Julian Borchardt1, Joseph R Berger2. 1. An Independent Statistical Consultant in Germany. Electronic address: julian.borchardt@gmx.de. 2. The Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
Abstract
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.
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 CSFlipid-specific IgM bands has the potential to make natalizumab a considerably safer drug.
Authors: Martijn T Wijburg; Iris Kleerekooper; Birgit I Lissenberg-Witte; Marlieke de Vos; Clemens Warnke; Bernard M J Uitdehaag; Frederik Barkhof; Joep Killestein; Mike P Wattjes Journal: JAMA Neurol Date: 2018-07-01 Impact factor: 18.302
Authors: Rachel A Sabol; Virginia Noxon; Oliver Sartor; Joseph R Berger; Zaina Qureshi; Dennis W Raisch; LeAnn B Norris; Paul R Yarnold; Peter Georgantopoulos; William J Hrushesky; Laura Bobolts; Paul Ray; Akida Lebby; Robert C Kane; Charles L Bennett Journal: Cancer Med Date: 2017-06-20 Impact factor: 4.452