Incidence of pneumonia among bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia: a systematic review and meta-analysis of clinical trials.

Bruton tyrosine kinase inhibitors (BTKi) are utilized in the front-line setting as well as for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). However, there are some uncertainties regarding the risk of infections, especially pneumonia, from different BTKi with varied immunomodulatory effects on the innate and adaptive immune system. The newer second-generation BTKi, acalabrutinib and zanubrutinib, have reduced off-target effects compared to ibrutinib. We identified clinical trials from MEDLINE, Embase, and CENTRAL databases from the inception to 30 June 2023 and the number of cases with any grade and grade ≥ 3 pneumonia, pneumocystis pneumonia (PJP), and other fungal pneumonia, along with the total number of patients in the arms with BTKi monotherapy were extracted. The meta-analysis was performed using the inverse variance method and the random-effects model. After two rounds of review, 18 clinical trials containing 20 arms of BTKi monotherapy were eligible for the meta-analysis. The pooled incidences of any grade and grade ≥ 3 pneumonia in patients with CLL on BTKi therapy were 13% and 8%, respectively. There were no differences in the incidences of any grade (p = 0.61) or grade ≥ 3 pneumonia (p = 0.30) among patients treated with different BTKi. However, the pooled incidences of any grade and grade ≥ 3 pneumonia were greater in R/R CLL patients compared to those who were treatment-naïve (15% vs 7%, p < 0.01 and 10% vs 5%, p = 0.04, respectively). The pooled incidences of PJP and other fungal pneumonia were 1% (I² = 10%) and 1% (I² = 0%), respectively. Our study showed no significant differences in the incidence of pneumonia of any grade or grade ≥ 3 among patients treated with second-generation BTKi or first-generation BTKi. The risk of pneumonia may not be a factor in choosing among BTKi. Of note, the incidence of pneumonia was higher in R/R CLL patients on BTKi therapy when compared to treatment-naïve CLL. Fungal pneumonia, including PJP, is uncommon in CLL, and the subgroup analyses were not able to distinguish any differences among different BTKi.