Bruton tyrosine kinase inhibitors (BTKis) have transformed the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenstrom macroglobulinemia [1–4]. Despite their favorable efficacy and tolerability, BTK inhibition also affects innate and adaptive immune signaling, increasing susceptibility to bacterial, viral, and opportunistic infections [5, 6]. Infectious complications therefore remain an important cause of morbidity and mortality throughout the course of BTKi therapy.

Although infectious adverse events are routinely reported in BTKi clinical trials and observational studies, considerable variability exists in how these outcomes are defined, graded, and summarized. Studies differ in the reporting of all-grade versus grade ≥ 3 infections, follow-up duration, infection-related mortality, microbiological characterization, and antimicrobial prophylaxis, limiting meaningful comparisons of infectious risk across studies and between individual BTKi agents. Consequently, apparent differences in infection burden may reflect differences in reporting practices as much as true biological variation.

We therefore systematically reviewed published clinical studies of BTKis in patients with B-cell malignancies to characterize current reporting of infectious outcomes and identify methodological limitations that may influence interpretation of infection-related safety data.

A systematic literature search of PubMed and Embase was performed to identify English-language clinical studies published between January 2013 and July 2025 evaluating covalent BTKi therapy in patients with B-cell malignancies. Study selection followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) principles (Fig. 1). Eligible studies included prospective clinical trials and observational cohort studies reporting infectious outcomes in patients receiving ibrutinib, acalabrutinib, zanubrutinib, orelabrutinib, or tirabrutinib. The noncovalent BTKi pirtobrutinib was outside the scope of this review. Reviews, case reports, conference abstracts, duplicate publications, pharmacokinetic-only studies, non-human studies, studies not involving hematologic malignancies, non-primary analyses, and studies without extractable infectious outcome data were excluded.

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Figure 1. PRISMA flow diagram of study selection. Flow diagram showing identification, screening, eligibility assessment, and inclusion of studies evaluating infectious outcomes among patients with B-cell malignancies receiving covalent Bruton tyrosine kinase inhibitors (BTKis). PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Two investigators (MK and OC) independently screened eligible studies and extracted study characteristics, including study design, disease subtype, treatment setting, BTKi agent, concomitant anticancer therapy, follow-up duration, antimicrobial prophylaxis, and reported infectious outcomes. We also recorded additional therapy given with the study regimen and reported immunosuppression contributors, such as neutropenia. The extraction did not systematically capture the timing of prior anti-CD20 exposure, corticosteroid use, prior chemotherapy, transplant history, or other prior immunosuppressive exposures. Infectious events were extracted as reported by the original investigators and categorized as all-grade or grade ≥ 3 events where available. Infection-related mortality was recorded only when explicitly attributed to infection by the study investigators.

Given the substantial heterogeneity amongst studies, pooled patient-level meta-analysis was not considered appropriate. Study characteristics and infectious outcomes were therefore summarized descriptively. Continuous variables were presented as mean with standard deviation or median with interquartile range, as appropriate, and categorical variables as frequencies and percentages. Reporting frequencies were compared between phase I and phase III studies using two-sided Fisher’s exact tests because of small cell counts. These comparisons evaluated study-level reporting practices rather than patient-level infection risk; they do not measure the completeness of safety data collection or isolate an effect of the trial phase. Statistical significance was defined as a two-sided P < 0.05. Analyses were performed using IBM SPSS Statistics for Windows, Version 32.0 (IBM Corp., Armonk, NY, USA).

A total of 40 studies comprising 5,486 patients treated with BTKis for B-cell malignancies were included. Studies without extractable infectious outcome data were excluded. Among studies reporting sex (n = 4,777), 69.0% were male and 31.0% female. The median reported age across 37 studies was 66 years (range 55–80). Twenty-one (52.5%) were phase I studies, 14 (35.0%) were phase III studies, and five (12.5%) were phase II or observational studies. CLL was the most frequently studied malignancy (25 studies, 62.5%), followed by MCL (10 studies, 25.0%), with the remainder including Waldenstrom macroglobulinemia and other B-cell malignancies. Ibrutinib was the most commonly evaluated BTKi, although acalabrutinib, zanubrutinib, orelabrutinib, and tirabrutinib were also represented. Concomitant anticancer therapy was administered in 11 studies (27.5%), most commonly anti-CD20 monoclonal antibodies, whereas BTKi monotherapy was evaluated in 29 studies (72.5%). Antimicrobial prophylaxis was reported in only 11 studies (27.5%). Study characteristics are summarized in Table 1.

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Table 1. Characteristics of Included BTKi Studies

Reporting of infectious outcomes varied considerably across studies. All-grade infections were reported in 29 studies (72.5%), whereas grade ≥ 3 infections were reported in 27 studies (67.5%). Pneumonia was the most frequently reported serious infection, followed by coronavirus disease 2019 (COVID-19), aspergillosis, and sepsis. Overall, 150 deaths explicitly attributed to infection by the study investigators were reported among 5,486 patients (2.73%), although attribution methods differed substantially between studies. Detailed infectious outcomes are summarized in Table 2.

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Table 2. Reported Infectious Complications Across BTKi Studies, Stratified by Study Phase

Marked heterogeneity was observed in the reporting of infectious adverse events. Studies differed in infection definitions, severity grading, reporting thresholds, and duration of follow-up. Many publications reported only selected infectious adverse events meeting prespecified frequency criteria, while others restricted reporting to grade ≥ 3 events or serious adverse events. Microbiological characterization, antimicrobial prophylaxis, infection-related mortality, and timing of infectious complications were inconsistently reported. The frequency with which specific infection outcomes appeared in the included publications differed numerically by study phase. The absence of an outcome from a publication does not establish that the trial did not collect it or that no such events occurred. Grade ≥ 3 infections were reported in 17 of 21 phase I studies (81.0%) compared with seven of 14 phase III studies (50.0%; odds ratio (OR), 4.25; P = 0.073). Aspergillosis was reported in seven phase I studies (33.3%) compared with one phase III study (7.1%; OR, 6.50; P = 0.108). Neither difference reached statistical significance. No significant phase-based differences were observed in the reporting of pneumonia, upper respiratory tract infection, urinary tract infection, skin or soft-tissue infection, cryptococcosis, viral reactivation, infection-related mortality, or antimicrobial prophylaxis (all P > 0.05). These unadjusted comparisons should be interpreted cautiously because phase I and phase III studies differ in patient populations, follow-up, safety monitoring, adverse-event table thresholds, and publication objectives.

BTKis have transformed the management of CLL and other B-cell malignancies, providing durable disease control and improved tolerability compared with conventional chemoimmunotherapy [1, 2]. Their expanding use across treatment settings has been accompanied by increasing recognition of infectious complications resulting from both disease-associated immune dysfunction and the immunomodulatory effects of BTK inhibition [3–5]. In this systematic review of 40 studies involving 5,486 patients, we identified substantial heterogeneity in the reporting of infectious outcomes, limiting meaningful comparisons across studies and between individual BTKi agents. The included studies enrolled patients with different B-cell malignancies, including CLL, MCL, and other diseases. Differences in baseline immune dysfunction, prior treatment, concomitant therapy, and follow-up may affect observed infectious outcomes. Accordingly, differences between studies or BTKi agents cannot be attributed to the inhibitor without accounting for underlying malignancy and these other factors.

Although differences in reported infection rates likely reflect variation in patient populations and disease characteristics, methodological differences in adverse-event reporting likely contribute substantially [6–16]. Studies varied considerably in infection-related outcomes. Consequently, reported infection frequencies should be interpreted as study-level reporting patterns rather than precise estimates of patient-level risk. These inconsistencies hinder cross-trial comparisons and complicate interpretation of infectious safety profiles of BTKis. Importantly, only 11 studies (27.5%) described antimicrobial prophylaxis, despite its potential influence on observed infectious outcomes. Variation in antibacterial, antiviral, or antifungal treatments may substantially modify infection rates independent of BTKi therapy itself.

The Consolidated Standards of Reporting Trials (CONSORT) Harms guidance provides a foundation for reporting how adverse outcomes are defined, assessed, graded, and counted within each treatment group [17]. For BTKi studies, those measures would be more informative if publications also described the infection site and organism when known, timing relative to treatment, antimicrobial prophylaxis, underlying malignancy, and relevant immunosuppressive exposures. We recommend presenting these details alongside infection counts and infection-related deaths. This would give readers the clinical context needed to interpret differences across studies without assuming that variation in published reporting reflects variation in infection risk. Table 3 summarizes our recommendations for future reporting in BTKi trials.

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Table 3. Recommended Reporting of Infectious Outcomes in Future BTKi Trials

The infectious complications reported in BTKi studies should also be interpreted within the broader therapeutic landscape. Chemoimmunotherapy regimens, especially venetoclax-based therapies, remain associated with substantial rates of serious infections [8, 9]. Opportunistic infections such as invasive aspergillosis and viral reactivation syndromes, although infrequently reported, remain of particular clinical concern because of their associated morbidity and mortality in immunocompromised patients receiving BTKi therapy [18, 19]. COVID-19 also emerged as a frequently reported serious infection in contemporary studies, illustrating how changing infectious epidemiology across publication eras further complicates comparisons between BTKi trials. Rather than suggesting superiority or inferiority of one treatment approach over another, these observations underscore the importance of standardized infection reporting.

This study has several limitations. The analysis relied on study-level data extracted from published English-language studies and was therefore dependent on the completeness and quality of reporting within the original publications. Substantial heterogeneity amongst studies precluded quantitative synthesis or direct comparisons between individual BTKi agents. Combination regimens, particularly those incorporating anti-CD20 monoclonal antibodies, may independently influence infectious risk and therefore further limit comparisons across studies. Although we recorded concomitant therapy and reported immunosuppression contributors, we did not systematically capture prior anti-CD20 exposure, corticosteroid use, prior chemotherapy, transplant history, or other immunosuppressive exposures. We therefore could not account for their potential effects on infectious outcomes. Most included studies evaluated ibrutinib, limiting generalizability to newer-generation BTKis. Nevertheless, this review provides a comprehensive assessment of infectious outcome reporting across contemporary BTKi studies and highlights opportunities to improve consistency in future clinical trials. Future BTKi clinical trials should incorporate standardized reporting of infectious outcomes to improve the interpretation and comparability of infectious safety data.

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