Natalizumab-PML survivors with subsequent MS treatment

Objective: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving diseasemodifying therapy (DMT). Methods: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression. Results: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up. Conclusion: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy. Neurol Neuroimmunol Neuroinflamm 2017;4:e346; doi: 10.1212/NXI.0000000000000346 GLOSSARY ARR 5 annual relapse rate; DMF 5 dimethyl fumarate; DMT 5 disease-modifying treatment; EDMUS 5 European Database for Multiple Sclerosis; IRIS 5 immune reconstitution inflammatory syndrome; Nz-PML 5 natalizumab-related progressive multifocal leukoencephalopathy; PML 5 progressive multifocal leukoencephalopathy; RR-MS 5 relapsing-remitting MS. Natalizumab (Nz) is a disease-modifying therapy (DMT) used to prevent relapses in patients with active relapsing-remitting MS (RR-MS). Progressive multifocal leukoencephalopathy (PML) has been reported as a serious adverse event affecting 1/1,000 to 1/100 Nz-treated patients with 20% of fatal issue. However, because patients treated with Nz usually experience an active form of MS, a subsequent treatment is often required after Nz discontinuation. This postNz strategy is challenging for 80% surviving patients because of the current lack of consensus on post-PML MS treatment strategy. In addition, rare cases of PML have been observed with dimethyl fumarate (DMF) and fingolimod (Fg). Few cases treated with Fg after Nz-PML have been recently reported without Nz-PML worsening. Of interest, a similar stability was reported with low dose of rituximab, with a documented follow-up period of 9 months. We report an observational multicenter retrospective cohort of 23 patients with MS surviving after Nz-PML. From the Department of Neurology (E.M., C. Louapre, C. Lubetzki, C.P.), Pitié-Salpêtrière Hospital, APHP, Paris; Department of Gerontology (J.-S.V.), Broca Hospital, APHP, Paris; Department of Neurology (D.B.), University Hospital of Toulouse; Department of Neurology (B.S.), SaintAntoine Hospital, APHP, Paris; Department of Neurology (A.F., T.M.), University Hospital of Dijon; Department of Neurology (J.d.S.), University Hospital of Strasbourg; Department of Neurology (F.T., P.C.), University Hospital of Clermont-Ferrand; Department of Neurology (B.B.), University Hospital of Rouen, France; Department of Neurology (V.D.), University Hospital of Liège, Belgium; APHM (A.R., J.P.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, Marseille; Department of Neurology (P.L.), University Hospital of Montpellier; Department of Neurology (A.T.), University Hospital of Reims, URCA Reims, and LPN EA 2027 University Paris 8, Saint-Denis; and Department of Neurology (C. Lebrun), University Hospital of Nice, France. SFSEP contributors are listed at Neurology.org/nn. Funding information and disclosures are provided at the end of the editorial. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Neurology.org/nn Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology 1 METHODS Eleven MS tertiary care centers, 10 in France and 1 in Belgium, collected data. All included patients fulfilled the following criteria: (1) RR-MS; (2) Nz-PML confirmed by detection of JC virus DNA in the CSF by PCR; (3) Nz-PML survivors, i.e., still alive after PML diagnosis and immune reconstitution inflammatory syndrome (IRIS); and (4) post-PML initiation of DMT. Patients who died before receiving DMT were then excluded. We describe the clinical and radiologic evolution after Nz-PML and IRIS including (1) disability progression—assessed by Expanded Disability Status Scale (EDSS) change between DMT initiation after PML and the end of follow-up, (2) disease activity— assessed clinically by annual relapse rate (ARR) and radiologically by the appearance of new T2 MS lesions or new gadoliniumenhanced T1 lesions on MRI over the period of follow-up, and (3) modification of PML lesions on MRI. Data collection. Data were anonymously collected through a questionnaire (sent in September 2014), which was completed by local neurologists. Data collection was stopped in February 2015. For each patient, we collected demographic data including age, sex, and clinical characteristics: age at disease onset; MS treatments before Nz with duration, efficacy and side effects; treatment by Nz with number of infusions, EDSS at onset, and after 1 year of Nz; clinical and radiologic description of PML; EDSS andMRI at PML onset and at onset of post-PML DMT; description of post-PML DMT with duration, efficacy and side effects, and delay of switch; EDSS and MRI at the end of the follow-up. The number of different post-PML MS treatments, the median, and the mean duration of each post-PML DMT were calculated. The ARR, defined as the number of relapses during the treatment period divided by the duration of the treatment, was calculated for each treatment. EDSS change was assessed from the onset of post-PML DMT and the end of the followup. All patients underwent an MRI at the onset of post-PML DMT and a second one at the end of the follow-up: the change in number and size of the lesions between PML diagnosis and post-PML DMT was visually assessed and classified as increased, decreased, or stable. Gadolinium enhancement was also reported. Standard protocol approvals, registrations, and patient consents. All patients gave oral informed consent to be included in the European Database for Multiple Sclerosis (EDMUS); therefore, no additional consent or institutional review board approval was sought. All anonymous data were gathered in the Pitié-Salpêtrière tertiary care center in Paris. Statistical analysis. General characteristics of the whole sample were analyzed using percentage and number for categorical variables and using mean and SD for numerical variables. SAMPLE ANALYSIS Clinical and demographic characteristics of the 23 included patients are summarized Table 1 General characteristics of patients with MS and Nz-PML General characteristics, mean (SD) Whole cohort (N 5 23) Age at MS onset, y 29.5 (7.6) Female, % (n) 65.2 (15) Age at PML onset, y 41.3 (7.8) Duration of MS before Nz onset, y 12.0 (5.3) No. of MS therapies before Nz onset 2.48 (1.38)