Autologous Stem Cell Transplantation in Autoimmune …Autologous Stem cell transplantation in...
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9/25/11
Autologous Stem Cell Transplantation in
Autoimmune Disorders
Dr Sunil DabadghaoSenior Consultant in Clinical Immunology, Haematology, BMT and Laboratory MedicineSahara Hospital , LucknowIndia
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Farge et al : Haematologica (2010) 95 : 284-92EBMT working Party on Autoimmune Disorders
Total No of ASCT done : 900
Period : 1996-2007
Prime Indications (88%): MS, SSc, SLE, RA, JIA, HIC
5 Year OS : 85 %
5 year PFS : 43%
Mortality (111/900)
TRM : 53%
Disease : 39 %
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Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial
Group Immuno-suppression
Regimen
n Follow up
(months) Result
TRM
HSCT Cy (200mg/kg)rATG (6.5 mg/kg)
10 12-24 100% NIL
StandardTherapy
Cy 1 gm/m2/ month x 6 months
9 *** 11% NIL
Burt R. et al Lancet (2011) 378: 498-06
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Autotransplantation in Autoimmune Disorders : Indications
Farge et al : Haematologica (2010) 95 : 284-92
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Is There a Middle Path ???
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High Dose Cyclophosphamide without stem cell rescue
High dose Cyclophosphamide without stem Cell rescue in Scleroderma Tehlirian et al Ann Rheum Dis (2008) 67: 775-81
Reduction of Disease activity and Disability with high dose cyclophosphamide in patients with agresive multiple sclerosis
Krishnan et al Arch Neurol (2008) 65 : 1044-51
John Hopkins Medical Institute, Baltimore
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HSCT versus Hi D Cy in multiple sclerosis Group
n
TRM Follow up Result (PFS)
EULAR-EBMT registry
345 2% > 5 years 45%
John Hopkins Medical Institute
9 NIL 2 years 78%
HSCT versus Hi D Cy in Systemic Sclerosis Group
n
TRM Follow up Result (PFS)
EULAR-EBMT registry
175 6% > 5 years 55%
John Hopkins Medical Institute
6 17% 2 years 50 %
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Comparison of HSCT with Hi D Cy in SLE
Group
n
TRM Follow up Result (PFS)
EULAR-EBMT registry
85 11% > 5 years 45%
John Hopkins Medical Institute
21 NIL 30 months 48 %
High-Dose Cyclophosphamide Versus Monthly Intravenous Cyclophosphamide for Systemic Lupus Erythematosus. A Prospective Randomized TrialPetri et alArthritis and Rheum (2010 ) 62 : 1487–93
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Immuno-suppression
Immuno-modulation
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Changes in Lymphocyte subsets following Autologous Stem cell transplantation in Autoimmune
Disorders
Immunological reconstitution after autologous hematopoietic stem cell transplantation in patients with systemic sclerosis: relationship between clinical benefits and intensity of immunosuppression
Bohgaki et al : J Rheumatol(2009)36:1240-8.
Good responder : low levels of “recent thymic emigrants” or Naïve T cells correlated best with clinical response
Farge et al: Arthritis and Rheum(2005) 52: 1555-63
Rate of Recovery of B lymphocyte numbers correlated with clinical response
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Tregs: CD4, CD25 foxp3 positive T-lymphocyte subset
A key player in autoimmune disorders! Autologous bone marrow transplantation in
autoimmune arthritis restores immune homeostasis through CD4CD25Foxp3 regulatory T cells
Roord et al Blood (2008)111 : 5233-41
Host CD4CD25 T cells can expand and comprise a major component of the Treg compartment after experimental HCT
Bayer et al Blood(2009) 113 : 733-43
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Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system
Alexander et al Blood (2009) 113 : 214-22
Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4CD25 immune regulatory network
de Kleer et al Blood (2006) 107 : 1696-72
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Th17 Lymphocyte subset: Another key player in development of Autoimmunity
Oukka M: Ann Rheum Dis 2007;66 (Suppl III):iii87–iii90
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Halofuginone inhibits TH17 cell differentiation by
activating the amino acid starvation response.
Sundrud M et al
Science 2009 Jun 5;324(5932):1334-8.
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Conclusion:
High Dose cyclophosphamide without stem cell rescue may be a more cost effective, less labour intensive and equally efficacious way to manage MS and SLE
For SSc currently HSCT appears to give the best chance for long term PFS
Post Hy-D-Cy or Auto-HSCT , immmuno-modulation should be seriously considered
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