Determinants of clinical outcomes for patients with Natalizumab-associated progressive multifocal leukoencephalopathy
ECTRIMS Online Library. McGuigan C. 09/11/19; 279397; 63
Chris McGuigan
Chris McGuigan
Contributions
Abstract

Abstract: 63

Type: Scientific Session

Abstract Category: Therapy - Risk management for disease modifying treatments

L. Kappos1, C. McGuigan2, T. Derfuss3, G. Giovannoni4, J. Oh5,6, Z. Ren7, K. McCarthy7, I. Chang7, N. Campbell7, P.-R. Ho7, L. Mason7

1Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland, 2School of Medicine and Medical Sciences, University College Dublin, St Vincent's University Hospital, Dublin, Ireland, 3Neurology Clinic and Policlinic, Departments of Medicine and Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland, 4Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 5Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada, 6Department of Neurology, Johns Hopkins University, Baltimore, MD, 7Biogen, Cambridge, MA, United States

Introduction: Natalizumab treatment for relapsing-remitting multiple sclerosis is associated with risk of progressive multifocal leukoencephalopathy (PML). Various PML treatments, such as rapid natalizumab clearance by plasma exchange (PLEX), have been adopted in clinical practice, but their impact on clinical outcomes has not been systematically evaluated.
Objectives: To investigate the impact of PLEX and patient characteristics on the outcome of natalizumab-associated PML.
Methods: Confirmed PML cases with known PLEX status as of 17 September 2018 were identified in Biogen pharmacovigilance (PV) data. The primary outcome was survival at 2 years after PML diagnosis. Cumulative survival was estimated by Kaplan-Meier analyses for patients with PLEX (PLEX+) and without PLEX (PLEX−) further stratified by JC virus log viral copy number (VCN) at diagnosis. Hazard ratios (HRs) of risks and predictors of death were based on Cox proportional hazards model for PLEX+ and PLEX− patients, adjusted for age, sex, asymptomatic PML at diagnosis, magnetic resonance imaging (MRI) presentation (widespread vs non-widespread), log VCN, and the total number of infusions.
Results: As of 17 September 2018, there were 787 confirmed natalizumab PML cases. Of these, 725 had a known PLEX status (PLEX+, 616 [85.0%]; PLEX−, 109 [15.0%]). A higher percentage of PLEX+ patients than PLEX− patients were symptomatic at diagnosis (87.8% vs 78.9%) and had a log VCN >7 (33.3% vs 17.4%). The cumulative probability of survival at 2 years post-PML diagnosis for PLEX+ vs PLEX− patients was 88.2% vs 89.3% (P=0.857) with log VCN ≤5, 73.8% vs 89.3% (P=0.097) with log VCN >5 to ≤7, and 68.2% vs 78.9% (P=0.435) with log VCN >7. Death within 2 years was less likely for patients who were asymptomatic (HR, [95% confidence interval (CI)]: 0.38 [0.17-0.81]; P=0.012), and more likely for patients aged >50 years (HR [95% CI]: 1.56 (1.09-2.24); P=0.014), with widespread MRI lesions (HR [95% CI]: 1.61 [1.14-2.27]; P=0.007) or higher log VCN (HR [95% CI]: 2.86 [1.74-4.70]; P< 0.001 with log VCN >7 vs ≤5).
Conclusions: Post-PML survival was more likely in patients who were younger, asymptomatic, had localized MRI lesions, and lower JCV VCN, reinforcing the importance of patient monitoring for early PML diagnosis. PLEX did not have a significant effect on survival. Numerically worse outcomes were observed with PLEX regardless of PML presentation, suggesting PLEX is not effective for improving post-PML outcome.
Disclosure: LK: University Hospital Basel institutional research support from steering committee, advisory board, and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, Sanofi, Santhera, Teva, Vianex; royalties for Neurostatus-UHB products; MS Center in Basel grant support from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, the Roche Research Foundations.
TD: speaker fees, research support, travel support, and/or served on advisory boards and/or steering committees of Actelion, Biogen, Celgene, GeNeuro, Sanofi Genzyme, MedDay, Merck Serono, Mitsubishi Pharma, Novartis, Roche..
CM: research grant support from Bayer, Biogen, Novartis, Sanofi Genzyme; advisory boards for Actelion, Biogen, Genzyme, Merck, Novartis; speaker's honoraria from Biogen, Genzyme, Merck, Novartis Teva.
GG: steering committees for AbbVie, Atara Bio, Biogen, Novartis, Roche, Teva; consulting fees from Biogen, Canbex, GlaxoSmithKline, Merck Serono, Novartis, Roche, Sanofi Genzyme, Synthon.
JO: grant funding from Brain Canada, the MS Society of Canada, the National MS Society; research funding support from Biogen, Sanofi Genzyme, Roche; personal compensation for consulting or speaking from Biogen, Celgene, EMD Serono, Genzyme, Novartis, Roche.
ZR, KM, IC, NC, P-RH, LM: employees of and hold stock and/or stock options in Biogen.
Biogen funded these analyses and writing support for the preparation of this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

Abstract: 63

Type: Scientific Session

Abstract Category: Therapy - Risk management for disease modifying treatments

L. Kappos1, C. McGuigan2, T. Derfuss3, G. Giovannoni4, J. Oh5,6, Z. Ren7, K. McCarthy7, I. Chang7, N. Campbell7, P.-R. Ho7, L. Mason7

1Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland, 2School of Medicine and Medical Sciences, University College Dublin, St Vincent's University Hospital, Dublin, Ireland, 3Neurology Clinic and Policlinic, Departments of Medicine and Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland, 4Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom, 5Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada, 6Department of Neurology, Johns Hopkins University, Baltimore, MD, 7Biogen, Cambridge, MA, United States

Introduction: Natalizumab treatment for relapsing-remitting multiple sclerosis is associated with risk of progressive multifocal leukoencephalopathy (PML). Various PML treatments, such as rapid natalizumab clearance by plasma exchange (PLEX), have been adopted in clinical practice, but their impact on clinical outcomes has not been systematically evaluated.
Objectives: To investigate the impact of PLEX and patient characteristics on the outcome of natalizumab-associated PML.
Methods: Confirmed PML cases with known PLEX status as of 17 September 2018 were identified in Biogen pharmacovigilance (PV) data. The primary outcome was survival at 2 years after PML diagnosis. Cumulative survival was estimated by Kaplan-Meier analyses for patients with PLEX (PLEX+) and without PLEX (PLEX−) further stratified by JC virus log viral copy number (VCN) at diagnosis. Hazard ratios (HRs) of risks and predictors of death were based on Cox proportional hazards model for PLEX+ and PLEX− patients, adjusted for age, sex, asymptomatic PML at diagnosis, magnetic resonance imaging (MRI) presentation (widespread vs non-widespread), log VCN, and the total number of infusions.
Results: As of 17 September 2018, there were 787 confirmed natalizumab PML cases. Of these, 725 had a known PLEX status (PLEX+, 616 [85.0%]; PLEX−, 109 [15.0%]). A higher percentage of PLEX+ patients than PLEX− patients were symptomatic at diagnosis (87.8% vs 78.9%) and had a log VCN >7 (33.3% vs 17.4%). The cumulative probability of survival at 2 years post-PML diagnosis for PLEX+ vs PLEX− patients was 88.2% vs 89.3% (P=0.857) with log VCN ≤5, 73.8% vs 89.3% (P=0.097) with log VCN >5 to ≤7, and 68.2% vs 78.9% (P=0.435) with log VCN >7. Death within 2 years was less likely for patients who were asymptomatic (HR, [95% confidence interval (CI)]: 0.38 [0.17-0.81]; P=0.012), and more likely for patients aged >50 years (HR [95% CI]: 1.56 (1.09-2.24); P=0.014), with widespread MRI lesions (HR [95% CI]: 1.61 [1.14-2.27]; P=0.007) or higher log VCN (HR [95% CI]: 2.86 [1.74-4.70]; P< 0.001 with log VCN >7 vs ≤5).
Conclusions: Post-PML survival was more likely in patients who were younger, asymptomatic, had localized MRI lesions, and lower JCV VCN, reinforcing the importance of patient monitoring for early PML diagnosis. PLEX did not have a significant effect on survival. Numerically worse outcomes were observed with PLEX regardless of PML presentation, suggesting PLEX is not effective for improving post-PML outcome.
Disclosure: LK: University Hospital Basel institutional research support from steering committee, advisory board, and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, Sanofi, Santhera, Teva, Vianex; royalties for Neurostatus-UHB products; MS Center in Basel grant support from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, the Roche Research Foundations.
TD: speaker fees, research support, travel support, and/or served on advisory boards and/or steering committees of Actelion, Biogen, Celgene, GeNeuro, Sanofi Genzyme, MedDay, Merck Serono, Mitsubishi Pharma, Novartis, Roche..
CM: research grant support from Bayer, Biogen, Novartis, Sanofi Genzyme; advisory boards for Actelion, Biogen, Genzyme, Merck, Novartis; speaker's honoraria from Biogen, Genzyme, Merck, Novartis Teva.
GG: steering committees for AbbVie, Atara Bio, Biogen, Novartis, Roche, Teva; consulting fees from Biogen, Canbex, GlaxoSmithKline, Merck Serono, Novartis, Roche, Sanofi Genzyme, Synthon.
JO: grant funding from Brain Canada, the MS Society of Canada, the National MS Society; research funding support from Biogen, Sanofi Genzyme, Roche; personal compensation for consulting or speaking from Biogen, Celgene, EMD Serono, Genzyme, Novartis, Roche.
ZR, KM, IC, NC, P-RH, LM: employees of and hold stock and/or stock options in Biogen.
Biogen funded these analyses and writing support for the preparation of this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

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