Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA's adverse event reporting system

Objective: To identify and summarize FDA's Adverse Event Reporting System (FAERS) cases of progressive multifocal leukoencephalopathy (PML) associated with biological and targeted cancer therapies (BTCT) that were approved between 2009 and 2015. Methods: FAERS was searched using each BTCT name as primary or secondary suspect drug and the adverse reaction of PML. Among BTCTs with >2 case reports of PML, proportional reporting ratios (PRR) and 95% confidence intervals (Cl) were calculated. Results: Among 49 new BTCTs, 82 cases of PML were found for 16 drugs. Significant PRR signals were found among 7 (14.6%) BTCTs including: brentuximab (24.5, Cl:14.8-40.6), ofatumumab (16.3, Cl:9.6-27.4), alemtuzumab (9.9, Cl:6.0-16.4), obinutuzumab (7.4, Cl:2.4-22.8), ibrutinib (5.6 Cl:3.0-10.5), belimumab (4.5 Cl:2.3-9.0), and idelalisib (4.1, Cl:1.3-12.6). Among the 82 cases with significant signals, confirmation of the diagnosis of PML using objective criteria was found in 56% of the cases. A limitation of FAERS data is that missing data are common. Conclusions: When using BTCTs, clinicians and patients consider the risk of PML versus the therapeutic benefit, particularly when used in combination with other drugs which may cause PML, such as rituximab. It is important to recognize that PML may occur in some conditions, such as chronic lymphocytic leukemia, regardless of drug therapy.