Cases reported as progressive multifocal leukoencephalopathy in Ocrelizumab-treated patients with multiple sclerosis
ECTRIMS Online Library. Clifford D. 09/12/19; 279330; P970
David Clifford
David Clifford
Contributions
Abstract

Abstract: P970

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

D.B. Clifford1, A. Gass2, N. Richert3, C. Tornatore4, P. Vermersch5, R. Hughes6, H. Koendgen6, R. Gold7

1Washington University School of Medicine, St. Louis, Missouri, MO, United States, 2University Hospital Mannheim, Heidelberg, Germany, 3NeuroRx Research, Montreal, QC, Canada, 4Georgetown University Hospital, Washington DC, DC, United States, 5University of Lille, Lille, France, 6F. Hoffmann-La Roche Ltd, Basel, Switzerland, 7Ruhr-University Bochum, Faculty of Medicine, St. Josef-Hospital, Bochum, Germany

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the CNS caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised. Three multiple sclerosis (MS) disease-modifying therapies (DMTs; natalizumab, fingolimod and dimethyl fumarate) have been associated with cases of PML in the absence of other DMT administration (unconfounded cases). A risk of PML with anti-CD20 antibody therapy in MS cannot be excluded, since PML has been observed in other disease areas with anti-CD20 therapies. Ocrelizumab (OCR), a humanised monoclonal antibody that selectively depletes CD20+ B cells, is approved for the treatment of relapsing and primary progressive MS. As of April 2019, approximately 100,000 patients with MS have initiated OCR therapy globally (clinical trials and post-marketing experience).
Objectives: To describe the characteristics of PML cases reported in OCR-treated patients with MS.
Methods: We evaluated the narrative descriptions and reviewed the DICOM images from MRIs obtained prior to and after initiating OCR therapy (where available) for PML cases in OCR-treated patients through April 2019. Further follow-up data are being collected to evaluate clinical outcomes and management of PML in these patients.
Results: Seven PML cases, assessed as carry-over and definite (according to AAN diagnostic criteria), during OCR treatment have been reported: six had previously received treatment with natalizumab (all anti-JCV antibody-positive in serum prior to PML diagnosis; index range: 1.06-4.11; treatment duration: 24-74 months) and one had received fingolimod (anti-JCV antibody-negative; treatment duration: 47 months). Time from OCR treatment to definite PML diagnosis was 16 days for fingolimod and ranged from 18 to 92 days for natalizumab. All patients had new and/or worsening clinical symptoms and/or MRI changes prior to receiving OCR and were non-fatal at the point of last update.
Conclusions: The PML cases reported to date with OCR have been associated and are confounded with prior MS treatment (natalizumab, fingolimod), usually referred to as cases of carry-over PML. No unconfounded cases of PML with OCR have been reported. Physicians must remain vigilant for signs of PML when switching from therapies associated with PML to a new MS therapy. If PML is suspected, dosing with OCR must be withheld. Observations to date do not suggest that this setting results in an increased proportion of fatal outcomes.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK.
D. B. Clifford has received support for consulting and serving on Data Safety Monitoring Boards or Adjudication Committees for Amgen, Dr. Reddy's, Takeda, Roche, Mitsubishi Tanabe, Genentech, Shire, Biogen, Atara Biotherapeutics, Inhibikase, GSK, Wave Life Sciences, and EMD Serono; payments for legal consultations from Sal Indomenico PC and Shevlin Smith; support for a lecture by Limits, LTD; royalties from Wolters Kluwer and Up-to-Date, and is supported by NIH grants AI069439, NS10719801, MH10734504, AG0617904, AG05326702 and UL1TR00234502.
A. Gass has received honoraria for lecturing and advisory boards from Novartis, Biogen, Merck Serono, Sanofi-Genzyme and Roche.
N. Richert is an Employee of NeuroRx research.
C. Tornatore has received either research support, acted as a consultant or is on the speaker board of the following: Genentech, Biogen, Serono, Sanofi, and MAPI
P. Vermersch has received honoraria and consulting fees from Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi Genzyme, Servier, Teva and Almirall, and research support from Bayer, Biogen, Merck, Novartis, Roche and Sanofi Genzyme.
R. Hughes is an employee and shareholder of F. Hoffmann-La Roche Ltd.
H. Koendgen is an employee and shareholder of F. Hoffmann-La Roche Ltd.
R. Gold has received speaker's and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Celgene, Genzyme, Janssen, Merck Serono, Novartis, Roche, Stendhal, Talecris, TEVA; and is a shareholder of Merck Serono and Roche; departmental grant support has been received from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis, and TEVA.

Abstract: P970

Type: Poster Sessions

Abstract Category: Therapy - Immunomodulation/Immunosuppression

D.B. Clifford1, A. Gass2, N. Richert3, C. Tornatore4, P. Vermersch5, R. Hughes6, H. Koendgen6, R. Gold7

1Washington University School of Medicine, St. Louis, Missouri, MO, United States, 2University Hospital Mannheim, Heidelberg, Germany, 3NeuroRx Research, Montreal, QC, Canada, 4Georgetown University Hospital, Washington DC, DC, United States, 5University of Lille, Lille, France, 6F. Hoffmann-La Roche Ltd, Basel, Switzerland, 7Ruhr-University Bochum, Faculty of Medicine, St. Josef-Hospital, Bochum, Germany

Background: Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the CNS caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised. Three multiple sclerosis (MS) disease-modifying therapies (DMTs; natalizumab, fingolimod and dimethyl fumarate) have been associated with cases of PML in the absence of other DMT administration (unconfounded cases). A risk of PML with anti-CD20 antibody therapy in MS cannot be excluded, since PML has been observed in other disease areas with anti-CD20 therapies. Ocrelizumab (OCR), a humanised monoclonal antibody that selectively depletes CD20+ B cells, is approved for the treatment of relapsing and primary progressive MS. As of April 2019, approximately 100,000 patients with MS have initiated OCR therapy globally (clinical trials and post-marketing experience).
Objectives: To describe the characteristics of PML cases reported in OCR-treated patients with MS.
Methods: We evaluated the narrative descriptions and reviewed the DICOM images from MRIs obtained prior to and after initiating OCR therapy (where available) for PML cases in OCR-treated patients through April 2019. Further follow-up data are being collected to evaluate clinical outcomes and management of PML in these patients.
Results: Seven PML cases, assessed as carry-over and definite (according to AAN diagnostic criteria), during OCR treatment have been reported: six had previously received treatment with natalizumab (all anti-JCV antibody-positive in serum prior to PML diagnosis; index range: 1.06-4.11; treatment duration: 24-74 months) and one had received fingolimod (anti-JCV antibody-negative; treatment duration: 47 months). Time from OCR treatment to definite PML diagnosis was 16 days for fingolimod and ranged from 18 to 92 days for natalizumab. All patients had new and/or worsening clinical symptoms and/or MRI changes prior to receiving OCR and were non-fatal at the point of last update.
Conclusions: The PML cases reported to date with OCR have been associated and are confounded with prior MS treatment (natalizumab, fingolimod), usually referred to as cases of carry-over PML. No unconfounded cases of PML with OCR have been reported. Physicians must remain vigilant for signs of PML when switching from therapies associated with PML to a new MS therapy. If PML is suspected, dosing with OCR must be withheld. Observations to date do not suggest that this setting results in an increased proportion of fatal outcomes.
Disclosure: Sponsored by F. Hoffmann-La Roche Ltd; writing and editorial assistance was provided by Articulate Science, UK.
D. B. Clifford has received support for consulting and serving on Data Safety Monitoring Boards or Adjudication Committees for Amgen, Dr. Reddy's, Takeda, Roche, Mitsubishi Tanabe, Genentech, Shire, Biogen, Atara Biotherapeutics, Inhibikase, GSK, Wave Life Sciences, and EMD Serono; payments for legal consultations from Sal Indomenico PC and Shevlin Smith; support for a lecture by Limits, LTD; royalties from Wolters Kluwer and Up-to-Date, and is supported by NIH grants AI069439, NS10719801, MH10734504, AG0617904, AG05326702 and UL1TR00234502.
A. Gass has received honoraria for lecturing and advisory boards from Novartis, Biogen, Merck Serono, Sanofi-Genzyme and Roche.
N. Richert is an Employee of NeuroRx research.
C. Tornatore has received either research support, acted as a consultant or is on the speaker board of the following: Genentech, Biogen, Serono, Sanofi, and MAPI
P. Vermersch has received honoraria and consulting fees from Bayer, Biogen, Celgene, MedDay, Merck, Novartis, Roche, Sanofi Genzyme, Servier, Teva and Almirall, and research support from Bayer, Biogen, Merck, Novartis, Roche and Sanofi Genzyme.
R. Hughes is an employee and shareholder of F. Hoffmann-La Roche Ltd.
H. Koendgen is an employee and shareholder of F. Hoffmann-La Roche Ltd.
R. Gold has received speaker's and board honoraria from Baxter, Bayer Schering, Biogen Idec, CLB Behring, Celgene, Genzyme, Janssen, Merck Serono, Novartis, Roche, Stendhal, Talecris, TEVA; and is a shareholder of Merck Serono and Roche; departmental grant support has been received from Bayer Schering, BiogenIdec, Genzyme, Merck Serono, Novartis, and TEVA.

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