Alemtuzumab as rescue therapy in a cohort of 50 relapsing–remitting MS patients with breakthrough disease on fingolimod: a multi-center observational study
- 948 Downloads
Relapsing–remitting multiple sclerosis (RRMS) requires efficient immunomodulatory treatment to reach “no evidence of disease activity” status at best. Alemtuzumab and fingolimod have proved to be efficient options in RRMS with active disease course. Yet, side effects and break-through disease may limit long-time treatment and necessitate switch of medication. Data on efficacy and safety of alemtuzumab following fingolimod treatment are limited, but useful for clinical practice.
Clinical and MRI data of 50 RRMS patients with a history of therapy switch from fingolimod to alemtuzumab were retrospectively analyzed. Data were acquired from nine large German MS Centers from 2013 to 2016 and analyzed using descriptive statistics.
On average, patients with disease duration of 12.9 years and median EDSS of 3.0 at baseline switched to alemtuzumab after 68 weeks of fingolimod treatment. Thereafter, patients on alemtuzumab were followed for a mean of 64 weeks. The annualized relapse rate decreased from 2.2 in the year prior to 0.34 in the following year after switching to alemtuzumab and EDSS stabilized. In a subgroup of patients (n = 23), MRI data point to a reduction in enhancing (4.47 vs. 0.26) and new/enlarging T2 lesions (5.8 vs. 0.27) after treatment adjustment. Side effects were generally as expected from published data for alemtuzumab (autoimmunity 2/50, severe infections 1/50). One patient suffered combined lethal necrotizing leukoencephalopathy and hemolytic anemia.
Therapy switch was highly effective in reducing clinical and MRI surrogates of disease activity and was mainly well tolerated within one year of follow-up. Hence, alemtuzumab constitutes a promising therapy in RRMS with refractory disease activity despite fingolimod treatment. Further studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up.
KeywordsAlemtuzumab Fingolimod Multiple sclerosis Disease-modifying treatment
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Compliance with ethical standards
Conflicts of interest
KH: received travel grants from Biogen, Novartis and Merck. AB: received personal compensation from Merck Serono, Biogen, Bayer Vital, Novartis, TEVA, Roche and Sanofi/Genzyme and grants for congress trips and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme and Merck Serono. BF: has received modest lecture and consulting fees from Bayer, Merck, Mylan, Sanofi Genzyme, Teva and Roche. KG: received honoraria as speaker or consultant from Bayer Healthcare, Biogen, Genzyme Sanofi, Novartis, Roche, Sanofi, TEVA. KH: received research honoraria from Bayer Healthcare, Biogen Idec Germany, Merck Serono, Teva Pharma, Novartis Pharma, Sanofi Genzyme, speaker honoraria from Bayer Healthcare, Biogen Idec Germany, Merck Serono, Teva Pharma, Novartis Pharma, Sanofi Genzyme and worked as a consultant for Teva Pharma, Sanofi Genzyme, Merck and Roche. BK: received personal compensation for activities with Bayer, Biogen, Genzyme, Merck, Novartis and TEVA. CK: received speaker and consultant honoraria as well as grants for research from Ablynx, Bayer Vital, Bristol-Myers Squibb, Biotronik, Boehringer Ingelheim, Biogen, CSL Behring, Daiichi-Sankyo, Desitin, Eisai, Ever Pharma, Sanofi-Genzyme, Merck Serono, Mylan, Medday, Novartis, Pfizer, Roche, Siemens, Stago, Teva. IK: received honoraria for consultancy or lectures and travel reimbursement from Bayer Health Care, Biogen Idec, Chugai, Merck, Novartis, Shire, and Roche and grant support from Chugai and Diamed. DHL: received travel support and/or compensation for activities with Biogen, Genzyme, Merck, Novartis, Roche and TEVA as well as research support from Novartis. MM: received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Almirall, Bayer Healthcare, Böhringer Ingelheim, Biogen, Genzyme/Sanofi Aventis, Merck Serono, Novartis, Roche, Talecris and Teva, MM serves on a steering committee for Biogen and Novartis and as a consultant for Biogen, Genzyme and Roche. SM: received honoraria for lecturing, travel expenses for attending meetings and financial research support from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. TR: received travel expenses and financial research support from Genzyme and Novartis and received honoraria for lecturing from Roche, Merck, Genzyme, Biogen, and Teva. RG: served on the scientific advisory board for Teva Laquinimod DSMB, received speaker honoraria from Biogen, Genzyme, Teva, Merck Serono, Bayer Schering, Ozgene, Novartis, is on the editorial board for SAGE Journal, Aktuelle Neurologie, Experimental Neurology. RAL: received travel support and/or compensation for activities with Almirall, Bayer Healthcare, Biogen, Fresenius, Genzyme, Merck, Novartis, Roche and TEVA as well as research support from Biogen, Merck and Novartis. SD, VL and PR have nothing to disclose.
- 4.Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362(5):387–401. https://doi.org/10.1056/NEJMoa0909494 CrossRefPubMedGoogle Scholar
- 5.Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, de Vera A, Jin J, Stites T, Wu S, Aradhye S, Kappos L (2010) Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 362(5):402–415. https://doi.org/10.1056/NEJMoa0907839 CrossRefPubMedGoogle Scholar
- 6.Kappos L, Radue EW, Comi G, Montalban X, Butzkueven H, Wiendl H, Giovannoni G, Hartung HP, Derfuss T, Naegelin Y, Sprenger T, Mueller-Lenke N, Griffiths S, von Rosenstiel P, Gottschalk R, Zhang Y, Dahlke F, Tomic D (2015) Switching from natalizumab to fingolimod: a randomized, placebo-controlled study in RRMS. Neurology 85(1):29–39. https://doi.org/10.1212/WNL.0000000000001706 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Jokubaitis VG, Li V, Kalincik T, Izquierdo G, Hodgkinson S, Alroughani R, Lechner-Scott J, Lugaresi A, Duquette P, Girard M, Barnett M, Grand’Maison F, Trojano M, Slee M, Giuliani G, Shaw C, Boz C, Spitaleri DL, Verheul F, Haartsen J, Liew D, Butzkueven H (2014) Fingolimod after natalizumab and the risk of short-term relapse. Neurology 82(14):1204–1211. https://doi.org/10.1212/WNL.0000000000000283 CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA (2012) Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380(9856):1829–1839. https://doi.org/10.1016/S0140-6736(12)61768-1 CrossRefPubMedGoogle Scholar
- 13.Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380(9856):1819–1828. https://doi.org/10.1016/S0140-6736(12)61769-3 CrossRefPubMedGoogle Scholar
- 15.Ziemssen T, Thomas K (2017) Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord 10(10):343–359. https://doi.org/10.1177/1756285617722706 CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Hill-Cawthorne GA, Button T, Tuohy O, Jones JL, May K, Somerfield J, Green A, Giovannoni G, Compston DA, Fahey MT, Coles AJ (2012) Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry 83(3):298–304. https://doi.org/10.1136/jnnp-2011-300826 CrossRefPubMedGoogle Scholar
- 17.Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, May K, Button T, Azzopardi L, Kousin-Ezewu O, Fahey MT, Jones J, Compston DA, Coles A (2015) Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry 86(2):208–215. https://doi.org/10.1136/jnnp-2014-307721 CrossRefPubMedGoogle Scholar
- 18.Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O’Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302. https://doi.org/10.1002/ana.22366 CrossRefPubMedPubMedCentralGoogle Scholar
- 21.Havrdova E, Arnold DL, Cohen JA, Hartung HP, Fox EJ, Giovannoni G, Schippling S, Selmaj KW, Traboulsee A, Compston DAS, Margolin DH, Thangavelu K, Rodriguez CE, Jody D, Hogan RJ, Xenopoulos P, Panzara MA, Coles AJ (2017) Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology 89(11):1107–1116. https://doi.org/10.1212/WNL.0000000000004313 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Coles AJ, Cohen JA, Fox EJ, Giovannoni G, Hartung HP, Havrdova E, Schippling S, Selmaj KW, Traboulsee A, Compston DAS, Margolin DH, Thangavelu K, Chirieac MC, Jody D, Xenopoulos P, Hogan RJ, Panzara MA, Arnold DL (2017) Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology 89(11):1117–1126. https://doi.org/10.1212/WNL.0000000000004354 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Willis M, Pearson O, Illes Z, Sejbaek T, Nielsen C, Duddy M, Petheram K, van Munster C, Killestein J, Malmestrom C, Tallantyre E, Robertson N (2017) An observational study of alemtuzumab following fingolimod for multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 4(2):e320. https://doi.org/10.1212/NXI.0000000000000320 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Obermann M, Ruck T, Pfeuffer S, Baum J, Wiendl H, Meuth SG (2016) Simultaneous early-onset immune thrombocytopenia and autoimmune thyroid disease following alemtuzumab treatment in relapsing-remitting multiple sclerosis. Mult Scler 22(9):1235–1241. https://doi.org/10.1177/1352458516638558 CrossRefPubMedGoogle Scholar