Feasibility and toxicity of hematopoietic stem cell transplant in multiple sclerosis

Document Type: Review Article


School of Healthy Aging, Medical Aesthetics and Regenerative Medicine, Faculty of Medicine and Health Science, UCSI University, Kuala Lumpur, Malaysia


Multiple sclerosis is a debilitating disease of the central nervous system. It affects people of all ages but is more prevalent among 20-40 year olds. Patients with MS can be presented with potentially any neurological symptom depending on the location of the lesion. A quarter of patients with MS suffer from bilateral lower limb spasticity among other symptoms. These devastating effects can be detrimental to the patient's quality of life. Hematopoietic stem cells (HSCs) have been used as a treatment for MS over the past 2 decades but their safety and efficacy has are undetermined. The objective of this study is to evaluate the feasibility and toxicity of autologous HSCs transplantation in MS. A literature search was done from 1997 to 2016 using different keywords. A total of 9 articles, which met the inclusion and exclusion criteria, were included in this review. The type of conditioning regimen and technique of stem cell mobilization are summarized and compared in this study. All studies reported high-dose immunosuppressive therapy with autologous HSCs transplantation being an effective treatment option for severe cases of multiple sclerosis. Fever, sepsis, and immunosuppression side effects were the most observed adverse effects that were reported in the selected studies. HSCs is a feasible treatment for patients with MS; nevertheless the safety is still a concern due to chemo toxicity.


1. Dieu R, Khorooshi RM, Mariboe A, Arpe M-LH, Owens T. editors. Innate Interferons Regulate CNS Inflammation. 13th ed. International Congress of Neuroimmunology; 2016.

2.  Kolandaiveloo L, Seghayat MS,  Amini F. Efficacy and safety of autologous bone marrow cell therapy in treatment of acute myocardial infarction. Regen Res 2016; 4:15-24.

3. Gourraud PA, Harbo HF, Hauser SL, Baranzini SE. The genetics of multiple sclerosis: an up‐to‐date review. Immunol Rev 2012; 248:87-103.

4. Fassas A, Passweg J, Anagnostopoulos A, Kazis A, Kozak T, Havrdova E, et al. Hematopoietic stem cell transplantation for multiple sclerosis. J Neurol 2002; 249:1088-1097.

5. Wiener C, Fauci A, Braunwald E, Kasper D, Hauser S, Longo D, et al. Harrisons Principles of Internal Medicine Self-Assessment and Board Review 18th Edition: McGraw Hill Professional; 2012.

6. O’Gorman C, Lucas R, Taylor B. Environmental risk factors for multiple sclerosis: a review with a focus on molecular mechanisms. Int J Mol Sci 2012; 13:11718-11752.

7. Villar LM, Espiño M, Cavanillas ML, Roldán E, Urcelay E, Emilio G, et al. Immunological mechanisms that associate with oligoclonal IgM band synthesis in multiple sclerosis. Clin Immunol 2010; 137:51-59.

8. Alderuccio F, Chan J, Scott DW, Toh BH. Gene therapy and bone marrow stem-cell transfer to treat autoimmune disease. Trends Mol Med 2009; 15:344-351.

9. Vosoughi R, Freedman MS. Therapy of MS. Clin Neurol Neurosurg 2010; 112:365-385.

10. Luchetti S, van Eden CG, Schuurman K, van Strien ME, Swaab DF, Huitinga I. Gender differences in multiple sclerosis: induction of estrogen signaling in male and progesterone signaling in female lesions. J Neuropathol Exp Neurol 2014; 73:123-135.

11. Gelfand JM. Multiple sclerosis: diagnosis, differential diagnosis, and clinical presentation. Handb Clin Neurol 2014; 122:269-290.

12. Gratwohl A, Passweg J, Bocelli-Tyndall C, Fassas A, Van Laar J, Farge D, et al. Autologous hematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant 2005; 35:869-879.

13. Milo R, Miller A. Revised diagnostic criteria of multiple sclerosis. Autoimmun Rev 2014; 13:518-524.

14. Deangelis TM, Miller A. Diagnosis of multiple sclerosis. Handb Clin Neurol 2014; 122:317-342.

15. Dalton CM, Brex PA, Miszkiel KA, Hickman SJ, MacManus DG, Plant GT, et al. Application of the new McDonald criteria to patients with clinically isolated syndromes suggestive of multiple sclerosis. Ann Neurol 2002; 52:47-53.

16. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50:121-127.

17. Yadav V, Bever C, Bowen J, Bowling A, Weinstock-Guttman B, Cameron M, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis report of the guideline development subcommittee of the American Academy of Neurology. Neurology 2014; 82:1083-1092.

18. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011; 69:292-302.

19. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005; 58:840-846.

20. Franklin RJ. Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 2002; 3:705-714.

21. Míguez J, JI Rojas, L Partucco, E Cristiano. Differencies in the severity of multiple sclerosis within gender determinated by age at onset. Neurology 2014; 82:4.164.

22. Bakhuraysah MM, Siatskas C, Petratos S. Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality? Stem Cell Res Ther 2016; 7:1.

23. Liau MT, Amini F, Ramasamy TS. The therapeutic potential of stem cells and progenitor cells for the treatment of Parkinson’s disease. Tissue Eng Regen Med 2016; 13:455.

24. Martinez-Morales PL, Revilla A, Ocana I, Gonzalez C, Sainz P, McGuire D, et al. Progress in stem cell therapy for major human neurological disorders. Stem Cell Rev  2013; 9:685-699.

25. Kai Ying V, Amini F. Efficacy and safety of stem cell therapy in cerebral palsy.  Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry  27 Aug - 30 Aug, 2016. Kuala Lumpur, Malaysia: Front. Cell. Neurosci. 2016.

26. Lajimi AA, Hagh MF, Saki N, Mortaz E, Soleimani M, Rahim F. Feasibility of cell therapy in multiple sclerosis: a systematic review of 83 studies. Int J Hematol Oncol Stem Cell Res 2013; 7:13-30.

27. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126:9-16.

28. Kolandaiveloo L, Seghayat M, Amin F. Efficacy and safety of autologous bone marrow cell therapy in treatment of acute myocardial infraction. Regen Res 2016; 4:15-24.

29. Fassas A, Anagnostopoulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant 1997; 20:631-638.

30. Fagius J, Lundgren J, Öberg G. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler 2009; 15:229-237.

31. Saccardi R, Kozak T, Bocelli-Tyndall C, Fassas A, Kazis A, Havrdova E, et al. Autologous stem cell transplantation for progressive multiple sclerosis: update of the European Group for Blood and Marrow Transplantation autoimmune diseases working party database. Mult Scler 2006; 12:814-823.

32. Huang X, Lin J, Demner-Fushman D. editors. PICO as a Knowledge Representation for Clinical Questions. AMIA 2006 Symposium Proceedings; 2006.

33. Nash RA, Bowen JD, McSweeney PA, Pavletic SZ, Maravilla KR, Park M-s, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood 2003; 102:2364-2372.

34. Carreras E, Saiz A, Marín P, Martínez C, Rovira M, Villamor N, et al. CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients. Haematologica 2003; 88:306-314.

35. Su L, Xu J, Ji BX, Wan SG, Lu CY, Dong HQ, et al. Autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Int J Hematol 2006; 84:276-281.

36. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasiev BV, Lisukov IA, Kozlov VA, et al. High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hematol 2008; 36:922-928.

37. Burman J, Iacobaeus E, Svenningsson A, Lycke J, Gunnarsson M, Nilsson P, et al. Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: the Swedish experience. J Neurol Neurosurg Psychiatry 2014; 85:1116-1121.

38. Mancardi GL, Sormani MP, Gualandi F, Saiz A, Carreras E, Merelli E, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis A phase II trial. Neurology 2015; 84:981-988.

39. Atkins HL, Bowman M, Allan D, Anstee G, Arnold DL, Bar-Or A, et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet 2016; 388:576-585.

40. Schoonheim MM, Vigeveno RM, Lopes FCR, Pouwels PJ, Polman CH, Barkhof F, et al. Sex‐specific extent and severity of white matter damage in multiple sclerosis: Implications for cognitive decline. Hum Brain Mapp 2014; 35:2348-2358.

41. Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006; 129:606-616.

42. Currò D, Mancardi G. Autologous hematopoietic stem cell transplantation in multiple sclerosis: 20 years of experience. Neurol Sci 2016; 37:857-865.

43. Gress RE, Emerson SG, Drobyski WR. Immune reconstitution: how it should work, what's broken, and why it matters. Biol Blood Marrow Transplant 2010; 16:S133-S137.

44. Burt RK, Balabanov R, Han X, Sharrack B, Morgan A, Quigley K, et al. Association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability in patients with relapsing-remitting multiple sclerosis. JAMA 2015; 313:275-284.

45. Mancardi G, Sormani M, Di Gioia M, Vuolo L, Gualandi F, Amato M, et al. Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience. Mult Scler J 2012; 18:835-842.

46. Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Griffith LM, et al. High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report. JAMA Neurol 2015; 72:159-169.

47. James J, Alix P, Blackburn DJ, Sokhi D, Craven I, Sharrack B, et al.  Autologous hematopoietic stem cell transplantation following pulsed cyclophosphamide in a severely disabled patient with malignant multiple sclerosis. J Neurol 2013; 260:914.

48. Pasquini MC, Voltarelli J, Atkins HL, Hamerschlak N, Zhong X, Ahn KW, et al. Transplantation for autoimmune diseases in north and South America: a report of the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2012; 18:1471-1478.