Disproportionality analysis of drug-associated progressive multifocal leukoencephalopathy: roles of underlying diseases and immunomodulatory therapies in FAERS

Background: Progressive multifocal leukoencephalopathy (PML), a rare and often fatal JC virus-mediated disease, is a significant concern in immunocompromised patients. Objective: Following READUS-PV guidelines, this study evaluated disproportionality signals for PML associated with specific drugs and underlying diseases using the FDA Adverse Event Reporting System (FAERS). Methods: We identified PML cases in FAERS (2004 Q1-2024 Q4) and excluded those associated with HIV/AIDS. For drugs with ≥3 PML reports, disproportionality was assessed using the reporting odds ratio (ROR) and proportional reporting ratio (PRR), reported with 95% confidence intervals and χ² statistics, respectively. Subgroup analyses were conducted by age, sex, reporting region, and patient outcome. We also characterized the spectrum of underlying diseases and time to onset (TTO). Results: We analyzed 6,864 PML reports; in a sensitivity analysis excluding cases with TTO ≤60 days, 6,258 reports remained. Fifty-four drugs showed significant signals in primary analysis with the exception of acalabrutinib in the analysis restricted to 6,258 cases, including established high-risk agents and potential novel associations. Notably, we observed signals with four monoclonal antibodies (daratumumab, elotuzumab, epcoritamab, and isatuximab); isatuximab had no previous mentions in regulatory labels or published literature to our knowledge. Among established agents, natalizumab had the highest number of reports (n=1,848; ROR 40.7), and rituximab also showed a strong signal (n=1,296; ROR 41.8). PML was most frequently reported in multiple sclerosis (32.28%) and B-cell non-Hodgkin lymphomas (9.44%). TTO varied by agent; natalizumab showed the longest median TTO (44.0 months; 95% CI: 41.8-46.7). Median TTO for antineoplastic drugs (13.6 months; 95% CI: 11.5-15.9) was significantly shorter than for non-antineoplastic drugs (42.4 months; 95% CI: 39.7-44.1). Conclusions: These findings reinforce established and emerging PML reporting signals with immunomodulatory therapies and support heightened pharmacovigilance-particularly for novel monoclonal antibodies used in hematologic malignancies.