“Beating the bushes” to identify previously unreported cases of a rare and potentially fatal adverse drug reaction: Comparison of HIV-negative rituximab-associated progressive multifocal leucoencephalopathy (PML) cases obtained by the Research on Adverse Drug Events and Report (RADAR), the FDA, the manufacturer, and a literature review

Abstract

6604 Background: PML is a rare and usually fatal viral reactivation syndrome. As of December 2008, notifications from the FDA and rituximab (R) manufacturers described 26 patients with R-associated PML. Potential risk factors for PML include chemotherapy, corticosteroids, and HIV-infection. The FDA and the manufacturer requested that clinicians report information on all potential cases of R-associated PML. In an independent pharmacovigilance effort, RADAR queried clinicians at academic lymphoma referral centers regarding possible unreported cases of R-associated PML. Methods: RADAR surveyed clinical lymphoma experts at 13 major academic centers and identified 21 previously unreported cases of R-associated PML. Quality of reports is compared to published case reports (n=15) and reports to the FDA and manufacturer of R (n= 20). Duplicate reports were identified based on age, sex, and underlying illness. The search period was from the first FDA approval granted for R in 1997 to December 31, 2008. Results: In this series, the case-fatality rate of R-associated PML was 90%. The estimated incidence is 1 PML case per 4,700 R-treated NHL patients (based on the number of cases in this report, manufacturer estimates of 1,560,000 total global R exposures, and an estimate of six R doses per patient). Conclusions: Clinicians at major academic referral centers assist independent pharmacovigilance efforts in part provided that the requests for information are brief (<20 minutes), patients and providers are assured confidentiality, and safety data is disseminated collaboratively as peer-reviewed abstracts and manuscripts. [Table: see text] No significant financial relationships to disclose.