Transplantation in Autoimmune Disease He Huang, M.D., Ph.D. Bone Marrow transplantation Center The First Affiliated Hospital Zhejiang University School of Medicine China
Contents • Rationale for HSCT • Auto-HSCT for autoimmune disease • Allo-HSCT for autoimmune disease
Autoimmune Disease (ADs) • Organ specific – Type 1 diabetes mellitus – Multiple sclerosis (MS) • Systemic diseases – Systemic lupus erythematosus (SLE) – Rheumatoid arthritis (RA) – Systemic sclerosis (SSc)
Severe Autoimmune Disease • May result in severe intractable health states • shorten lives considerably • cause significant disability
Pathogenesis of ADs • Parallels the lymphoproliferative disorders • Lymphoproliferative disorders – failure of cell cycle regulation and subsequent clonal expansion of a transformed precursor • Autoimmune conditions – failure to inhibit polyclonal expansion and activation upon exposure to self-antigens
Pathogenesis of ADs • Genetic susceptibility • The failure of the checkpoints available to prevent autoimmunity following exposure to environmental challenges
Therapy for Autoimmune Disease • Replacement therapies for organ specific disease • For systemic diseases – Glucocorticoids – Immunosuppressive agents – Biologics • Could not be cured • Can carry their own burden of side effects
Haematopoietic stem cell transplantation in ADs • A ‘one - off’ intensive treatment • Can induce prolonged remissions, stabilization and potentially cure • Initially in animal models starting three decades ago • Initially in the first clinical studies from 1995
HSCT in Ads: experimental models • the curative potential of autologous bone marrow transplantation was discovered in rats with induced Arthritis and induced EAE DW Van Berkkum et al, BMT 2003
Rationale for HSCT • Transformed hematopoietic precursors beget transformed progeny • precursors in patients with autoimmune disease beget progeny with a new repertoire of characteristics • ‘resetting’ or ‘rebooting’ the immune system
Rationale for HSCT • The types of protocol used in transplantation have been both myeloablative and lymphoablative. • Patients suffer from a genetic predisposition that leads to regulatory escape and subsequent self- reactivity. • transplanted patients will develop a new repertoire.
HSCT: Resetting • S. Abrahamsson et al. autoimmumty 2008
Auto-HSCT: Just Immune Suppression? • A profound lymphopenia in the first year after transplantation. – B cells, natural killer (NK) cells, and CD81 T cells display a rapid and complete reconstitution to pretransplantation levels – the recovery of CD41 T cells has consistently been observed to be delayed, and often incomplete • Is Auto-HSCT Just Immune Suppression?
Auto-HSCT: Just Immune Suppression? • CD4+ T cells recover after a 2-year follow-up in young adults treated for MS and RA. – Quantitative recovery of lymphocytes was not correlated to inflammatory activity or disease relapse • Immune deficit is an insufficient explanation for a prolonged absence of autoimmune disease activity after autologous HCT Muraro et al, J Exp Med. 2005 Snowden JA et al, J Rheumatol. 2004
Auto-HSCT: Immune Resetting • regeneration of a new, naïve T cell repertoire emerging from the thymus. Muraro et al, J Exp Med. 2005
Auto-HSCT: Immune Resetting • A detailed analysis of T cell receptor showed the regeneration of a different and more diverse TCR posttransplant. Muraro et al, J Exp Med. 2005
Auto-HSCT: Immune Resetting • Regeneration of naïve T cell also can be seen in SLE. Alexander T et al, Blood. 2009
Auto-HSCT: Immune Resetting • forkhead transcription factor 3 (FoxP3) – Expressed by CD4+CD25+ cell – suppressors of immune responses normal expression after HSCT Low expression in SLE patients Alexander T et al, Blood. 2009
Contents • Rationale for HSCT • Auto-HSCT for autoimmune disease • Allo-HSCT for autoimmune disease • Economic costs
Auto-HSCT for ADs SaccArdi R et al. autoimmunity,2008
Auto-HSCT for ADs: EBMT • EBMT Registry • Patients 1122 Male/Female % 37/63 • Centres/Countries 198/ 30 • Transplant Procedure 1152 • Median Follow Up 2.8 Years • Autograft 1074 First 1064 Second 10 • Allograft 77 First 57 Second 15 Third 3 Data courtesy of EBMT: update to Jan 2010
Auto-HSCT for ADs: EBMT • distribution for diagnosis • Multiple Sclerosis 417 • Connective Tissue Disease 355 • Arthritis 172 • Inflammatory Bowel 40 • Hematological 68 • Vasculitis 34 • Other 55 Data courtesy of EBMT: update to Jan 2010
Auto-HSCT for ADs: EBMT • number of HSCT per year Data courtesy of EBMT: update to Jan 2010
Auto-HSCT for ADs: EBMT • Transplants by year 1996-2009 Data courtesy of EBMT: update to Jan 2010
Auto-HSCT for ADs: TRM • TRM for 1995 – 2000 was 7.3%; • TRM for 2001 – 2007 was 1.3%. Data courtesy of EBMT
Auto-HSCT for ADs: EBMT • Overall Survival Farge et al, Haematogica, 2010.
Auto-HSCT for ADs: EBMT • D100 TRM Farge et al, Haematogica, 2010.
Auto-HSCT for ADs: EBMT • PFS Farge et al, Haematogica, 2010.
Auto-HSCT for ADs: EBMT • PFS Farge et al, Haematogica, 2010.
Auto-HSCT for ADs: Stem Cells Harvest • mobilisition – Cyclophosphamide (1.5 – 4.0 g/m2 total dose over 1 – 2 days) – Followed by daily granulocyte colony-stimulating factor (G-CSF; 5 –12 μg/kg/day) until harvest – Can also be mobilised with G-CSF alone, but flare of the disease with occurrence of neurological symptoms has been reported • Stem cells dose: 3 × 10⁶ CD34+ cells/kg bodyweight
Auto-HSCT for ADs: conditioning regimen • usually done within 30 – 60 days of stem-cell collection – BEAM – Carmustine + CTX – TBI+CTX – BuCy or Bu alone – fludarabine + CTX • in-vivo T-cell depletion: ATG or monoclonal antibodies
Auto-HSCT for MS • After a follow-up period of 3 years, a median of 60 – 70% of treated cases did not progress. – assessed by expanded disability status scale (EDSS) scores • Some patients improved, but in most cases, the EDSS score remained stable
Auto-HSCT for MS • the number of stable patients was reduced with time – Barcelona group: PFS 85% for 3 years – 62.5% for 6 years – Italian prospective trial: PFS 84% for 3 years – 58% for 8.5 years
Auto-HSCT for MS: Conditioning Regimen • A EBMT retrospective multicenter study • 20 centers, 85 patients R Saccardi et al, Multiple Sclerosis 2006
Auto-HSCT for MS: Conditioning Regimen • Confirmed-Progression-free Survival + 95% CI – BEAM 79 ± 13 – Cyclophosphamide 90 ± 19 – Radiation or Busulphan based 51 ± 35 – P=0.21 • High-intensity regimens do not result in a better neurological outcome R Saccardi et al, Multiple Sclerosis 2006
Auto-HSCT for MS: Age • Another EBMT retrospective multicenter study • 169 patients • Median age: 34 y, range from 15 to 58 y. • Median disease duration: 6.7 y. range from 0.2-28.5 y. Mancardi GL et al, Lancet Neurol 2008
Auto-HSCT for MS: Age • patients younger than 40 years of age had a significantly better outcome, independently of disease duration Mancardi GL et al, Lancet Neurol 2008
Auto-HSCT for MS: Quality of Life • The collaborative Italian BMT study group addressed the effect of AHSCT on the patients’ quality of life • life-54 questionnaire • 19 patients • median follow-up of 36 months (range, 12 to 72 months) R Saccardi et al, blood 2005
Auto-HSCT for MS: Quality of Life treatment was followed by significant improvements in the physical and mental health composite scores R Saccardi et al, blood 2005
Auto-HSCT for MS: Quality of Life • Another retrospective study • SF-36 questionnaire • Total SF-36 score raise from 52.2 to 78.9 RK Burt et al, Lancet Neurol 2009
Auto-HSCT for MS: Ongoing Clinical Trails L Griffth et al, BBMT in press
Auto-HSCT for SLE • A single-arm trial • 50 patients with SLE refractory to standard immunosuppressive therapies • Either organ- or lifethreatening visceral involvement • Peripheral blood stem cells • Conditioning Regimen: CTX + ATG RK Burt et al, JAMA 2010
Auto-HSCT for SLE RK Burt et al, JAMA 2010
Auto-HSCT for SLE • The level of ANA RK Burt et al, JAMA 2010
Auto-HSCT for SLE • The SLE Disease Activity Index RK Burt et al, JAMA 2010
Auto-HSCT for SLE: heart failure • Cyclophosphamide-based HSCT protocols is the risk of cardiotoxicity • A retrospective analysis of the Chicago group • A subgroup of 6 patients with cardiac dysfunction • Conditioning Regimen: CTX + ATG/alemtuzumab Y Loh et al, BMT 2007
Auto-HSCT for Type 1 Diabetes Mellitus • Transplantation for MS and SLE – patients are the most severe cases and generally have not responded to usual therapies. – significant mortality rates • Type 1 diabetes mellitus – Well controlled by insulin – Is HSCT necessary?
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