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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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