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Autologous hematopoietic stem cell transplantation in multiple sclerosis: a global approval and availability review

Bone Marrow Transplantation volume 56, pages 1754–1756 (2021)Cite this article

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Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disorder of the central nervous system. With a prevalence of ~100 per 100,000 population in Europe, it is one of the most common and severe neurologic disorders of young adults [1]. The majority (80–90%) of patients present initially with a relapsing-remitting (RRMS) and later secondary progressive (SPMS) course, while a minority present with a primary progressive course (PPMS) [2]. Disability accumulation over the years has enormous consequences and causes significant impairment of quality of life and ability to work. In the last two decades, efficient therapies that drastically reduce relapses and alter the course of the disease with significant impact on prognosis have been developed and approved [3, 4], however, progression of disability is often not prevented. A novel concept, the status of no evidence of disease activity (NEDA or NEDA-3, characterized by absence of relapses, new MRI lesions, and disability accrual), has therefore emerged as a metric of therapeutic efficacy [5], with the goal to achieve a sustained, prolonged, and perhaps permanent NEDA status. In addition, employing an induction treatment strategy (as opposed to an escalation strategy) to block disease activity as early and completely as possible is increasingly discussed [6]. Despite great reduction and in many cases elimination of relapses and MRI activity with newer approved therapies, 2-year-pooled NEDA is maximally 48% [7]. Moreover, a minority of patients with aggressive MS remains clinically and/or radiologically active despite use of approved high-efficacy treatments and shows rapid disability accrual. Similarly, in a subset of patients transitioning from RRMS to SPMS, the progression cannot be halted with current high-efficacy treatments. It is in meticulously selected cases of aggressive, high-efficacy treatment-refractory RRMS or early PP and SPMS with an inflammatory component that autologous hematopoietic stem cell transplantation (aHSCT) has emerged over the last two decades as a treatment option [8]. Although aHSCT is intensive and until 2000 had shown significant mortality [9], it is increasingly safe with mortality reported to the European Blood and Marrow Transplantation Society from 2012 to 2016 of 0.2% in MS [7] and, importantly, it is presently the most effective immunotherapy with 2-year pooled NEDA ranging from 70 to 92%, in comparison to 32–48% with ocrelizumab, natalizumab, alemtuzumab, or cladribine [7,8,9]. Several studies from different countries across several continents have demonstrated the high efficacy of aHSCT (reviewed in [10]). Furthermore, the use of aHSCT is currently rapidly increasing [8], and the main premise, establishment of a new adaptive immune system, particularly of CD4+ T cells, has been demonstrated [11].

Based on (a) the growing evidence of high efficacy, (b) the fact that aHSCT is safe, well established, and approved for several indications including another autoimmune disease, systemic sclerosis, (c) the fact that phase III clinical trials of aHSCT compared to best available therapy are difficult to perform due to the high cost and lack of support from commercial, private, and government entities, but also due to recruitment difficulties as aHSCT is indicated in a small number of patients with MS, (d) a clear desire of patients with aggressive disease to have access to aHSCT, (e) the fact that many patients with MS are willing to travel to countries where aHSCT is offered widely, and (f) socioeconomic considerations that aHSCT as a one-time treatment will reduce overall disease cost long term, we applied for approval of aHSCT in MS to the Swiss Health Authorities (Federal Office of Public Health, FOPH) early in 2018. As part of the arguments that were presented to the FOPH, we assessed the availability and approval status of aHSCT in other countries. With support from the MS International Federation, we sent a questionnaire to national MS societies from 43 countries. The questionnaire asked whether (1) aHSCT in MS is available in the country in question, (2) guidelines for the application of aHSCT exist, (3) activities for the promotion of aHSCT in MS are performed, (4) the cost of aHSCT is reimbursed upon recommendation by an MS specialist or a general neurologist, (5) specific conditions need to be fulfilled for reimbursement, and (6) a formalized reimbursement policy exists (see Table 1). Twenty-nine of 43 (67.4%) countries responded. Nineteen of the 29 (65.5%) countries reported that aHSCT has been performed as treatment of MS, although it had been performed in just a few selected cases in 8 of the 19 (42.1%) countries. National guidelines for the application of aHSCT existed at the time of the questionnaire in 7 of the 19 (36.8%) countries where aHSCT has been applied for MS treatment; in another 4 (21.1%) countries, guidelines were center specific. Activities for the promotion of aHSCT in MS were described in 8 of 19 (42.1%) countries performing the treatment in selected MS patients. In 14 of 19 (73.7%) countries performing aHSCT in MS, treatment was reimbursed upon recommendation by a specialized team comprised of MS experts and hematologists. Furthermore, in 5 of 19 (26.3%) countries performing aHSCT in MS, treatment was also reimbursed upon recommendation by a general neurologist. As far as conditions for reimbursement are concerned, in 7 of 19 (36.8%) countries no particular conditions were specified for reimbursement, in the remaining 12 countries (63.2%) conditions were center specific and/or relying on scientific consensus regarding aHSCT indications; of those, only 4 countries required participation in a aHSCT registry in addition. Finally, only in 5 of 19 (26.3%) countries was the reimbursement procedure formalized in a document.

Table 1 Summary of information captured by the questionnaire, which was sent out to 43 countries.
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Acknowledgements

The authors would like to thank Prof. Xavier Montalban, Dr. Anne Helme, and Dr. Joanna Laurson-Doube for help with drafting and distributing the questionnaire, all those individuals who contributed questionnaire responses, and Dr. Clare Walton for valuable discussions. The questionnaire was sent to the MS societies of Argentina, Australia, Austria, Belgium, Brazil, Canada, Cyprus, Denmark, Egypt, Estonia, Finland, France, Germany, Greece, Guatemala, Iceland, India, Iran, Ireland, Italy, Japan, Latvia, Lebanon, Luxembourg, Malta, Mexico, the Netherlands, New Zealand, Norway, Poland, Portugal, Russia, Slovakia, Slovenia, South Korea, Spain, Sweden, Switzerland, Tunisia, Turkey, the United Kingdom, Uruguay, and the United States of America. MS societies from Argentina, Australia, Austria, Belgium, Canada, Cyprus, Denmark, Finland, France, Germany, Guatemala, India, Iran, Ireland, Italy, Japan, the Netherlands, New Zealand, Norway, Portugal, Russia, Spain, Sweden, Switzerland, Tunesia, Turkey, the United Kingdom, Uruguay, and the United States kindly responded to our query.

Funding

The work was supported by a grant of the Swiss National Science Foundation (SNF) 32003B_185003, “Examining the Mechanisms of Autologous Hematopoietic Stem Cell Transplantation to Understand the Pathogenesis of Multiple Sclerosis”, to RM.

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Authors and Affiliations

  1. Department of Neuroimmunology and Multiple Sclerosis Research Section, Neurology Clinic, University Hospital Zurich, Zurich, Switzerland

    P. Stathopoulos, K. Léger, M. Foege, A. Lutterotti, I. Jelcic & R. Martin

  2. Department of Medical Oncology and Hematology and Stem Cell Transplant, University Hospital Zurich, Zurich, Switzerland

    A. Müller & U. Schanz

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  1. P. Stathopoulos
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Correspondence to P. Stathopoulos or R. Martin.

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Conflict of interest

Andreas Lutterotti received financial compensation and/or travel support for lectures and advice from Biogen, Merck, Novartis, Teva, Genzyme, Bayer, Celgene, and he is a co-founder and co-owner of Cellerys, a company that pursues antigen-specific tolerization. He is co-inventor on a patent held by the University of Zurich on the use of peptide-coupled cells for treatment of MS. Ilijas Jelcic has received speaker honoraria or unrestricted grants from Biogen Idec and Novartis and has served as advisor for Alexion, Neuway, Merck, Novartis and Sanofi Genzyme. Roland Martin has served as advisor or member of speaker’s boards for Biogen, Novartis, Roche, Genzyme, Teva, Merck-Serono, CellProtect, Neuway and Third Rock Ventures. He is listed as inventor on a UZH-held patent on novel target antigens for MS and is, together with Andreas Lutterotti, a cofounder and co-owner of Cellerys. The group of Roland Martin has received unrestricted grants from Biogen, Novartis and Roche.

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Stathopoulos, P., Léger, K., Foege, M. et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a global approval and availability review. Bone Marrow Transplant 56, 1754–1756 (2021). https://doi.org/10.1038/s41409-021-01276-z

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