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  • Print publication year: 2011
  • Online publication date: December 2011

44 - Hematopoietic stem cell transplantation to treat multiple sclerosis

from Section III - Clinical trials of multiple sclerosis therapies

Summary

Terilunomide is being investigated in a comprehensive program of clinical trials in patients with multiple sclerosis (MS) with relapses and in patients with a clinically isolated syndrome (CIS). This program evaluates the efficacy and safety of terilunomide on a range of clinical and magnetic resonance imaging (MRI) end-points when administered either as monotherapy or as an adjunctive therapy to ongoing treatment with conventional disease-modifying therapies (DMTs). Clinical data indicates that terilunomide is generally well tolerated with an acceptable safety profile, with no significant safety concerns identified to date. Safety data from the open-label extension phase of the study are consistent with the safety profile of terilunomide observed in the double-blind treatment phase, without the emergence of any new safety concerns. Based on currently available data on monotherapy and adjunctive therapy, terilunomide appears to have a favorable benefit/risk ratio in relapsing MS, and as such, represents a promising new first-line treatment.

References

1. Wobus AM, Holzhausen H, Jakel P, Schoneich J. Characterization of a pluripotent stem cell line derived from a mouse embryo. Exp Cell Res 1984; 152:212–19.
2. Carpenter MK, Rosler E, Rao MS. Characterization and differentiation of human embryonic stem cells. Cloning Stem Cells 2003; 5:79–88.
3. Edwards RG. Stem cells today: A. Origin and potential of embryo stem cells. Reprod Biomed Online 2004; 8:275–306.
4. Edwards RG. In vitro fertilization: past and future. Ann Biol Clin 1987; 45:321–9.
5. Burt RK, Verda L, Kim DA, et al. Embryonic stem cells as an alternate marrow donor source: engraftment without graft-versus-host disease. J Exp Med 2004; 199:895–904.
6. Zhang S-C, Wernig M, Duncan ID, et al. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 2001; 19:1129–33.
7. Reubinoff BE, Itsykson P, Turetsky T, et al. Neuralprogenitors from human embryonic stem cells. Nat Biotechnol 2001; 19:1134–40.
8. Xian HQ, McNichols E, St Clair A, Gottlieb DI. A subset of ES-cell-derived neural cells marked by gene targeting. Stem Cells 2003; 21:41–9.
9. Burt RK, Fassas A, Snowden J, et al. Collection of hematopoietic stem cells from patients with autoimmune diseases. Bone Marrow Transpl 2001; 28:1–12.
10. Openshaw H, Stuve O, Antel JP, et al. Multiple sclerosis flares associated with recombinant granulocyte colonystimulating factor. Neurology 2000; 54:2147–50.
11. Verda L, Luo K, Kim DA, et al. Effect of hematopoietic growth factors on severity of experimental autoimmune encephalomyelitis. Bone Marrow Transpl 2006; 38(6):453–60.
12. Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as a potential source of hepatic oval cells. Science 1999; 284:1168–70.
13. Krause DS, Theise ND, Collector MI, et al. Multiorgan, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105:369–77.
14. Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410:701–5.
15. Eglitis MA, Mezey E. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 1997; 94:4080–5.
16. Burt RK, Burns W, Hess A. Bone marrow transplantation for multiple sclerosis. Bone Marrow Transpl 1995; 16:1–6.
17. Schwartz RH. T cell anergy. Annu Rev Immunol 2003; 21:305–34.
18. Muraro PA, Douek DC, Packer A, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med 2005; 201:805–16.
19. Dubinsky AN, Burt RK, Martin R, Muraro PA. T-cell clones persisting in the circulation after autologous hematopoietic SCT are undetectable in the peripheral CD34+ selected graft. Bone Marrow Transpl 2010 Feb; 45(2):325–31.
20. Burt RK, Padilla J, Begolka WS, et al. Effect of disease stage on clinical outcome after syngeneic bone marrow transplantation for relapsing experimental autoimmune encephalomyelitis. Blood 1998; 91:2609–16.
21. Karussis DM, Slavin S, Lehmann D, et al. Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation. J Immunol 1992; 148:1693–8.
22. van Gelder M, van Bekkum DW. Effective treatment of relapsing experimental autoimmune encephalomyelitis with pseudoautologous bone marrow transplantation. Bone Marrow Transpl 1996; 18:1029–34.
23. van Gelderm, Mulder AH, van bekkum DW. Treatment of relapsing experimental autoimmune encephalomyelitis with largely MHC-mismatched allogeneic bone marrow transplantation. Transplantation 1996; 62:810–18.
24. Karussis DM, Vourka-Karussis U, Lehmann D, et al. Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high-dose cytoreductive treatment followed by syngeneic bone marrow transplantation. J Clin Invest 1993; 92:765–72.
25. van Gelder M, Kinwel-Bohré EP, van Bekkum DW. Treatment of experimental allergic encephalomyelitis in rats with total body irradiation and syngeneic BMT. Bone Marrow Transpl 1993; 11:233–41.
26. Miller SD, Vanderlugt CL, Begolka WS, et al. Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading. Nat Med 1997; 3:1133–6.
27. Burt RK, Padilla J, Dal Canto MC, Miller SD. Viral hyperinfection of the central nervous system and high mortality after hematopoietic stem cell transplantation for treatment of Theiler's murine encephalomyelitis virus-induced demyelinating disease. Blood 1999; 94:2915–22.
28. Burt RK, Abinun M, Farge-Bancel D, et al. Risks of immune system treatments. Science 2010; 328(5980):825–6.
29. Burt RK, Loh Y, Pearce W, Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. J Am Med Assoc 2008 Feb 27; 299(8):925–36.
30. Monje ML, Mizumatsu S, Fike JR, et al. Irradiation induces neural precursor-cell dysfunction. Nat Med 2002; 8:955–62.
31. Loh Y, Oyama Y, Statkute L, et al. Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used. Blood 2007 Mar 15; 109(6):2643–8.
32. Fassas A, Anagnostopoulos A, Kazis A, et al. Autologous stem cell transplantation in progressive multiple sclerosis – an interim analysis of efficacy. J Clin Immunol 2000; 20:24–30.
33. Kozak T, Havrdova E, Pit'ha J, et al. Immunoablative therapy with autologous stem cell transplantation in the treatment of poor risk multiple sclerosis. Transplant Proc 2001; 33:2179–81.
34. Saiz A, Blanco Y, Carreras E, et al. Clinical and MRI outcome after autologous hematopoietic stem cell transplantation in MS. Neurology 2004; 62:282–4.
35. Saiz A, Blanco Y, Berenguer J, et al. Clinical outcome 6 years after autologous hematopoietic stem cell transplantation in multiple sclerosis. Neurologia 2008 Sep; 23(7):405–7.
36. Mancardi GL, Saccardi R, Filippi M, et al. Autologous hematopoietic stem cell transplantation suppresses Gd enhanced MRI activity in MS. Neurology 2001; 57:62–8.
37. Burt RK, Cohen BA, Russell E, et al. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores. Blood 2003; 102:2373–8.
38. Nash RA, Bowen JD, McSweeney PA, et al. High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Blood 2003; 102:2364–72.
39. Openshaw H, Lund BT, Kashyap A, et al. Peripheral blood stem cell transplantation in multiple sclerosis with busulfan and cyclophosphamide conditioning: report of toxicity and immunological monitoring. Biol Blood Marrow Transpl 2000; 6:563–75.
40. Fassas A, Passweg JR, Anagnostopoulos A, et al. Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multi-center study. J Neurol 2002; 249:1088–97.
41. Saccardi R, Kozak T, Bocelli-Tyndall C, et al. Autoimmune Diseases Working Party of EBMT. 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(6):814–23.
42. Su L, Xu J, Ji BX, et al. Autologous peripheral blood stem cell transplantation for severe multiple sclerosis. Int J Hematol 2006; 84(3):276–81.
43. Xu J, Ji BX, Su L, et al. Clinical outcomes after autologous haematopoietic stem cell transplantation in patients with progressive multiple sclerosis. Chin Med J (Engl) 2006; 119(22):1851–5.
44. Ni XS, Ouyang J, Zhu WH, Wang C, Chen B. Autologous hematopoietic stem celltransplantation for progressive multiple sclerosis: report of efficacy and safety at three yr of follow up in 21 patients. Clin Transpl 2006; 20(4):485–9.
45. Samijn JPA, te Boekhurst PAW, Mondria T, et al. Intense T cell depletion followed by autologous bone marrow transplantation for severe multiple sclerosis. J Neurol Neurosurg Psychiatry 2006; 77:46–50.
46. Shevchenko YL, Novik AA, Kuznetsov AN, et al High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis. Exp Hematol 2008; 36(8):922–8.
47. Fagius J, Lundgren J, Oberg G. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler 2009; 15(2):229–37.
48. Burt RK, Loh Y, Cohen B, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study. Lancet Neurol. 2009; 8(3):244–53. Epub 2009 Jan 29. Erratum in: Lancet Neurol. 2009; 8(4):309.
49. Hamerschlak N, Rodrigues M, Moraes DA, et al. Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG. Bone Marrow Transpl 2010; 45(2):239–48.
50. Fassas A, Anagnostopoulos A, Kazis A, et al. Peripheral blood stem cell transplantation in the treatment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transpl 1997; 20(8):631–8.
51.ASTI MS (Autologous Stem cell Transplantation International Multiple Sclerosis). Available from: http://www. astims.org.
52. HALT-MS (High Dose Immunosuppression and Autologous Stem Cell Transplantation for Poor Prognosis Multiple Sclerosis). Available from: http://www.halt-ms.org and www.clinicaltrials.gov/ct21/show/record/NCT00288626.
53. Freedman MS, Atkins HL. Suppressing immunity in advancing MS: too much too late, or too late for much? Neurology 2004; 62(2):168–9.
54. Mancardi GL, Murialdo A, Rossi P, et al. Autologous stem cell transplantation as rescue therapy in malignant forms of multiple sclerosis. Mult Scler 2005; 11(3):367–71.
55. Saccardi R, Mancardi GL, Solari A, et al. Autologous HSCT for severe progressive multiple sclerosis in a multicenter trial: impact on disease activity and quality of life. Blood 2005; 105:2601–7.
56.Autologous Stem Cell Transplant for Multiple Sclerosis (MS/BMT). Available from: http://www.halt-ms.org and www.clinicaltrials.gov/ct21/show/record/ NCT01099930.
57.Multiple Sclerosis International Stem Cell Transplant trial (MIST). Available from: http://www.clinicaltrials.gov (NCT00273364).
58. Lu JQ, Joseph JT, Nash RA et al. Neuroinflammation and demyelination in multiple sclerosis after allogeneic hematopoietic stem cell transplantation. Arch Neurol 2010; 67(6):716–22.
59. Lu JQ, Storek J, Metz L, et al. Continued disease activity in a patient with multiple sclerosis after allogeneic hematopoietic cell transplantation. Arch Neurol. 2009; 66(1):116–20.
60. Verda L, Kim DA, Ikehara S, et al. Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in NOD mice. Stem Cells 2008; 26(2):381–6.
61. Di Nicola M, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99:3838–43.
62. Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005; 106:1755–61.
63. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105:1815–22.
64. Zhao RC, Liao L, Han Q. Mechanisms of and perspectives on the mesenchymal stem cells in immunotherapy. J Lab Clin Med 2003; 143:284–91.
65. Bai L, Lennon DP, Eaton V, et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009; 57:1192–203.
66. Rafei M, Birman E, Forner K, Galipeau J. Allogeneic mesenchymal stem cells for treatment of experimental autoimmune encephalomyelitis. Mol Ther 2009; 17:1799–803.
67. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroidresistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371:1579–86.
68. Liang J, Zhang H, Hua B, et al. Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis. Mult Scler 2009; 15:644–6.
69. Mohyeddin Bonab M, Yazdanbakhsh S, et al. Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iran J Immunol 2007; 4:50–7.
70. Josse C, Schoemans R, Niessen NA, et al. Systematic chromosomal aberrations found in murine bone marrow-derived mesenchymal stem cells. Stem Cells Dev 2010; 19(8):1167–73.
71. Chen JT, Collins DL, Atkins HL, et al; Canadian MS BMT Study Group. Brain atrophy after immunoablation and stem cell transplantation in multiple sclerosis. Neurology 2006; 66(12):1935–7.
72. Roccatagliata L, Rocca M, Valsasina P et al. Italian GITMO-NEURO Intergroup on Autologous Stem Cell Transplantation. The long-term effect of AHSCT on MRI measures of MS evolution: a five-year follow-up study. Mult Scler 2007; 13(8):1068–70.