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Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis

Key Points

  • Ablative therapy and autologous haematopoietic stem cell transplantation (AHSCT) is an increasingly studied and used strategy for the treatment of multiple sclerosis (MS)

  • AHSCT confers benefits for patients with MS by achieving radical suppression of inflammatory MS activity

  • Qualitative changes in the reconstituted immune system and durable remissions without additional immune intervention support the notion that AHSCT regenerates the immune system (a process known as immune resetting)

  • Complete suppression of MS disease activity for 4–5 years has been documented in 70–80% of patients with relapsing–remitting MS who have undergone AHSCT; neurological improvements have also been demonstrated

  • Optimal candidates for AHSCT are young, ambulatory and have inflammatory-active relapsing–remitting MS (RRMS); current appropriate indications for AHSCT include aggressive and highly active treatment-refractory RRMS

  • Clinical trials to compare AHSCT with approved drugs in RRMS and determine its benefits in inflammatory-active progressive MS are warranted, but progress is hindered by a lack of investment and funding

Abstract

Autologous haematopoietic stem cell transplantation (AHSCT) is a multistep procedure that enables destruction of the immune system and its reconstitution from haematopoietic stem cells. Originally developed for the treatment of haematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders. Results from 20 years of research make a compelling case for selective use of AHSCT in patients with highly active multiple sclerosis (MS), and for controlled trials. Immunological studies support the notion that AHSCT causes qualitative immune resetting, and have provided insight into the mechanisms that might underlie the powerful treatment effects that last well beyond recovery of immune cell numbers. Indeed, studies have demonstrated that AHSCT can entirely suppress MS disease activity for 4–5 years in 70–80% of patients, a rate that is higher than those achieved with any other therapies for MS. Treatment-related mortality, which was 3.6% in studies before 2005, has decreased to 0.3% in studies since 2005. Current evidence indicates that the patients who are most likely to benefit from and tolerate AHSCT are young, ambulatory and have inflammatory MS activity. Clinical trials are required to rigorously test the efficacy, safety and cost-effectiveness of AHSCT against highly active MS drugs.

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Figure 1: Outline of the AHSCT procedure.
Figure 2: Proposed model of therapeutic mechanisms of AHSCT.
Figure 3: Proportion of patients for whom NEDA was achieved at 2 years with disease-modifying therapies and AHSCT.
Figure 4: Estimated lymphoablative and myeloablative effects of AHSCT protocols for multiple sclerosis.
Figure 5: Number of AHSCT procedures for treatment of multiple sclerosis and treatment-related mortality.

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Acknowledgements

P.A.M. was supported by the UK MS Society [Grant no. 938/10 to P.M.], the Medical Research Council (MR/N026934/1) and the Italian MS Society (ref 22/16/F14) and is grateful for support from the NIHR Biomedical Research Centre funding scheme. R.M. is supported by an Advanced Grant of the European Research Council (No. 340733) and the Neuroimmunology and MS Research Section by the Clinical Research Priority Project-MS of the University of Zurich. We gratefully acknowledge Manuela Badoglio from the EBMT Paris Study Office for providing data from the EBMT registry.

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Correspondence to Paolo A. Muraro.

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Competing interests

P.A.M. declares honoraria for speaking and travel support from Bayer, Biogen, Merck Serono and Novartis. G.L.M. has received support from Biogen (honoraria for lecturing, travel expenses for attending meetings and financial support for research), Genzyme (honorarium for lecturing), Merck Serono, Novartis, Teva (financial support for research) and Sanofi (honorarium for speaking). R.N. declares compensation and support from Biogen (principal investigator, funds for staff, research, organizing education, honorarium for speaking, advisory boards), Genzyme (honorarium for speaking, advisory boards, organizing education), NICE diagnostics advisory committee, Expert NICE Alemtuzumab committee; Novartis (principal investigator, honorarium for speaking, advisory boards), Roche (advisory boards). M.P.S. has received personal compensation for consulting services and for speaking activities from Biogen, Genzyme, Merck Serono, Novartis, Roche and Teva. R.S. has received honoraria for lecturing from Sanofi.

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Glossary

Leukoapheresis

A process that separates white blood cells from the peripheral blood, which, in the context of AHSCT for MS, is carried out with a semi-automated medical device to harvest the patients autologous haematopoietic stem cell-enriched blood product after mobilization.

Bone marrow aplasia

A state in which the bone marrow fails to generate adequate numbers of haematopoietic stem cells to repopulate the blood with red blood cells, white blood cells and platelets; in the context of AHSCT for MS, this state follows the conditioning regimen, irreversibly after myeloablative conditioning, which necessitates haematopoietic stem cell support for survival.

Pattern II MS pathology

One of four described patterns of tissue pathology in MS, characterized by anti-myelin antibodies and complement factors.

T cell receptor excision circles

Episomal DNA circles that are by-products of intra-thymic T cell receptor rearrangement and persist in T cells as detectable markers of their recent thymic origin.

Recent thymic emigrants

T cells that have recently emerged from the thymus after differentiation and thymic selection.

Antithymocyte globulin

A T-cell-depleting polyclonal immunoglobulin from horse or rabbit.

Uhtoff phenomenon

The recurrence or worsening of pre-existing neurological symptoms, usually transient, experienced by patients with MS after exposure to internal (fever) or external (heat) high temperatures

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Muraro, P., Martin, R., Mancardi, G. et al. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol 13, 391–405 (2017). https://doi.org/10.1038/nrneurol.2017.81

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