2023 Society of Hematologic Oncology (SOHO). Annual Meeting; September 6-9, 2023; Houston, TX. Abstract CLL-428.