Re-evaluating the incidence of natalizumab-associated progressive multifocal leukoencephalopathy.

Objective: To estimate the prospective risk of developing PML during therapy with natalizumab in JCV-seropositive patients.

Methods: We analyzed postmarketing data about the incidence of PML on natalizumab, and quantified the risk by either applying the Kaplan-Meier estimator or, where this was not possible due to the unavailability of the respective raw data, using formulae yielding very similar figures.

Results: In JCV-seropositive patients with prior immunosuppressant (IS) use, the incidence of PML during months 25-48 of natalizumab therapy is about 19.5 per thousand. Without prior IS use, the incidence during months 25-48 is approximately 7.4 per thousand, and during months 49-72, it is approximately 10.8 per thousand. If one additionally assumes that the JCV index is in the range 0.9-1.5, then the incidence during months 49-72 is around 6.2 per thousand in comparison to 17.0 per thousand when the JCV index exceeds 1.5.

Conclusions: Biogen's statistics concerning the risk of PML on natalizumab, while in principle helpful, underestimate the true incidence systematically and significantly; realistic estimates of the longterm risk of PML are nearly double those previously published, with some patient groups carrying a risk that is almost nine times higher. Fortunately, a refined risk-stratification algorithm with the incorporation of such markers as L-selectin and CSF lipid-specific IgM bands has the potential to make natalizumab a considerably safer drug.