(170) Pulmonary Related Adverse Events Associated with Bruton's Tyrosine Kinase Inhibitor: A Disproportionality Analysis in a Spontaneous Reporting Database

Publication Number: 501

Background: Bruton's tyrosine kinase inhibitors (BTKIs) are used to treat B cell leukemias and lymphomas, but their association with pulmonary-related adverse events is not well defined.

Objectives: To detect possible safety signals of BTKI associated pulmonary-related Adverse events through disproportionality analysis in the FDA Adverse Event Reporting System (FAERS) Database.

Methods: The case/non-case retrospective disproportionality analysis was performed in a publicly available FAERS database using OpenVigil 2.1(2014Q1- 2021Q3). The drugs included for analysis were Acalabrutinib, Ibrutinib, and Zanubrutinib. Proportional reporting ratio (PRR) and Reporting odds ratio (ROR) was used as the data mining algorithm for analysis. All the preferred terms in the category of system organ classification as per MedDRA-v24 falling under "Respiratory, thoracic and mediastinal disorders" "Infection and infestation" (related to the respiratory system) having 50 unique events were included in the study. Value of ROR- 1.96SE>1 and PRR>2 with an associated X2 value of 4 or more were considered the threshold for a positive signal.

Results: The FAERS database identified a total of 26,856 events related to BTKIs (1153 for Acalabrutinib, 25,632 for Ibrutinib, and 137 for Zanubrutinib), out of which pulmonary-related AEs were 79(6.8%), 2726(10.7%), and 15(10.94%) for Acalabrutinib, Ibrutinib, and Zanubrutinib respectively. Signal strength for Pneumonitis [PRR=7.5(Chi-square=38.6),ROR=7.5], Tachypnoea [PRR=6.4(13.3),ROR=6.4], and Pleural effusion [PRR=5.9(64.7),ROR=5.9] was found to be greater than other events for Acalabrutinib. Ibrutinib associated Cryptococcal pneumonia [PRR=20.2(258.5),ROR=20.2],Hemothorax[PRR=17.5(888.5),ROR=17.5], and Aspergillus infection [PRR=15.7(1412.8),ROR=15.8] were detected, whereas Pneumonia [PRR=5.6(33.9), ROR=5.9] and Cough [PRR=3.6(7),ROR=3.7] were predominantly reported for Zanubrutinib. Pneumonia (n=1028) was a common adverse event for all three drugs out of the total, whereas adverse events like Pneumonitis(n=98), Pulmonary edema(n=150), and Pleural effusion(n=407) were associated with Acalabrutinib and Ibrutinib.

Conclusions: On analysis, the data identified signals for pulmonary toxicities associated with the use of BTKIs, but more research with a superior epidemiological study design of a defined population is required to corroborate these findings.