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PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study

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Abstract

Background

Natalizumab (NTZ) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients.

Materials and methods

The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as “lack of efficacy”, “progressive multifocal leukoencephalopathy (PML) risk” or “other”.

Results

Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stop** therapy (HR 2.94, 95% CI 1.22–4.75; p = 0.02; HR 1.36, 95% CI 1.18–5.41; p = 0.04).

Conclusions

Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.

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Availability of data and material

Dataset is available under reasonable request to the corresponding author.

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Acknowledgements

Carlo Avolio, Roberto Balgera, Paola Banfi, Paolo Bellantonio, Placido Bramanti, Lorenzo Capone, Guido Cavalletti, Luca Chiveri, Raffaella Clerici, Marinella Clerico, Francesco Corea, Vincenzo Dattola, Francesca De Robertis, Giancarlo Di Battista, Simonetta Galgani, Maurizia Gatto, Maria Grazia Grasso, Lorenzo Lo Russo, Francesco Ottavio Logullo, Renato Mantegazza, Alessandra Protti, Monica Rezzonico, Mariarosa Rottoli, Marco Salvetti, Elio Scarpini, Leonardo Sinisi, Maddalena Sparaco, Daniele Spitaleri, Tiziana Tassinari, Simone Tonietti, Paola Valentino, Franco Valzania, Simonetta Venturi.

Funding

This study was not funded.

Author information

Authors and Affiliations

  1. Department “GF. Ingrassia”, Section of Neurosciences, University of Catania, via S. Sofia 78, 95129, Catania, Italy

    Clara G. Chisari & Francesco Patti

  2. Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Giancarlo Comi

  3. Neurology Unit and MS Center, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Massimo Filippi

  4. Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, Neurophysiology Unit, IRCCS San Raffaele Institute, Milan, Italy

    Massimo Filippi

  5. Vita-Salute San Raffaele University, Milan, Italy

    Massimo Filippi

  6. Department of Basic Medical Sciences, Neurosciences and Sense Organs, School of Medicine, University of Bari Aldo Moro, Bari, Italy

    Damiano Paolicelli & Pietro Iaffaldano

  7. Multiple Sclerosis Center, ASST Della Valle Olona, Gallarate Hospital, Gallarate (VA), Italy

    Mauro Zaffaroni

  8. Multiple Sclerosis Clinical Care and Research Centre, Department of Neuroscience, Reproductive Science and Odontostomatology, Multiple Sclerosis Centre, University Federico II, Naples, Italy

    Vincenzo Brescia Morra

  9. Multiple Sclerosis Centre Binaghi Hospital, ATS Sardegna-University of Cagliari, Cagliari, Italy

    Eleonora Cocco

  10. Multiple Sclerosis Clinical and Research Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy

    Girolama Alessandra Marfia

  11. Unit of Neurology, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

    Girolama Alessandra Marfia

  12. Foundation Institute “G. Giglio”, MS Center, Cefalù-Palermo, Italy

    Luigi Maria Grimaldi

  13. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy

    Matilde Inglese

  14. San Martino Hospital-IRCCS, Genoa, Italy

    Matilde Inglese

  15. Second Division of Neurology, Department of Advanced Medical and Surgical Sciences, MRI Research Center SUN-FISM, AOU-University of Campania “Luigi Vanvitelli”, Naples, Italy

    Simona Bonavita

  16. IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy

    Alessandra Lugaresi

  17. Department of Biomedic and Neuromotor Sciences, University of Bologna, Bologna, Italy

    Alessandra Lugaresi

  18. Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy

    Giuseppe Salemi

  19. Multiple Sclerosis Center, Neurology Clinic, Policlinico SS Annunziata, University of Chieti-Pescara, Chieti, Italy

    Giovanna De Luca

  20. Department of Neurology, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy

    Salvatore Cottone

  21. Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy

    Antonella Conte

  22. IRCCS Neuromed Pozzili, Pozzili (IS), Italy

    Antonella Conte

  23. Department of Neuroscience, UO of Neurology, AOU Policlinico OB, Modena, Italy

    Patrizia Sola

  24. Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy

    Umberto Aguglia

  25. Great Metropolitan Hospital, Reggio Calabria, Italy

    Umberto Aguglia

  26. Neurological Clinic and Multiple Sclerosis Center, Cardarelli Hospital, Naples, Italy

    Giorgia Teresa Maniscalco

  27. Department of Neurology, Multiple Sclerosis Centre, San Camillo-Forlanini Hospital, Rome, Italy

    Claudio Gasperini

  28. Neuroimmunology Center for Multiple Sclerosis, Cerebrovascular Department, ASST Crema, Crema, Italy

    Maria Teresa Ferrò

  29. Multiple Sclerosis Center, Fidenza-S. Secondo Hospital, Fidenza, Parma, Italy

    Ilaria Pesci

  30. Division Neurological Rehabilitation, Department of NEUROFARBA, University of Florence, Florence, Italy

    Maria Pia Amato

  31. Department of Neurorehabilitation, IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy

    Maria Pia Amato

  32. IRCCS Don C. Gnocchi Foundation ONLUS, Milan, Italy

    Marco Rovaris

  33. Rehabilitation Department, CRRF Mons L Novarese, Moncrivello VC, Italy

    Claudio Solaro

  34. Multiple Sclerosis Center, II Division of Neurology, Department of Clinical and Experimental Medicine, Second University of Naples, Naples, Italy

    Giacomo Lus

  35. Multiple Sclerosis Center, Neurology Unit, ARNAS Garibaldi, Catania, Italy

    Davide Maimone

  36. IRCCS Mondino Foundation, Pavia, Italy

    Roberto Bergamaschi

  37. Neurosciences Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy

    Franco Granella

  38. Department of Neurology, Regina Montis Regalis Hospital, Mondovì, Italy

    Alessia Di Sapio

  39. Neurologia & CRESM (Centro Riferimento Regionale SM), AOU San Luigi Gonzaga, Orbassano, Italy

    Antonio Bertolotto

  40. Demyelinating Disease Center, Department of Neurology, San Salvatore Hospital, L’Aquila, Italy

    Rocco Totaro

  41. Unit of Neurology, Cà Foncello Hospital, Treviso, Italy

    Marika Vianello

  42. Multiple Sclerosis Center, Department of Neuroscience and Mental Health, City of Health and Science University Hospital of Turin, Torino, Italy

    Paola Cavalla

  43. Unit of Neurology and Neurorehabilitation, IRCCS Neuromed, Pozzilli, IS, Italy

    Paolo Bellantonio

  44. Coreserach Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy

    Vito Lepore

  45. Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy

    Vito Lepore

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  1. Clara G. Chisari
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Consortia

the Italian MS Register Study Group.

  • Carlo Avolio
  • , Roberto Balgera
  • , Paola Banfi
  • , Paolo Bellantonio
  • , Placido Bramanti
  • , Lorenzo Capone
  • , Guido Cavalletti
  • , Luca Chiveri
  • , Raffaella Clerici
  • , Marinella Clerico
  • , Francesco Corea
  • , Vincenzo Dattola
  • , Francesca De Robertis
  • , Giancarlo Di Battista
  • , Simonetta Galgani
  • , Maurizia Gatto
  • , Maria Grazia Grasso
  • , Lorenzo Lo Russo
  • , Francesco Ottavio Logullo
  • , Renato Mantegazza
  • , Alessandra Protti
  • , Monica Rezzonico
  • , Mariarosa Rottoli
  • , Marco Salvetti
  • , Elio Scarpini
  • , Leonardo Sinisi
  • , Maddalena Sparaco
  • , Daniele Spitaleri
  • , Tiziana Tassinari
  • , Simone Tonietti
  • , Paola Valentino
  • , Franco Valzania
  •  & Simonetta Venturi

Contributions

CGC: contributed to the data collection, performed the statistical analysis and interpreted data, drafted the work and revised it critically for important intellectual content, approved the final version of the paper. GC: contributed to the data collection, approved the final version of the paper. MF contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. DP contributed to the design of the work and to the data collection, approved the final version of the paper. PI: contributed to the data collection, approved the final version of the paper. MZ: contributed to the data collection, approved the final version of the paper. VBM: contributed to the data collection, approved the final version of the paper. EC: contributed to the data collection, approved the final version of the paper. GAM: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. LMG: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. MI: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. SB: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. AL contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. Giuseppe Salemi: contributed to the data collection, approved the final version of the paper. GDL: contributed to the data collection, approved the final version of the paper. SC: contributed to the data collection, approved the final version of the paper. AC: contributed to the data collection, approved the final version of the paper. PS: contributed to the data collection, approved the final version of the paper. UA: contributed to the data collection, approved the final version of the paper. GTM: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. CG: contributed to the data collection, approved the final version of the paper. MTF: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. IP: contributed to the data collection, approved the final version of the paper. MPA: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. MR: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. CS: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. GL: contributed to the data collection, approved the final version of the paper. DM: contributed to the data collection, approved the final version of the paper. RB: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. FG: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. ADS: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. AB: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. RT: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. MV: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. PC: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. PB: contributed to the data collection, revised it critically for important intellectual content, approved the final version of the paper. VL: contributed to the study design, approved the final version of the paper. FP: contributed to the data collection, performed the statistical analysis and interpreted data, drafted the work and revised it critically for important intellectual content, approved the final version of the paper.

Corresponding author

Correspondence to Francesco Patti.

Ethics declarations

Conflicts of interest

Clara Grazia Chisari has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Giancarlo Comi has served as a Biogen, Merck, Mylan, Novartis, Roche, Sanofi/Genzyme and Teva Advisory Board Member. He received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Massimo Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Merck-Serono, Novartis, Teva Pharmaceutical Industries, Roche, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). Damiano Paolicelli has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Pietro Iaffaldano has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Mauro Zaffaroni has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Vincenzo Brescia Morra: has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Eleonora Cocco has no conflict of interest. Girolama Alessandra Marfia: has served as an advisory board member and received speaker honoraria, congress, travel and accommodation expense compensations from Merck, Teva, Mylan, Bayer, Novartis, Roche, Almirall, Biogen and Sanofi Genzyme. Luigi Maria Grimaldi: has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Matilde Inglese: received honoraria or consultation fees from Roche, Biogen, Merck-Serono, Novartis, Genzyme and research grants from NIH, NMSS, FISM, and Teva Neuroscience. Simona Bonavita: Speaker and/or advisory board fee, and7or travel grant from Novartis, Teva, Sanofi-Genzyme, Roche, Biogen-Idec, Merck-Serono. Alessandra Lugaresi has served as a Biogen, Merck, Mylan, Novartis, Roche, Sanofi/ Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis. Paola Cavalla has served as an advisory board member for Almirall, Biogen, Merck-Serono, Sanofi-Genzyme, Roche, Teva; she has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Giuseppe Salemi: has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Giovanna De Luca has no conflict of interest. Salvatore Cottone: has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Antonella Conte: declares no conflict of interest. Patrizia Sola declares no conflict of interest. Umberto Aguglia has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Giorgia Teresa Maniscalco has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Claudio Gasperini declares no conflict of interest. Maria Teresa Ferrò: has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Ilaria Pesci declares no conflict of interest. Maria Pia Amato has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Marco Rovaris: received travel grants and fees for consulting and public speaking from Almirall, Biogen, Genzyme-Sanofi, Merck Serono, Mylan and Novartis. Claudio Solaro has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Giacomo Lus declares no conflict of interest. Davide Maimone declares no conflict of interest. Roberto Bergamaschi: declares no conflict of interest. Franco Granella has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Alessia Di Sapio received personal compensation for speaking and consulting by Biogen and Novartis and has been reimbursed by Merck, Biogen, Genzyme and Roche for attending several conferences. Antonio Bertolotto has received grants to attend scientific congresses or speaker honoraria from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Rocco Totaro: declares no conflict of interest. Marika Vianello declares no conflict of interest. Paolo Bellantonio declares no conflict of interest. Vito Lepore declares no conflict of interest. Francesco Patti has received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he also served as advisory board member the following companies: Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA; he was also funded by Pfizer and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Genzyme, and TEVA.

Ethical approval

This study protocol was approved by the local Ethical Committee of the University of Catania (Catania 1) and by the Ethical Committee of the participating centers.

Informed consent

Each patient participating to the study signed an Informed Consent specifically designed to participate to the Italian MS Register.

Additional information

The members of the Italian MS Register Study Group are listed in acknowledgements.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 15 KB)

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Chisari, C.G., Comi, G., Filippi, M. et al. PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an Italian multicenter retrospective study. J Neurol 269, 933–944 (2022). https://doi.org/10.1007/s00415-021-10676-6

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  • DOI: https://doi.org/10.1007/s00415-021-10676-6

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