Pneumonia emerges as the most reproducible respiratory warning sign across four BTK inhibitors

Bruton tyrosine kinase (BTK) inhibitors have transformed the treatment of chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia and other B-cell malignancies, but their respiratory safety record has been difficult to pin down. A new pharmacovigilance analysis published in Frontiers in Oncology systematically compared respiratory adverse-event reports for four of these drugs—ibrutinib, acalabrutinib, zanubrutinib and the non-covalent agent pirtobrutinib—across two independent spontaneous-reporting systems: the U.S. FDA Adverse Event Reporting System (FAERS) and the Japanese Adverse Drug Event Report database (JADER). The study, led by Pengfei Jin and colleagues at Beijing Hospital, found that pneumonia was the most reproducible clinically important respiratory signal, while other respiratory events replicated across databases only for ibrutinib.

The researchers screened preferred terms within the MedDRA system organ class Respiratory, thoracic and mediastinal disorders, using the reporting odds ratio (ROR) as the primary disproportionality measure. A signal required at least three reports and a lower 95% confidence limit of the ROR above 1. Cross-database replication demanded that the same drug–event combination meet this criterion independently in both FAERS and JADER. After data cleaning and restriction to reports in which the BTK inhibitor was the primary or suspected drug, FAERS yielded 84,217 target-drug reports with 255,010 adverse-event records, while JADER contained 1,368 reports and 2,035 adverse-event records—a stark difference in scale that shaped what the analysis could detect.

Within the formal respiratory organ class, 70 drug–event combinations met the ROR criterion in FAERS, including 47 for ibrutinib, 15 for acalabrutinib, seven for zanubrutinib and one for pirtobrutinib. JADER produced only five such signals, all involving ibrutinib. Just three combinations replicated across both databases, and all were ibrutinib-associated: epistaxis, haemothorax and pleural effusion. In FAERS, ibrutinib’s largest respiratory RORs included haemothorax at 14.96 (95% CI 12.67–17.66), pleural effusion at 5.31, epistaxis at 3.58 and pulmonary oedema at 3.14. Acalabrutinib and zanubrutinib also showed high haemothorax estimates, while pirtobrutinib’s only qualifying respiratory term in FAERS was pleural effusion (ROR 6.10, 95% CI 2.90–12.82).

The haemorrhagic component of this profile has a plausible biological basis. BTK and the related kinase TEC participate in platelet activation downstream of the collagen receptor glycoprotein VI, and their inhibition can impair collagen-dependent platelet aggregation. A 2025 platelet-function study cited in the paper found marked inhibition of collagen-induced aggregation across BTK inhibitors, supporting a class-level effect while revealing differences among agents. The authors stress, however, that this mechanism is supportive rather than causal evidence: haemothorax in patients with hematologic malignancy can also follow thrombocytopenia, anticoagulant therapy, pleural malignancy, infection, trauma or invasive procedures.

Pneumonia demanded separate treatment because MedDRA formally classifies it under Infections and infestations rather than the respiratory organ class. Evaluated with the exact preferred term Pneumonia, the event met the primary ROR criterion for all four agents in FAERS and for ibrutinib, acalabrutinib and pirtobrutinib in JADER. To test robustness, the team added three supportive algorithms—the proportional reporting ratio, the Bayesian confidence propagation neural network and the multi-item gamma Poisson shrinker. Ibrutinib and pirtobrutinib met all four algorithm criteria in FAERS, and ibrutinib, acalabrutinib and pirtobrutinib met all four in JADER. Zanubrutinib met only two of four in FAERS and none in JADER, where a single pneumonia record was available—an example of sparse data rather than evidence of no association, the authors emphasize.

The pneumonia ROR for pirtobrutinib in FAERS was comparatively high at 4.86 (95% CI 3.36–7.03), but the researchers caution against ranking drugs by such figures. Pirtobrutinib entered the market recently, initially approved in the United States for relapsed or refractory mantle cell lymphoma after at least two prior systemic therapies including a BTK inhibitor, so its users are heavily pretreated and may have substantial baseline infection susceptibility. Reporting intensity for newer agents may also differ. Clinical trial evidence points the same way: a 2025 meta-analysis of 18 trials found pooled pneumonia incidences of 13% for any-grade and 8% for grade 3 or higher events during BTK inhibitor monotherapy in CLL, with no significant difference among the three covalent agents, and higher rates in relapsed or refractory disease than in treatment-naïve patients.

Biological plausibility for infection during BTK inhibition extends beyond B cells. BTK participates in myeloid-cell function, and mechanistic experiments have shown that its inhibition impairs several neutrophil effector functions against Aspergillus fumigatus. A 2026 meta-analysis of 88 studies involving 23,737 patients estimated a pooled prevalence of proven or probable invasive fungal infection of 2.83%, with aspergillosis the most frequently reported fungal infection and corticosteroid exposure and multiple prior treatment lines among the main risk factors. The authors note, however, that the pneumonia preferred term does not specify pathogen, radiographic pattern or microbiologic confirmation, so the reported signal represents a broad clinical phenotype rather than any specific infectious etiology.

The temporal analysis added a distinct dimension. Using exact treatment-start and event-onset dates, the team fitted Weibull distributions to pneumonia time-to-onset data where sufficient reports existed. In FAERS, ibrutinib-associated pneumonia had a median time to onset of 114.5 days and an early-failure pattern (beta = 0.55, 95% CI 0.53–0.58), meaning reports clustered early in treatment. Acalabrutinib showed a similar early-failure pattern in FAERS (median 112.0 days; beta = 0.69, 95% CI 0.59–0.83). In JADER, by contrast, the corresponding estimates were compatible with random-failure patterns, though they rested on only 36 evaluable ibrutinib reports and seven acalabrutinib reports, leaving the acalabrutinib result exploratory. The authors interpret these patterns as descriptions of reported onset among analyzable cases, not population hazard functions, and they do not support a single fixed surveillance window.

The two databases proved complementary rather than interchangeable. FAERS offered vastly more records but suffered from missing age in 52.2% to 70.5% of reports and a large consumer-reporting component, whereas JADER was smaller, predominantly physician-reported, and concentrated in older patients—more than half of JADER reports for all four agents came from patients aged 75 to 89. Only 102 respiratory organ-class records were available across the four JADER cohorts, compared with 12,911 in FAERS. Zanubrutinib contributed just 54 JADER reports, all from 2025, roughly five years after its U.S. approval; pirtobrutinib contributed 83 reports from 2024–2025, about 17 months after its U.S. approval. Non-replication for these newer agents therefore reflects limited reporting opportunity and reduced statistical power, not demonstrated safety.

The study’s limitations are those inherent to spontaneous reporting: underreporting, stimulated reporting, missing data, duplicates and the absence of exposure denominators, which makes incidence, relative risk and causality impossible to estimate. Confounding by indication is particularly relevant because B-cell malignancies themselves predispose patients to infection, bleeding and pulmonary complications through hypogammaglobulinemia, cytopenias and prior immunochemotherapy. The authors frame their findings as hypothesis-generating reporting patterns rather than evidence of incidence, comparative safety ranking or causation. Practically, they support continued respiratory and infection surveillance throughout BTK inhibitor treatment, with heightened attention in the early months after initiation, and they urge that respiratory symptoms not be automatically attributed to infection, since bleeding, pneumonitis, cardiac-related oedema and malignancy remain important alternatives. Prospective studies linking pharmacovigilance data with electronic health records and microbiology will be needed to determine whether these replicated reporting patterns correspond to measurable differences in clinical risk.

Subject of Research: Respiratory adverse-event reporting signals of four BTK inhibitors in the FAERS and JADER pharmacovigilance databases

Article Title: Respiratory adverse-event signals of four Bruton tyrosine kinase inhibitors: cross-database replication and temporal characterization in FAERS and JADER

Article References: Zheng, Z., Zhao, F., Zhao, Z., & Jin, P. (2026). Respiratory adverse-event signals of four Bruton tyrosine kinase inhibitors: cross-database replication and temporal characterization in FAERS and JADER. Frontiers in Oncology, 16, Article 1998864. https://doi.org/10.3389/fonc.2026.1998864

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1998864

Keywords: BTK inhibitors, pharmacovigilance, FAERS, JADER, pneumonia, ibrutinib, acalabrutinib, zanubrutinib, pirtobrutinib, reporting odds ratio, Weibull analysis, respiratory adverse events