Infectious Complications in CLL/SLL Patients Receiving Bruton Tyrosine Kinase Inhibitors- Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: The development of BTK inhibitors (BTKi) has revolutionized the management of chronic lymphocytic leukemia (CLL). Increased infections were observed in patients taking BTKi in several clinical trials. In a previous systematic review, infectious complications occurred in 56% of patients taking single agent ibrutinib and in 52% of those on combination therapy, with approximately one in five patients developing pneumonia. We aimed to compare the risk of infection in patients receiving BTKi with other regimens in CLL/ SLL patients.

Methods: Systematic review and meta-analysis of randomized controlled trials comparing BTKi-containing regimes in patients with CLL. We searched PubMed, the Cochrane Central Register of Controlled Trials, and conference proceedings and references until July 2024. Two reviewers (SB, GT) independently extracted data from the included trials and evaluated the quality of the methodologies. The primary outcome was the frequency of any infection related to BTKi and the frequency of grade 3-4 infection related to BTKi. Secondary outcomes included the following adverse events related to BTKi: pneumonia, sepsis, septic shock, covid-19 infection, fungal infection, fatal infection, bacteremia and neutropenic fever. For dichotomous data, risk ratios (RR) with 95% confidence intervals (CIs) were estimated and pooled

Results: Our search yielded 10 trials with a total of 5,084 patients. Most trials included cohorts that compared BTKi (with or without additional treatment such as anti-CD20) vs. another comparator (chemoimmunotherapy including anti CD20, chemotherapy alone or anti-CD20), and two included trials that compared ibrutinib to other BTKi. BTKi-containing regimens compared to other regimens, were not associated with an increased rate of infections compared to other regimens [RR, 1.03 (95% CI ; 0.95-1.13, I²=55%), random effects model, 7 trials]. Grade 3-4 infections were reported in six trials: BTKi-containing regimens were not associated with an increased rate of grade 3-4 infections compared to other regimens [RR, 1.08 (95% CI ; 0.92-1.27, I²=66%), random effects model, 6 trials]. There was no difference between the study groups in the risk of sepsis events [RR, 0.45 (95% CI ; 0.92-1.27, I²=66%), random effects model, 6 trials] and febrile neutropenia [RR, 0.53 (95% CI ; 0.23-1.22, I²=71%), random effects model, 8 trials]. There was no difference between the study groups in the risk of pneumonia (RR, 1.07; 95% CI ; 0.85-1.37; 7 trials) and in the risk of fungal infections (RR, 1.05; 95% CI ; 0.42-2.64; 6 trials).

Discussion: Our systematic review demonstrates that BTKi are not associated with an increased risk of infections and grade 3-4 infections when compared to other regimens (as chemo-immunotherapy) for the treatment of CLL. Therefore, with this respect they can be administered safely to this group of patients that is prone a- priori to infectious complications

Gurion:AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Medison: Consultancy, Honoraria; Lilly: Consultancy, Honoraria. Shacham Abulafia:GSK: Consultancy; Megapharm: Consultancy; Novrtis: Consultancy. Raanani:GSK: Consultancy; Lilly: Consultancy; AstraZenecca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy; Pfizer: Consultancy, Honoraria; Novrtis: Consultancy, Honoraria. Gafter-Gvili:Medison: Consultancy; Neopharm: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Bayer: Research Funding; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.