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Observational Study
. 2020 Jan 1;77(1):94-102.
doi: 10.1001/jamaneurol.2019.2670.

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France

Sandra Vukusic  1   2   3 , Fabien Rollot  1   4   5   6 , Romain Casey  1   4   5   6 , Julie Pique  1   2 , Romain Marignier  1   2   7 , Guillaume Mathey  8   9 , Gilles Edan  10 , David Brassat  11 , Aurélie Ruet  12   13   14 , Jérôme De Sèze  15 , Elisabeth Maillart  16 , Hélène Zéphir  17 , Pierre Labauge  18   19 , Nathalie Derache  20 , Christine Lebrun-Frenay  21 , Thibault Moreau  22 , Sandrine Wiertlewski  23   24 , Eric Berger  25 , Xavier Moisset  26 , Audrey Rico-Lamy  27   28 , Bruno Stankoff  29   30 , Caroline Bensa  31 , Eric Thouvenot  32   33 , Olivier Heinzlef  34 , Abdullatif Al-Khedr  35 , Bertrand Bourre  36 , Mathieu Vaillant  37 , Philippe Cabre  38 , Alexis Montcuquet  39 , Abir Wahab  40 , Jean-Philippe Camdessanché  41 , Ayman Tourbah  42   43 , Anne-Marie Guennoc  44 , Karolina Hankiewicz  45 , Ivania Patry  46 , Chantal Nifle  47 , Nicolas Maubeuge  48 , Céline Labeyrie  49 , Patrick Vermersch  17 , David-Axel Laplaud  23   24 ; OFSEP Investigators
Affiliations
Observational Study

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France

Sandra Vukusic et al. JAMA Neurol. .

Abstract

Importance: Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated.

Objective: To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013.

Design, setting, and participants: This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018.

Exposures: Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation.

Main outcomes and measures: Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016).

Results: In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016.

Conclusions and relevance: The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vukusic reported receiving grants, personal fees, and nonfinancial support from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; personal fees from Celgene; grants from Medday; and personal fees from Teva outside the submitted work. Dr Marignier reported receiving consulting and lecturing fees, travel grants, and research support from Biogen, Sanofi Genzyme, Novartis, Merck Serono, Roche, Sanofi-Aventis, and Teva. Dr Mathey reported receiving nonfinancial support from Biogen outside the submitted work. Dr Edan reported receiving consultancy and lecturing fees from Bayer-Schering, Biogen, LFB, Merck, Novartis, Roche, and Sanofi; receiving research grants from Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Teva, and ARSEP Foundation; and being principal investigator in clinical studies conducted by Bayer, Biogen, Merck, Novartis, Sanofi-Aventis Teva, and 4 academic programs on multiple sclerosis sponsored by Rennes University Hospital. Dr Brassat reported receiving personal fees and travel support from Biogen, Novartis, Sanofi, and Roche; grants from Medday; personal fees from Teva; and consultancy fees from Chugai outside the submitted work. Dr Ruet reported receiving nonfinancial support from Biogen; grants and nonfinancial support from Teva and Roche; grants, personal fees, and nonfinancial support from Merck, Sanofi Genzyme, and Novartis; personal fees and nonfinancial support from Medday; grants from Bayer; and consultancy fees, speaker fees, research grants (nonpersonal), and honoraria approved by the institutions from Novartis, Biogen Idec, Genzyme, Medday, Roche, Teva, and Merck outside the submitted study. Dr De Sèze reported receiving grants, personal fees, and nonfinancial support from Biogen outside the submitted work, as well as consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, Sanofi-Aventis, and Teva Pharma. Dr Maillart reported receiving grants, personal fees, and nonfinancial support from Roche and Novartis; personal fees and nonfinancial support from Merck, Teva, Biogen, and Sanofi Genzyme; personal fees from Ad Scientiam outside the submitted work; consulting and lecturing fees from Biogen, Novartis, Genzyme, Teva Pharmaceuticals, Merck Serono, Roche, and Ad Scientiam; and research support from Novartis and Roche. Dr Zéphir reported receiving personal fees and nonfinancial support from Biogen Idec, Merck, Novartis, Sanofi, Bayer, and Genzyme, and grants, personal fees, and nonfinancial support from Teva and Roche outside the submitted work; consulting or lecture fees and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi Genzyme, Novartis, and Bayer; research support from Teva and Roche; and academic research grants from Académie de Médecine, Ligue Française Contre la Sclérose en Plaques (SEP), Fédération Hospitalo-Universitaire, and ARSEP Foundation. Dr Labauge reported receiving consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, and Teva Pharma. Dr Derache reported receiving personal fees from Biogen, Novartis, and Teva; personal fees and nonfinancial support from Sanofi Genzyme; nonfinancial support from Roche outside the submitted work; and speaker’s honoraria from Merck Serono, Biogen Idec, Sanofi Genzyme, Novartis, and Roche. Dr Lebrun-Frénay reported receiving personal fees and nonfinancial support from Biogen, Merck, Roche, Genzyme, and Novartis, as well as personal fees from Medday during the conduct of the study. Dr Moreau reported receiving personal fees from Biogen, Teva, Sanofi Genzyme, and Novartis, and grants, personal fees, and nonfinancial support from Roche and Merck Serono, as well as grants and personal fees from Medday outside the submitted work; and fees as a scientific adviser to Biogen, Medday, Novartis, Genzyme, and Sanofi. Dr Wiertlewski reported receiving consulting and lecturing fees as well as travel grants from Biogen, Genzyme, Novartis, Merck Serono, Roche, Sanofi, and Teva Pharma. Dr Berger reported receiving research support from Biogen as well as honoraria and consulting fees from Novartis, Sanofi-Aventis, Biogen, Genzyme, Roche, and Teva Pharma. Dr Moisset reported receiving personal fees from Biogen, Novartis, Teva, Sanofi Genzyme, Merck Serono, and Roche; nonfinancial support from SOS Oxygène, Pfizer, and Sanofi Pasteur MSD; grants from Ligue Française Contre la SEP; funding from Teva, Novartis, Sanofi Genzyme, Merck Serono, and Astellas; and nonfinancial support from Biogen, Sanofi Pasteur MSD, GSK, AstraZeneca, Pfizer, and Roche outside the submitted work. Dr Stankoff reported receiving personal fees from Biogen, Novartis, and Teva and grants from Merck Serono, Roche, and Genzyme outside the submitted work; consulting and lecturing fees and travel grants from Biogen Idec, Merck Serono, Novartis, and Genzyme; and unconditional research support from Merck Serono, Genzyme, and Roche. Dr Bensa reported receiving personal fees and nonfinancial support from Novartis, Biogen, and Roche and personal fees from Merck and Genzyme outside the submitted work; and consulting and lecturing fees and travel grants from Biogen, Genzyme, Novartis, Merck Serono, Roche, and Teva Pharma. Dr Thouvenot reported receiving personal fees from Actelion, Genzyme, Merck, and Teva Pharma; grants and personal fees from Roche, Novartis, and Biogen outside the submitted work; consulting and lecturing fees, travel grants, or unconditional research support from Actelion, Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharma; a patent pending for biomarkers of neurodegeneration and neuroregeneration; and academic research support from Programme Hospitalier de Recherche Clinique, and the ARSEP Foundation. Dr Heinzlef reported receiving consulting and lecturing fees from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall, and Biogen Idec, travel grants from Novartis, Teva, Genzyme, Merck Serono, and Biogen Idec; and research support from Roche, Merck, and Novartis. Dr Bourre reported serving on scientific advisory board for Biogen, Genzyme, Merck Serono, Novartis, and Roche, as well as funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Roche, and Teva. Dr Vaillant reported receiving personal fees from Novartis, Roche, and Genzyme outside the submitted work, as well as funding from Roche, Novartis, Biogen, Merck Serono, and Teva. Dr Montcuquet reported receiving nonfinancial support from Teva and personal fees and nonfinancial support from Novartis, Biogen, Roche, Merck, and Sanofi Genzyme outside the submitted work; and funding for travel from Merck Serono, Teva, Novartis, Sanofi Genzyme, and Biogen. Dr Tourbah reported receiving grants, personal fees, and nonfinancial support from Medday and Biogen; grants and personal fees from Novartis; personal fees from Sanofi Genzyme, Merck, and Teva outside the submitted work; consulting and lecturing fees, travel grants, and research support from Medday, Biogen, Sanofi Genzyme, Novartis, Merck Serono, Teva Pharma, and Roche. Dr Guennoc reported receiving personal fees from Roche and Sanofi outside the submitted work, as well as consulting or lecture fees from Biogen, Merck, Sanofi Genzyme, and Roche. Dr Patry reported receiving honoraria and consulting fees from Novartis, Genzyme, and Roche; research support from Biogen and Novartis; travel grants from Genzyme, Novartis, and Roche; grants and personal fees from Novartis, Genzyme, Biogen, and Roche outside the submitted work. Dr Nifle reported receiving personal fees from Novartis, SAS Pharma, and Genzyme during the conduct of the study; honoraria and consulting fees from Roche and Genzyme; research support from Biogen and Novartis; and travel and inscription fees for conferences from Biogen, Sanofi Genzyme, Bayer, Novartis, Teva, Roche, and Merck Serono. Dr Labeyrie reported receiving consulting and lecturing fees from Biogen, Novartis, and Genzyme. Dr Vermersch reported receiving honoraria and consulting fees from Biogen, Sanofi Genzyme, Novartis, Teva, Merck, Roche, Servier, Celgene, Medday, and Almirall, as well as research support from Biogen, Novartis, Sanofi Genzyme, Roche, and Merck. Dr Laplaud reported receiving grants from the ARSEP Foundation and Medday; personal fees from Biogen, Sanofi Genzyme, Merck, and Teva; grants and personal fees from Novartis outside the submitted work; and consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, Sanofi-Aventis, and Teva Pharma. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
MS indicates multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder; OFSEP, Observatoire Français de la Sclérose en Plaques (French MS registry); and PML, progressive multifocal leukoencephalopathy.
Figure 2.
Figure 2.. Evolution of Annual Crude Incidence Rates of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy in France Between 2007 and 2016
Figure 3.
Figure 3.. Poisson Regression Graphical Representation of the Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy (PML) Before and After 2013
Figure 4.
Figure 4.. Conditional Survival Estimates of the Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy by Treatment Duration
See this image and copyright information in PMC

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