Autologo us Hematopo i etic Stem Cells Transplantati on and its Current Role in Multiple Sclerosis Tre atment

Czech version

Authors: E. Krasulová ¹; M. Trněný ²; T. Kozák ³; E. Havrdová ¹
Authors‘ workplace: Ne urologická klinika 1. LF UK a VFN v Praze, 2I. interní klinika 1. LF UK a VFN v Praze, 3Oddělení klinické hematologi e 3. LF UK a FNKV, Praha ¹
Published in: Cesk Slov Neurol N 2009; 72/105(3): 227-234
Category: Review Article

Overview

Multiple sclerosis (MS) is the most frequent a uto immune disorder of the central nervo us system in o ur ge ographical regi on. The dise ase can le ad to vari able degree of ne urological disability according to aggressiveness of MS co urse itself, e arly tre atment initi ati on and its invidividu al efficacy. In abo ut 3% of the pati ents MS co urse can be classifi ed as malignant with severe attacks from the beginning of the dise ase and rapid accumulati on of ne urological disability despite adequ ate tre atment. In such cases the tre atment with high‑dose immuno ablati on with a utologo us hematopo i etic stem cells support (ASCT) sho uld be considered. The tre atment rati onale comprises the effort of a uto aggressive immune system eliminati on by high‑dose cytostatic tre atment followed by return of pati ents’ own hematopo i etic stem cells as reso urces for a new immune system. The aim is to enable reconstituti on of potenti ally less a uto aggressive immune system. The progressi on free survival 10 ye ars in 47% of the pati ents has been achi eved in the first ASCT gro up with the longest follow‑up since 1995 – gre at result in comparison with any other currently available MS drug. More than 400 pati ents worldwide have been tre ated with ASCT procedure so far. Nowadays optimal indicati on for ASCT tre atment involves highly active MS within first five ye ars of the dise ase and ability to walk at le ast 100 metres witho ut aid. Despite its risks (including 2.3% mortality) ASCT presents promising tre atment for malignant MS with po or prognosis also in the Czech Republic, where ASCT rese arch – still so needful and essenti al – started in 1998.

Key words:
multiple sclerosis – malignant – immuno ablati on – stem cell transplantati on – ASCT

Sources

1. Havrdová E. Ne uro imunologi e. Praha: Maxdorf 2001.

2. Hawkes CH. Smoking is a risk factor for multiple sclerosis: a metanalysis. Mult Scler 2007; 13(5): 610– 615.

3. Medana I, Martinic MA, Wekerle H, Ne umann H. Transecti on of major histocompatibility complex class I‑induced ne urites by cytotoxic T lymphocytes. Am J Pathol 2001; 159(3): 809– 815.

4. Bsibsi M, Ravid R, Gveric D, van No ort JM. Bro ad expressi on of Toll‑like receptors in the human central nervo us system. J Ne uropathol Exp Ne urol 2002; 61(11): 1013– 1021.

5. Serafini B, Rosicarelli B, Magli ozzi R, Stigli ano E, Alo isi F. Detecti on of ectopic B- cell follicles with germinal centres in the meninges of pati ents with secondary progressive multiple sclerosis. Brain Pathol 2004; 14(2): 164– 174.

6. Marmont AM, Gu alandi F, Occhini D, Morandi F, Ferretti E, Pezzolo A et al. Catastrophic relapse of Evans syndrome five ye ars after allogeneic BMT notwithstanding full donor chimerism. Terminal hemolytic– uremic syndrome. Auto immunity 2006; 39(6): 505– 511.

7. Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC. The natural history of multiple sclerosis: a ge ographically based study 9: observati ons on the progressive phase of the dise ase. Brain 2006; 129(3): 584– 594.

8. IFNB Multiple Sclerosis Study Gro up. Interferon beta‑lb is effective in relapsing- remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, do uble- blind, placebo- controlled tri al. Ne urology 1993; 43(4): 655– 661.

9. Paty DW, Li DK. Interferon beta‑1b is effective in relapsing- remitting multiple sclerosis. II. MRI analysis results of a multicenter, randomized, do uble- blind, placebo- controlled tri al. Ne urology 1993; 43(4): 662– 667.

10. IFNB Multiple Sclerosis Study Gro up and the University of British Columbi a MS/ MRI Analysis Gro up. Interferon beta‑1b in the tre atment of multiple sclerosis: final o utcome of the randomized controlled tri al. Ne urology 1995; 45(7): 1277– 1285.

11. Jacobs LD, Co okfair DL, Rudick RA, Herndon RM, Richert JR, Salazar AM et al. Intramuscular interferon beta‑1a for dise ase progressi on in relapsing multiple sclerosis. Ann Ne urol 1996; 39(3): 285– 294

12. Simon JH, Jacobs LD, Campi on M, Wende K, Simoni an N, Co okfair DL et al. Magnetic resonance studi es of intramuscular interferon beta‑1a for relapsing multiple sclerosis. Ann Ne urol 1998; 43(1): 79– 87.

13. PRISMS (Preventi on of Relapses and Disability by Interferon beta‑1a Subcutane o usly in Multiple Sclerosis) Study Gro up. Randomised do uble- blind placebo-controlled study of interferon beta‑1a in relapsing/ remitting multiple sclerosis. Lancet 1998; 352(9139): 1498– 1504.

14. Johnson KP, Bro oks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP et al. Copolymer 1 reduces relapse rate and improves disability in relapsing- remitting multiple sclerosis: results of a phase III multicenter, do uble- blind placebo- controlled tri al. Ne urology 1995; 45(7): 1268– 1276.

15. Polman CH, O‘Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH et al. A randomized, placebo- controlled tri al of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354(9): 899– 910.

16. Sorensen PS, Fazekas F, Lee M. Intraveno us immunoglobulin G for the tre atment of relapsing- remitting multiple sclerosis: a meta‑analysis. Eur J Ne urol 2002; 9(6): 557– 563.

17. Smith DR, Weinstock- Guttman B, Cohen JA, Wei X,Gutmann C, Bakshi R et al. A randomized blinded tri al of combinati on therapy with cyclophosphamide in pati ents- with active multiple sclerosis on interferon beta. Mult Scler 2005; 11(5): 573– 582.

18. Edan G, Miller D, Clanet M, Confavre ux C, Lyon- Caen O, Lubetzki C et al. Therape utic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active dise ase using MRI and clinical criteri a. J Ne urol Ne urosurg Psychi atry 1997; 62(2): 112– 118.

19. Le Page E, Leray E, Ta urin G, Co ustans M, Chaperon J, Morrissey SP et al. Mitoxantrone as inducti on tre atment in aggressive relapsing remitting multiple sclerosis: tre atment response factors in a 5 ye ar follow‑up observati onal study of 100 consecutive pati ents. J Ne urol Ne urosurg Psychi atry 2008; 79(1): 52– 56.

20. Europe an Study Gro up on interferon beta‑1b in secondary progressive MS. Placebo- controlled multicentre randomised tri al of interferon beta‑1b in tre atment of secondary progressive multiple sclerosis. Lancet 1998; 352(9139): 1491– 1497.

21. Weiner HL, Mackin GA, Orav EJ, Hafler DA, Dawson DM, LaPi erre Y et al. Intermittent cyclophosphamide pulse therapy in progressive multiple sclerosis: final report of the Northe ast Co operative Multiple Sclerosis Tre atment Gro up. Ne urology 1993; 43(5): 910– 918.

22. Hartung HP, Gonsette R, König N, Kwi ecinski H, Guse o A, Morrissey SP et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, do uble- blind, randomised, multicentre tri al. Lancet 2002; 360(9350): 2018– 2025.

23. Karussis DM, Slavin S, Lehmann D, Mizrachi- Koll R, Abramsky O, Ben- Nun A. Preventi on of experimental a uto immune encephalomyelitis and inducti on of tolerance with acute immunosuppressi on followed by syngeneic bone marrow transplantati on. J Immunol 1992; 148(6): 1693– 1698.

24. Karussis DM, Slavin S, Ben- Nun A, Ovadi a H, Vo urka- Karussis U, Lehmann D et al. Chronic‑relapsing experimental a uto immune encephalomyelitis (CR- EAE): tre atment and inducti on of tolerance, with high dose cyclophosphamide followed by syngeneic bone marrow transplantati on. J Ne uro immunol 1992; 39(3): 201– 210.

25. van Gelder M, Kinwel– Bohré EP, van Bekkum DW. Tre atment of experimental allergic encephalomyelitis in rats with total body irradi ati on and syngeneic BMT. Bone Marrow Transplant 1993; 11(3): 233– 241.

26. Burt RK, Padilla J, Begolka WS, Canto MC, Miller SD. Effect of dise ase stage on clinical o utcome after syngeneic bone marrow transplantati on for relapsing experimental a uto immune encephalomyelitis. Blo od 1998; 91(7): 2609– 2616.

27. Ikehara S, Go od RA, Nakamura T, Sekita K, Ino ue S,Oo MM et al. Rati onale for bone marrow transplantati on in the tre atment of a uto immune dise ases. Proc Natl Acad Sci USA 1985; 82(8): 2483– 2487.

28. van Bekkum DW. Stem cell transplantati on for a uto immune disorders. Preclinical experiments. Best Pract Res Clin Haematol 2004; 17(2): 201– 222.

29. McAllister LD, Be atty PG, Rose J. Allogeneic bone marrow transplant for chronic myelogeno us le ukemi a in a pati ent with multiple sclerosis. Bone Marrow Transplant 1997; 19(4): 395– 397.

30. Snowden JA, Patton WN, O‘Donnell JL, Hannah EE, Hart DN. Prolonged remissi on of longstanding systemic lupus erythematosus after a utologo us bone marrow transplant for non‑Hodgkin‘s lymphoma. Bone Marrow Transplant 1997; 19(12): 1247– 1250.

31. Fassas A, Anagnostopo ulos A, Kazis A, Kapinas K, Sakellari I, Kimiskidis V et al. Peripheral blo od stem cell transplantati on in the tre atment of progressive multiple sclerosis: first results of a pilot study. Bone Marrow Transplant 1997; 20(8): 631– 638.

32. Fassas A, Anagnostopo ulos A, Kazis A, Kapinas K,Sakellari I, Kimiskidis V et al. Autologo us stem cell transplantati on in progressive multiple sclerosis – an interim analysis of efficacy. J Clin Immunol 2000; 20(1): 24– 30.

33. Kozák T, Havrdová E, Pitha J, Gregora E, Pytlík R, Maalo ufová J et al. High‑dose immunosuppressive therapy with PBPC support in the tre atment of po or risk multiple sclerosis. Bone Marrow Transplant 2000; 25(5): 525– 531.

34. Su L, Xu J, Ji BX, Wan SG, Lu CY, Dong HQ et al. Autologo us peripheral blo od stem cell transplantati on for severe multiple sclerosis. Int J Hematol 2006; 84(3): 276– 281.

35. Xu J, Ji BX, Su L, Dong HQ, Sun XJ, Li u CY. Clinical o utcomes after a utologo us haematopo i etic stem cell transplantati on in pati ents with progressive multiple sclerosis. Chin Med J (Engl) 2006; 119(22): 1851– 1855.

36. Shevchenko YL, Novik AA, Kuznetsov AN, Afanasi ev BV, Lisukov IA, Kozlov VA et al. High‑dose immunosuppressive therapy with a utologo us hematopo i etic stem cell transplantati on as a tre atment opti on in multiple sclerosis. Exp Hematol 2008; 36(8): 922– 928.

37. Samijn JP, te Boekhorst PA, Mondri a T, van Do orn PA, Flach HZ, van der Meché FG et al. Intense T cell depleti on followed by a utologo us bone marrow transplantati on for severe multiple sclerosis. J Ne urol Ne urosurg Psychi atry 2006; 77(1): 46– 50.

38. Carreras E, Saiz A, Marín P, Martínez C, Rovira M, Villamor N et al. CD34+ selected a utologo us peripheral blo od stem cell transplantati on for multiple sclerosis: report of toxicity and tre atment results at one ye ar of follow‑up in 15 pati ents. Haematologica 2003; 88(3): 306– 314.

39. Loh SM, Ratnagopal P, Tan HC, Goh YT, Koh BC, Koh LP et al. Successful a utologo us hematopo i etic stem cell transplantati ons for severe multiple sclerosis with fludarabine and cyclophosphamide conditi oning. Int J Hematol 2006; 83(4): 368– 369.

40. Burt RK, Cohen BA, Russell E, Spero K, Joshi A, Oyama Y et al. Hematopo i etic stem cell transplantati on for progressive multiple sclerosis: failure of a total body irradi ati on‑based conditi oning regimen to prevent dise ase progressi on in pati ents with high disability scores. Blo od 2003; 102(7): 2373– 2378.

41. Openshaw H, Lund BT, Kashyap A, Atkinson R, Sni ecinski I, Weiner LP et al. Peripheral blo od stem cell transplantati on in multiple sclerosis with busulfan and cyclophosphamide conditi oning: report of toxicity and immunological monitoring. Bi ol Blo od Marrow Transplant 2000; 6(5A): 563– 575.

42. Gu alandi F, Bruno B, Van Lint MT, Luchetti S, Uccelli A,Capello E et al. Autologo us stem cell transplantati on for severe a uto immune dise ases: a 10- ye ar experi ence. Ann N Y Acad Sci 2007; 1110: 455– 464.

43. Fassas A, Passweg JR, Anagnostopo ulos A, Kazis A,Kozak T, Havrdova E et al. Hematopo i etic stem cell transplantati on for multiple sclerosis. A retrospective multicenter study. J Ne urol 2002; 249(8): 1088– 1097.

44. Saccardi R, Kozak T, Bocelli- Tyndall C, Fassas A, Kazis A, Havrdova E et al. Autologo us stem cell transplantati on for progressive multiple sclerosis: update of the Europe an Gro up for Blo od and Marrow Transplantati on a uto immune dise ases working party database. Mult Scler 2006; 12(6): 814– 823.

45. Kurtzke JF. Disability rating scales in multiple sclerosis. Ann N Y Acad Sci 1984; 436: 347– 360.

46. Saiz A, Blanco Y, Carreras E, Berenguer J, Rovira M, Pujol T et al. Clinical and MRI o utcome after a utologo us hematopo i etic stem cell transplantati on in MS. Ne urology 2004; 62(2): 282– 284.

47. Saiz A, Blanco Y, Berenguer J, Gómez- Choco M, Carreras E, Arbizu T et al. Clinical o utcome 6 ye ars after a utologo us hematopo i etic stem cell transplantati on in multiple sclerosis. Ne urologi a 2008; 23(7): 405– 407.

48. Mancardi G, Saccardi R. Autologo us haematopo i etic stem- cell transplantati on in multiple sclerosis. Lancet Ne urol 2008; 7(7): 626– 636.

49. Bowen J. High‑Dose Immunosuppressi on and Autologo us Transplantati on for Multiple Sclerosis (HALT MS) Study. Dostupné z URL: http:/ / www.clinicaltri al.gov/ ct2/ show/ NCT00288626?term=halt+ms&rank=1.

50. Burt R. Stem Cell Therapy for Pati ents With Multiple Sclerosis Failing Interferon A Randomized Study. Dostupné z URL: http:/ / www.clinicaltri al.gov/ ct2/ show/ NCT00273364?term=transplantati on+and+multiple+sclerosis&rank=10.

51. Nash RA, Bowen JD, McSweeney PA, Pavletic SZ, Maravilla KR, Park MS et al. High‑dose immunosuppressive therapy and a utologo us peripheral blo od stem cell transplantati on for severe multiple sclerosis. Blo od 2003; 102(7): 2364– 2372.

52. Mancardi GL, Saccardi R, Filippi M, Gu alandi F, Muri aldo A, Inglese M et al. Autologo us hematopo i etic stem cell transplantati on suppresses Gd- enhanced MRI activity in MS. Ne urology 2001; 57(1): 62– 68.

53. Filippi M, Rovaris M, Capra R, Gasperini C, Yo usry TA, Sormani MP et al. A multi‑centre longitudinal study comparing the sensitivity of monthly MRI after standard and triple dose gadolini um- DTPA for monitoring dise ase activity in multiple sclerosis. Implicati ons for phase II clinical tri als. Brain 1998; 121(10): 2011– 2020.

54. Saccardi R, Mancardi GL, Solari A, Bosi A, Bruzzi P,Di Bartolome o P et al. Autologo us HSCT for severe progressive multiple sclerosis in a multicenter tri al: impact on dise ase activity and qu ality of life. Blo od 2005; 105(6): 2601– 2607.

55. Inglese M, Mancardi GL, Pagani E, Rocca MA, Muri aldo A, Saccardi R et al. Brain tissue loss occurs after suppressi on of enhancement in pati ents with multiple sclerosis tre ated with a utologo us haematopo i etic stem cell transplantati on. J Ne urol Ne urosurg Psychi atry 2004; 75(4): 643– 644.

56. Chen JT, Collins DL, Atkins HL, Freedman MS, Galal A,Arnold DL. Brain atrophy after immuno ablati on and stem cell transplantati on in multiple sclerosis. Ne urology 2006; 66(12): 1935– 1937.

57. Roccatagli ata L, Rocca M, Valsasina P, Bonzano L, Sormani M, Saccardi R et al. The long‑term effect of AHSCT on MRI me asures of MS evoluti on: a five- ye ar follow‑up study. Mult Scler 2007; 13(8): 1068– 1070.

58. Rocca MA, Mondri a T, Valsasina P, Sormani MP, Flach ZH, Te Boekhorst PA et al. A three- ye ar study of brain atrophy after a utologo us hematopo i etic stem cell transplantati on in rapidly evolving secondary progressive multiple sclerosis. AJNR Am J Ne uroradi ol 2007; 28(9): 1659– 1661.

59. Metz I, Lucchinetti CF, Openshaw H, Garci a- Merino A,Lassmann H, Freedman MS et al. Autologo us haematopo i etic stem cell transplantati on fails to stop demyelinati on and ne urodegenerati on in multiple sclerosis. Brain 2007; 130(5): 1254– 1262.

60. Martin R. Is haematopo i etic stem cell transplantati on a tre atment opti on for severe MS or not? Brain 2007; 130(5): 1181– 1182.

61. Nash RA, Stuve O, Bowen JD, Frohman EM, Griffith LM, Hutton GJ et al. Autologo us HSCT for advanced MS: is the glass half- empty or re ally half- full? Brain 2008; 131(2): e89.

62. Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ. Me asurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain 2002; 125(8): 1676– 1695.

63. Chen JT, Collins DL, Atkins HL, Freedman MS, Arnold DL; Canadi an MS/ BMT Study Gro up. Magnetizati on transfer rati o evoluti on with demyelinati on and remyelinati on in multiple sclerosis lesi ons. Ann Ne urol 2008; 63(2): 254– 262.

64. Fassas A, Mancardi GL. Autologo us hemopo i etic stem cell transplantati on for multiple sclerosis: Is it worthwile? Auto immunity 2008; 41(8): 601– 610.

65. Sun W, Popat U, Hutton G, Zang YC, Krance R, Carrum G et al. Characteristics of T- cell receptor reperto ire and myelin‑re active T cells reconstituted from a utologo us haematopo i etic stem- cell grafts in multiple sclerosis. Brain 2004; 127(5): 996– 1008.

66. Muraro PA, Do uek DC, Packer A, Chung K, Guenaga FJ, Cassi ani– Ingoni R et al. Thymic o utput generates a new and diverse TCR reperto ire after a utologo us stem cell transplantati on in multiple sclerosis pati ents. J Exp Med 2005; 201(5): 805– 816.

67. de Kleer I, Vastert B, Klein M, Teklenburg G, Arkesteijn G, Yung GP et al. Autologo us stem cell transplantati on for a uto immunity induces immunologic self- tolerance by reprogramming a utore active T cells and restoring the CD4+CD25+ immune regulatory network. Blo od 2006; 107(4): 1696– 1702.

68. Mezey E, Key S, Vogelsang G, Szalayova I, Lange GD, Crain B. Transplanted bone marrow generates new ne urons in human brains. Proc Natl Acad Sci USA 2003; 100(3): 1364– 1369.

69. Wagers AJ, Sherwo od RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopo i etic stem cells. Sci ence 2002; 297(5590): 2256– 2259.

70. Castro RF, Jackson KA, Go odell MA, Robertson CS, Li u H, Shine HD. Failure of bone marrow cells to transdifferenti ate into ne ural cells in vivo. Sci ence 2002; 297(5585): 1299.

71. Burt RK, Fassas A, Snowden J, van Laar JM, Kozak T,Wulffraat NM et al. Collecti on of hematopo i etic stem cells from pati ents with a uto immune dise ases. Bone Marrow Transplant 2001; 28(1): 1– 12.

72. Statkute L, Verda L, Oyama Y, Traynor A, Villa M, Sho ok T et al. Mobilizati on, harvesting and selecti on of peripheral blo od stem cells in pati ents with a uto immune dise ases undergo ing a utologo us hematopo i etic stem cell transplantati on. Bone Marrow Transplant 2007; 39(6): 317– 329.

73. Openshaw H, Stuve O, Antel JP, Nash R, Lund BT, Weiner LP et al. Multiple sclerosis flares associ ated with recombinant granulocyte colony- stimulating factor. Ne urology 2000; 54(11): 2147– 2150.

74. Gratwohl A, Passweg J, Bocelli- Tyndall C, Fassas A, van Laar JM, Farge D et al. Autologo us hematopo i etic stem cell transplantati on for a uto immune dise ases. Bone Marrow Transplant 2005; 35(9): 869– 879.