Infectious complications in CLL/SLL patients receiving Bruton's Tyrosine Kinase inhibitors – systematic review and meta-analysis of randomized controlled trials

Abstract The development of Bruton Tyrosine Kinase inhibitors (BTKis) has revolutionized the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, increased infection rates have been reported in patients receiving BTKis in multiple clinical trials. This study aimed to evaluate the risk of infections associated with BTKis compared to other therapeutic regimens in CLL/SLL patients. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted. We included trials comparing BTKi-containing regimens (e.g., BTKi alone or combined with anti-CD20 or venetoclax) to other therapeutic regimens, as well as studies comparing different BTKis or BTKi combinations. Primary outcomes were the risk of any infection and grade 3–4 infections. Secondary outcomes included pneumonia, sepsis, septic shock, COVID-19, fungal infections, fatal infections, bacteremia, and febrile neutropenia. Pooled risk ratios (RR) with 95% confidence intervals (CIs) were estimated using fixed or random effects models based on heterogeneity. Eighteen trials encompassing 8,324 patients were included. BTKi-containing regimens, either as monotherapy or combined with anti-CD20 or venetoclax, were not associated with a significantly increased risk of any infection compared to other regimens BTKi + anti-CD20 or venetoclax: RR 0.93 (95% CI: 0.79–1.09, I 2 = 46%), 3 trials; BTKi monotherapy: RR 1.12 (95% CI: 0.94–1.34, I 2 = 73%), 3 trials. Similarly, BTKi monotherapy was not associated with an increased risk of grade 3–4 infections RR 1.05 (95% CI: 0.76–1.44, I 2 = 61%), 5 trials. The risk of sepsis was not significantly increased with BTKi regimens BTKi + anti-CD20: RR 0.48 (95% CI: 0.12–1.84, I 2 = 69%), 4 trials; BTKi monotherapy: RR 0.50 (95% CI: 0.25–1.01, I 2 = 0%), 5 trials. However, pneumonia risk was increased in the BTKi + anti-CD20 vs other regimens, RR 2.18; 95% CI 1.29–3.70; I 2 = 3%, 4 trials. The risk of febrile neutropenia was reduced in trials comparing BTKi-containing regimens to other therapies. BTKi-containing regimens were not associated with an increased risk of overall infections or grade 3–4 infections compared to other regimens. However, an elevated risk of pneumonia was observed with BTKi combinations, highlighting the need for careful consideration when selecting treatment regimens for CLL/SLL patients.