Natalizumab to fingolimod washout in patients at risk of PML: When good intentions yield bad outcomes Gavin Giovannoni and Robert T. Naismith Neurology 2014;82;1196-1197 Published Online before print March 7, 2014 DOI 10.1212/WNL.0000000000000296 This information is current as of March 7, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/82/14/1196.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Natalizumab to fingolimod washout in patients at risk of PML When good intentions yield bad outcomes
Gavin Giovannoni, MBBCh, PhD Robert T. Naismith, MD
Correspondence to Dr. Giovannoni: [email protected] Neurology® 2014;82:1196–1197
With more choices for multiple sclerosis (MS) disease-modifying therapies, data are urgently required to support clinical decisions regarding safe transitioning and sequencing of therapies. With more than 7 years of clinical experience, natalizumab has been confirmed as highly effective in reducing MS disease activity. However, natalizumab carries a risk of progressive multifocal leukoencephalopathy (PML),1 with more than 400 cases of natalizumabrelated PML to date.2 Because 2 of the 3 initial natalizumab-associated PML cases were on the combination natalizumab plus interferon, the concern was that combining agents led to a heightened risk of infectious complications. In these early times, uncertainty revolved around 2 points: the theoretical risk of PML if natalizumab was transiently combined with another immune-altering agent and the value of transiently “reconstituting” CNS immune surveillance by washout of natalizumab in an effort to clear theoretical subclinical JC virus within the CNS.3 The optimal length of natalizumab washout became the subject of intense consternation and debate, with no clear guidelines to inform practice. However, upon withdrawing natalizumab, resumption of disease activity was soon observed, beginning 3–4 months after the last dose of natalizumab.4–10 Postnatalizumab return of disease raised concern that the washout may harm the patient by a severe relapse with incomplete recovery. In this issue of Neurology®, Jokubaitis et al.11 provide valuable data on switching between therapies using real-world data from the MSBase register. MSBase is a collaborative database dedicated to evaluating outcomes data in MS, with 24,898 patients from 183 clinics based in 66 countries.11–14 MSBase investigators studied 536 patients who started fingolimod, 89 of whom were switched from natalizumab. The median washout period from the last infusion was 79 days, and prophylactic methylprednisolone was used for only 1 patient. Of patients transitioned to fingolimod, 20% relapsed after stopping natalizumab, with relapses equally distributed within the first, second, and third trimester after discontinuation.
Patients with a clinical relapse within the final 6 months of natalizumab treatment had an increased relative risk of a postswitch relapse of 1.6 (95% confidence interval [CI] 1.19–2.13). Stratified by washout durations, patients had a 2.12 (95% CI 1.04–4.32) relative risk of a postswitch relapse with a 2- to 4-month treatment washout compared to the no washout gap and a nonsignificant relapse risk of 1.54 (95% CI 0.92–2.59) with a washout gap of ,2 months vs no washout gap. This study by Jokubaitis et al. adds to an emerging literature suggesting that a prolonged washout does more harm than good. Rinaldi et al.15 observed 22 patients with relapsing-remitting MS who were switched from natalizumab to fingolimod. For patients who underwent a 3-month washout period, 50% had a clinical relapse or new MRI activity. A French study of 59 patients who switched from natalizumab to fingolimod reported that 50% of patients had a relapse with a washout of 3 or more months, compared to 7% of patients who had a relapse with a washout of less than 3 months.16 Novartis, the manufacturer of fingolimod, investigated the effect of different natalizumab washout periods on clinical and MRI disease activity in 142 patients switching from natalizumab to fingolimod.17 This double-blind placebo-controlled trial randomized patients with relapsing-remitting MS within 7 days after the last natalizumab infusion to 8, 12, or 16 weeks washout before starting fingolimod. Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24. Mean number of active MRI lesions from the last natalizumab infusion was markedly increased with the 16-week washout (8.2 lesions) compared to the 8- and 12-week washouts (2.1 and 1.7 lesions). More patients demonstrated freedom from gadolinium-enhancing lesions on the week 24 MRI with shorter washout periods (75% with the 8-week washout, 61.3% with the 12-week washout, and 47.5% with the 16-week washout). Annualized relapse rates after switching were higher with the 16-week washout (0.36 with 8-week washout, 0.33 with 12-week washout, 0.65 with 16-week washout).
See page 1204 From the Queen Mary University of London (G.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK; and the Department of Neurology (R.T.N.), Washington University School of Medicine, St. Louis, MO. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1196
© 2014 American Academy of Neurology
These emerging data tell a consistent story that any washout should be kept to a minimum and should be no longer than 2 months—at least with fingolimod—with some studies suggesting that no washout is optimal. The pharmacodynamics of the next agent to become clinically effective are also critical so that efficacy is achieved before natalizumab saturation of VLA4 falls to a level that allows trafficking of lymphocytes back into the CNS. Hence, recommendations based on fingolimod may not necessarily be similar for other agents, for example with dimethyl fumarate and glatiramer acetate. Glatiramer acetate may need to be started prior to stopping natalizumab, as it has a delayed onset of action. How do we apply these studies to clinical practice? Currently, the evidence-based harm of a breakthrough relapse causing sustained disability outweighs the theoretical concern that overlapping therapies will result in more PML. These studies indicate that fingolimod, when start-up is properly timed, can be effective postnatalizumab. Patients who switch from natalizumab to fingolimod with a washout period of 2 months or less have a lower risk of rebound and an even lower risk with no washout period, i.e., less than 4 weeks. While we have experience with and data on converting patients from natalizumab to fingolimod or an injectable disease-modifying therapy, we are still acquiring experience with the efficacy and safety of newer agents (i.e., dimethylfumarate, teriflunomide) and have virtually no experience with switching from natalizumab to emerging monoclonal antibodies with prolonged consequences on the immune system (i.e., alemtuzumab, daclizumab, ocrelizumab). As Jokubaitis et al. clearly demonstrate, patient registries such as MSBase, along with industry-sponsored switching studies, will be required to provide necessary data tailored to the therapeutic agent and patient scenario. AUTHOR CONTRIBUTIONS Gavin Giovannoni: drafting/revising the manuscript. Robert Naismith: drafting/revising the manuscript, study concept or design, analysis or interpretation of data.
STUDY FUNDING No targeted funding reported.
DISCLOSURE G. Giovannoni has received research grant support from Bayer-Schering Healthcare, Biogen-Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, and Sanofi-Aventis and personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from Bayer-Schering Healthcare, Biogen-Idec, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals. R.T. Naismith has received research funding from Acorda Therapeutics, the NIH, and the National MS Society; consulting honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, Genzyme Corp., Genentech, EMD Serono, Sanofi, and Questcor; and speaking
honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, and Genzyme Corp. Go to Neurology.org for full disclosures.
REFERENCES 1. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–1880. 2. Giovannoni G. Natalizumab PML update: September 2013. Available at: http://multiple-sclerosis-research.blogspot.com/ 2013/10/natalizumab-pml-update-september-2013.html. Accessed November 17, 2013. 3. Hunt D, Giovannoni G. Natalizumab-associated progressive multifocal leucoencephalopathy: a practical approach to risk profiling and monitoring. Pract Neurol 2012;12: 25–35. 4. Martinelli V, Colombo B, Dalla Costa G, et al. Recurrent disease-activity rebound in a patient with multiple sclerosis after natalizumab discontinuations for pregnancy planning. Mult Scler Epub 2013 Jun 17. 5. Schiess N, Calabresi PA. Natalizumab: bound to rebound? Neurology 2009;72:392–393. 6. Update: postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology 2008;71:780. 7. Fox RJ, Kappos L. Is natalizumab overshooting its rebound? Neurology 2008;70:1073–1074. 8. Vellinga MM, Castelijns JA, Barkhof F, Uitdehaag BM, Polman CH. Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology 2008;70:1150–1151. 9. Naismith RT, Bourdette D. Interruption of natalizumab therapy for multiple sclerosis: what are the risks? Neurology 2011;76:1854–1855. 10. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011;76: 1858–1865. 11. Jokubaitis VG, Li V, Kalincik T, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 2014;82:1204–1211. 12. Kister I, Chamot E, Cutter G, et al. Increasing age at disability milestones among MS patients in the MSBase Registry. J Neurol Sci 2012;318:94–99. 13. Hughes S, Spelman T, Trojano M, et al. The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry. J Neurol Neurosurg Psychiatry 2012;83:305–310. 14. Butzkueven H, Chapman J, Cristiano E, et al. MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis. Mult Scler 2006; 12:769–774. 15. Rinaldi F, Seppi D, Calabrese M, Perini P, Gallo P. Switching therapy from natalizumab to fingolimod in relapsingremitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler 2012;18:1640–1643. 16. de Seze J, Ongagna J-C, Collongues N, et al. Reduction of the washout time between natalizumab and fingolimod. Mult Scler 2013;19:1248–1248. 17. Kappos L, Radue EW, Comi G, et al. Disease control and safety in relapsing remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallelgroup study. Mult Scler 2013;19(S1):50. Oral Presentation 167. Neurology 82
April 8, 2014
1197
Natalizumab to fingolimod washout in patients at risk of PML: When good intentions yield bad outcomes Gavin Giovannoni and Robert T. Naismith Neurology 2014;82;1196-1197 Published Online before print March 7, 2014 DOI 10.1212/WNL.0000000000000296 This information is current as of March 7, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/14/1196.full.html
References
This article cites 14 articles, 12 of which you can access for free at: http://www.neurology.org/content/82/14/1196.full.html##ref-list1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Clinical trials Observational study (Cohort, Case control) http://www.neurology.org//cgi/collection/clinical_trials_observati onal_study_cohort_case_control Encephalitis http://www.neurology.org//cgi/collection/encephalitis Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/82/14/1196.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Natalizumab to fingolimod washout in patients at risk of PML When good intentions yield bad outcomes
Gavin Giovannoni, MBBCh, PhD Robert T. Naismith, MD
Correspondence to Dr. Giovannoni: [email protected] Neurology® 2014;82:1196–1197
With more choices for multiple sclerosis (MS) disease-modifying therapies, data are urgently required to support clinical decisions regarding safe transitioning and sequencing of therapies. With more than 7 years of clinical experience, natalizumab has been confirmed as highly effective in reducing MS disease activity. However, natalizumab carries a risk of progressive multifocal leukoencephalopathy (PML),1 with more than 400 cases of natalizumabrelated PML to date.2 Because 2 of the 3 initial natalizumab-associated PML cases were on the combination natalizumab plus interferon, the concern was that combining agents led to a heightened risk of infectious complications. In these early times, uncertainty revolved around 2 points: the theoretical risk of PML if natalizumab was transiently combined with another immune-altering agent and the value of transiently “reconstituting” CNS immune surveillance by washout of natalizumab in an effort to clear theoretical subclinical JC virus within the CNS.3 The optimal length of natalizumab washout became the subject of intense consternation and debate, with no clear guidelines to inform practice. However, upon withdrawing natalizumab, resumption of disease activity was soon observed, beginning 3–4 months after the last dose of natalizumab.4–10 Postnatalizumab return of disease raised concern that the washout may harm the patient by a severe relapse with incomplete recovery. In this issue of Neurology®, Jokubaitis et al.11 provide valuable data on switching between therapies using real-world data from the MSBase register. MSBase is a collaborative database dedicated to evaluating outcomes data in MS, with 24,898 patients from 183 clinics based in 66 countries.11–14 MSBase investigators studied 536 patients who started fingolimod, 89 of whom were switched from natalizumab. The median washout period from the last infusion was 79 days, and prophylactic methylprednisolone was used for only 1 patient. Of patients transitioned to fingolimod, 20% relapsed after stopping natalizumab, with relapses equally distributed within the first, second, and third trimester after discontinuation.
Patients with a clinical relapse within the final 6 months of natalizumab treatment had an increased relative risk of a postswitch relapse of 1.6 (95% confidence interval [CI] 1.19–2.13). Stratified by washout durations, patients had a 2.12 (95% CI 1.04–4.32) relative risk of a postswitch relapse with a 2- to 4-month treatment washout compared to the no washout gap and a nonsignificant relapse risk of 1.54 (95% CI 0.92–2.59) with a washout gap of ,2 months vs no washout gap. This study by Jokubaitis et al. adds to an emerging literature suggesting that a prolonged washout does more harm than good. Rinaldi et al.15 observed 22 patients with relapsing-remitting MS who were switched from natalizumab to fingolimod. For patients who underwent a 3-month washout period, 50% had a clinical relapse or new MRI activity. A French study of 59 patients who switched from natalizumab to fingolimod reported that 50% of patients had a relapse with a washout of 3 or more months, compared to 7% of patients who had a relapse with a washout of less than 3 months.16 Novartis, the manufacturer of fingolimod, investigated the effect of different natalizumab washout periods on clinical and MRI disease activity in 142 patients switching from natalizumab to fingolimod.17 This double-blind placebo-controlled trial randomized patients with relapsing-remitting MS within 7 days after the last natalizumab infusion to 8, 12, or 16 weeks washout before starting fingolimod. Brain MRI was performed at baseline and weeks 8, 12, 16, 20, and 24. Mean number of active MRI lesions from the last natalizumab infusion was markedly increased with the 16-week washout (8.2 lesions) compared to the 8- and 12-week washouts (2.1 and 1.7 lesions). More patients demonstrated freedom from gadolinium-enhancing lesions on the week 24 MRI with shorter washout periods (75% with the 8-week washout, 61.3% with the 12-week washout, and 47.5% with the 16-week washout). Annualized relapse rates after switching were higher with the 16-week washout (0.36 with 8-week washout, 0.33 with 12-week washout, 0.65 with 16-week washout).
See page 1204 From the Queen Mary University of London (G.G.), Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK; and the Department of Neurology (R.T.N.), Washington University School of Medicine, St. Louis, MO. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 1196
© 2014 American Academy of Neurology
These emerging data tell a consistent story that any washout should be kept to a minimum and should be no longer than 2 months—at least with fingolimod—with some studies suggesting that no washout is optimal. The pharmacodynamics of the next agent to become clinically effective are also critical so that efficacy is achieved before natalizumab saturation of VLA4 falls to a level that allows trafficking of lymphocytes back into the CNS. Hence, recommendations based on fingolimod may not necessarily be similar for other agents, for example with dimethyl fumarate and glatiramer acetate. Glatiramer acetate may need to be started prior to stopping natalizumab, as it has a delayed onset of action. How do we apply these studies to clinical practice? Currently, the evidence-based harm of a breakthrough relapse causing sustained disability outweighs the theoretical concern that overlapping therapies will result in more PML. These studies indicate that fingolimod, when start-up is properly timed, can be effective postnatalizumab. Patients who switch from natalizumab to fingolimod with a washout period of 2 months or less have a lower risk of rebound and an even lower risk with no washout period, i.e., less than 4 weeks. While we have experience with and data on converting patients from natalizumab to fingolimod or an injectable disease-modifying therapy, we are still acquiring experience with the efficacy and safety of newer agents (i.e., dimethylfumarate, teriflunomide) and have virtually no experience with switching from natalizumab to emerging monoclonal antibodies with prolonged consequences on the immune system (i.e., alemtuzumab, daclizumab, ocrelizumab). As Jokubaitis et al. clearly demonstrate, patient registries such as MSBase, along with industry-sponsored switching studies, will be required to provide necessary data tailored to the therapeutic agent and patient scenario. AUTHOR CONTRIBUTIONS Gavin Giovannoni: drafting/revising the manuscript. Robert Naismith: drafting/revising the manuscript, study concept or design, analysis or interpretation of data.
STUDY FUNDING No targeted funding reported.
DISCLOSURE G. Giovannoni has received research grant support from Bayer-Schering Healthcare, Biogen-Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva, and Sanofi-Aventis and personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from Bayer-Schering Healthcare, Biogen-Idec, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma, and Vertex Pharmaceuticals. R.T. Naismith has received research funding from Acorda Therapeutics, the NIH, and the National MS Society; consulting honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, Genzyme Corp., Genentech, EMD Serono, Sanofi, and Questcor; and speaking
honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, and Genzyme Corp. Go to Neurology.org for full disclosures.
REFERENCES 1. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–1880. 2. Giovannoni G. Natalizumab PML update: September 2013. Available at: http://multiple-sclerosis-research.blogspot.com/ 2013/10/natalizumab-pml-update-september-2013.html. Accessed November 17, 2013. 3. Hunt D, Giovannoni G. Natalizumab-associated progressive multifocal leucoencephalopathy: a practical approach to risk profiling and monitoring. Pract Neurol 2012;12: 25–35. 4. Martinelli V, Colombo B, Dalla Costa G, et al. Recurrent disease-activity rebound in a patient with multiple sclerosis after natalizumab discontinuations for pregnancy planning. Mult Scler Epub 2013 Jun 17. 5. Schiess N, Calabresi PA. Natalizumab: bound to rebound? Neurology 2009;72:392–393. 6. Update: postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology 2008;71:780. 7. Fox RJ, Kappos L. Is natalizumab overshooting its rebound? Neurology 2008;70:1073–1074. 8. Vellinga MM, Castelijns JA, Barkhof F, Uitdehaag BM, Polman CH. Postwithdrawal rebound increase in T2 lesional activity in natalizumab-treated MS patients. Neurology 2008;70:1150–1151. 9. Naismith RT, Bourdette D. Interruption of natalizumab therapy for multiple sclerosis: what are the risks? Neurology 2011;76:1854–1855. 10. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology 2011;76: 1858–1865. 11. Jokubaitis VG, Li V, Kalincik T, et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology 2014;82:1204–1211. 12. Kister I, Chamot E, Cutter G, et al. Increasing age at disability milestones among MS patients in the MSBase Registry. J Neurol Sci 2012;318:94–99. 13. Hughes S, Spelman T, Trojano M, et al. The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry. J Neurol Neurosurg Psychiatry 2012;83:305–310. 14. Butzkueven H, Chapman J, Cristiano E, et al. MSBase: an international, online registry and platform for collaborative outcomes research in multiple sclerosis. Mult Scler 2006; 12:769–774. 15. Rinaldi F, Seppi D, Calabrese M, Perini P, Gallo P. Switching therapy from natalizumab to fingolimod in relapsingremitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler 2012;18:1640–1643. 16. de Seze J, Ongagna J-C, Collongues N, et al. Reduction of the washout time between natalizumab and fingolimod. Mult Scler 2013;19:1248–1248. 17. Kappos L, Radue EW, Comi G, et al. Disease control and safety in relapsing remitting multiple sclerosis (RRMS) patients switching from natalizumab to fingolimod: a 32-week, rater- and patient-blind, randomized, parallelgroup study. Mult Scler 2013;19(S1):50. Oral Presentation 167. Neurology 82
April 8, 2014
1197
Natalizumab to fingolimod washout in patients at risk of PML: When good intentions yield bad outcomes Gavin Giovannoni and Robert T. Naismith Neurology 2014;82;1196-1197 Published Online before print March 7, 2014 DOI 10.1212/WNL.0000000000000296 This information is current as of March 7, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/14/1196.full.html
References
This article cites 14 articles, 12 of which you can access for free at: http://www.neurology.org/content/82/14/1196.full.html##ref-list1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Clinical trials Observational study (Cohort, Case control) http://www.neurology.org//cgi/collection/clinical_trials_observati onal_study_cohort_case_control Encephalitis http://www.neurology.org//cgi/collection/encephalitis Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
