Analysis of Fungal Infections in CLL Patients with BTK Inhibitors from 12 Randomized Clinical Trials

Background: Approval of BTK inhibitors (BTKi), including ibrutinib (ibr), has provided an effective non-chemotherapeutic option for patients (pts) with chronic lymphocytic leukemia (CLL). Although generally well tolerated, a series of adverse events (AEs), including fungal infections, has been a force to be reckoned with. Pts with CLL were reported to have a higher risk of fungal infections with BTKi compared to other B-cell malignancies, as a result of off-target effect on adaptive immune system. Here, we performed a cumulative analysis of the incidence of fungal infections from 12 randomized clinical trials of CLL pts with BTKi.

Methods: Incidence of all fungal infections and severe fungal infections were analyzed using pooled data from AE reports from 12 randomized clinical trials, including ibr, acalabrutinib (aca) and zanubrutinib (zanu). Arms containing BTKi were pooled as groups distinguished by different drugs, while pts with standard-of-care therapies were pooled as a separate group (comparator group). Events were identified by comprehensive data extraction of terms from AE reports in supplementary materials. Severe fungal infections are defined as grade 3 or higher AEs based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Additionally, data from ClinicalTrials.gov were also utilized as a supplementary source. Subset analyses were also conducted according to treatment lines of pts when using BTKi.

Results: In total, 4664 pts were included for analysis, comprising 1816 pts receiving ibr (cumulative exposure, 3287.0 patient-years), 779 pts receiving aca (1878.2 patent-years), 680 pts receiving zanu (1457.2 patient-years) and 1600 pts receiving standard-of-care therapies (comparator group) (1215.80 patient-years). 93 pts (1.99%) experience AEs related to fungal infections, including 62 pts (1.33%) with severe fungal infection. Based on exposure-adjusted event rates per 100 patient-years, ibr group (1.369; [95% CI 1.012-1.844]) and aca group (1.331 [95% CI 0.882-1.989]) has a slightly elevated incidence of infections compared to pts without BTKi (1.152; [95% CI 0.656-1.975]) while zanu (0.618; [95% CI 0.302-1.214]) reduced the incidence. This change persisted when comparing severe infections between comparator group (0.576; [95% CI 0.253-1.239]) and BTK inhibitor groups (ibr: 0.882; [95% CI 0.602-1.282], aca:1.012 [95% CI 0.628-1.607], zanu:0.480; [95% CI 0.211-1.034]). Considering treatment lines, incidence of fungal infections and severe fungal infections is markedly elevated in previously-treated pts (ibr: all infections 1.618 [95% CI 1.147-2.269], severe infections: 1.156 [95% CI 0.766-1.728]) (aca: all infections 1.997 [95% CI 1.272-3.090], severe infections 1.426 [95% CI 0.840-2.398]) (zanu: all infections 1.219 [95% CI 0.568-2.487], severe infections 0.914 [95% CI 0.372-2.084) compared to treatment-naïve pts (ibr: all infections 0.889 [95% CI 0.452-1.686], severe infections 0.356 [95% CI 0.114-0.974]) (aca: all infections 0.484 [95% CI 0.155-1.324], severe infections 0.484 [95% CI 0.155-1.324]) (zanu: all infections 0.125 [95% CI 0.007-0.807], severe infections 0.125 [95% CI 0.007-0.807]). Besides, a total of 4 fatal cases (0.051 per 100 patients-years) were reported, 3 occurred in pts with ibr (2 cases due to Pneumocystis Jirovecii pneumonia and 1 case due to unspecified fungal infections) and 1 occurred in pts with zanu due to cryptococcal pneumonia. All fatal cases occurred in previously treated pts.

Conclusions: This pooled analysis of 12 BTKi clinical trials demonstrates that risk of fungal infections and severe fungal infections with ibr and aca is slightly higher than pts without BTKi while zanu group reduced the risk based on exposure-adjusted analysis. Previously treated pts are highly more prone to developing fungal infections and severe fungal infections compared to treatment-naïve pts after using BTKi. Among 3 drugs, incidence of fungal infections and severe infections in aca group was comparable to that in ibr group, but in previously treated pts risk was markedly higher in aca group than ibr group. Mortality of fungal infections is relatively low, with the majority of fatalities resulting from lung infections. Additional analyses with large cohorts will continue to further characterize the relationship between fungal infections and BTKi.

No relevant conflicts of interest to declare.