AUTOLOGOUS STEM CELL TRANSPLANTATION for AUTOIMMUNE DISEASES? YES

Transcription

1 AUTOLOGOUS STEM CELL TRANSPLANTATION for AUTOIMMUNE DISEASES? YES Pr Dominique Farge, Hôpital St Louis, Paris 7 Denis Diderot University, France, ADWP EBMT Chair The European Group for Blood and Marrow Transplantation

2 ASCT: Bone Marrow, Peripheral BSC, Mesenchymal SC, Cord Bood? RESET of TOLERANCE MSC HSCT.. CPM po, iv Anti TNF, Anti-CD2, Anti-Blys CORTICOSTEROIDS MTX AZATHIOPRINE ATG CYCLO A 199 MMF NEORAL SEVERE or RAPIDLY EVOLUTIVE FORMS of AD: Systemic Sclerosis: 5 yrs survival 3% 4% Systemic Lupus:1 yrs survival /ESRF: 7 / 5% 9 / 35% Multiple Sclerosis: DMD IFN, copaxone, natalizumab, mitoxantrone, fingolimod, cladribine Crohn s: DMD 5-ASA, steroids, Aza, Metho infliximab, Adalimumab, natalizumab Early onset of non KA type I DM: life-long Insulin therapy

3 Systemic Sclerosis: prevalence 7 5 / Million SKIN THICKNESS joint contractures, GI, lung, heart, kidney Diffuse Cutaneous Intermedia te Late Limited Cutaneous pulmopnary hypertension malabsorption Late Intermediate 5 1 Arthr Rhum Steen 2 2 N risk factors Total no. of pts Nb / RR of deaths J. Fransen, D. EUSTAR 21

4 IMPROVED THERAPY OVER THE LAST 2 YRS in SLE prevalence 4-5 / % ERD at 5-1 yrs, 1 yr survival : % percentage 81% 1st remission, 1/3 relapse, TT TOXICITY: infection + metabolic, bone, ovary dysfunctions PRONOSTIC FACTORS: Compliance, Response 1st treatment **, Race, socio-economic factor, HBP Activity / Chronicity Index, SAPL Initial Renal failure, Relapse nephritic Cook J Rheumatol 2 ** Houssiau Arth Rheum 24 Doria, Am J Med 26: SLE 35%, 64% infection Illei G Ann Rheum Dis 211 ESRF Mortality All SLE mortality 5 SLEDAI years 76-8% * * RR* Survival n= 27

5 Haematopoietic stem cell transplantation (HSCT) in severe auto-immune diseases: updated guidelines written on behalf of the EBMT ADWP and PDWP J Snowden, R Saccardi, M Allez, S Ardizzone, R Arnold, R Cervera, C Denton, JM van Laar, M Labopin, G Mancardi, R Martin, JJ Moore, J Passweg, C Peters, M Rabusin, M Rovira, D Farge (BMT 211 in press) Per Ljungmann BMT 29 Level II = at least one well designed clinical trial without randomisation: cohort or case controlled analytical studies (preferably > one centre), multiple time series studies Disease Sib donor Well matched unrelated Mismatched donor Autologous MS D/III SSc D/III SLE D/III Crohn s RA Vasculitis CIPD Cytopenia D/III T1D D/III RCD Type II D/III PolymyositisDermatomyositis Special report Blood and marrow stem cell transplants in auto-immune disease: a consensus report written on behalf of the EULAR and the EBMT A Tyndall and A Gratwohl BMT 1997

6 Number of HSCT per year: EBMT Registry *All transplants not yet registered for *

7 Number of HSCT: 1357 HSCT (1254 autologous) Centres /Countries Overall Follow up MULTIPLE SCLEROSIS CONNECTIVE TISSUE D. SSc SLE PM-DM Sjogren Antiphosph. syndrome Other/Unknown ARTHRITIS Rheumatoid arthritis Juvenile chronic arthritis : - Systemic JIA 49 - Other JIA - Polyarticular JIA Psoriatic arthritis Other INFLAMMATORY BOWEL Crohn's disease Ulcerative colitis Other /31 2.9y (<1-24) HAEMATOLOGICAL ITP Evan s AIHA Other VASCULITIS Wegener s Behcet s Takayasu Microscopic poly. nodosa Classical poly. nodosa Churg-Strauss Other/Unknown OTHER NEUROLOGICAL Myasthenia gravis Other/Unknown INSULIN DEPENDANT DIABETES 1 OTHER/UNKNOWN/MISSING

8 ADs: HSCT per Country September 211* *All transplants not yet registered for Ita ly rm e G U y an te ni d ng i K d om a a n a y d a el e i i i n e m r l c n n. c s a c e i. iu s d ga ola Is r an tra ubli ree Ch s. Sp g u e r l n s d R Be F P n G p Sw A u Hu e lr a R e h h t ec z Ne C

9 Overall Survival at 3 yrs (n= 9) Progression Free Survival at 3 yrs (n=9) % SSc % MS % SLE 1, 1, % JIA (n = 65) % HIC (n=37) % RA (n = 89),8, % RA (n = 89) % MS (n = 345) % SLE (n = 85) % JIA (n = 65) % HIC (n=37) 8 + 3% SSc (n = 137),6,4,2 (n = 137) (n = 345) (n = 85),6,4,2,, Center effect related to activity Farge et al Hematologica

10 DETERMINANTS OF CLINICAL RESPONSE? Farge Arthr Rheum 25 Verrecchia F Rheumatology 27 Aschwanden Daikeler et al ARD 28 Launay D J Rheumatol 29

11 ASTIS: Pts rapidly progressive or severe SSc (n = 156 ) 4 yrs + skin score 15 (-51) + involvement heart/lung/kidney 2 yrs + skin score 2 + ESR>25mm/1st hr and/or Hb<11 gr/dl Immunoablation + AST = 1. Mobilisation CYC4 g/m 2,G-CSF 1 m g/kg 2. Leukapheresis /CD34-selection 3. Conditioning C YC 2 mg/kg, ATG 7.5 mg/kg Reinfusion CD34+ cells Standard-therapy 12x monthly 2 i.v. pulse CYC 75 mg/m EFS = survival minus persistent major organ failure (heart, lung, kidney) Exclusion criteria: PHT > 5 mmhg, DLCO < 4%, creat.cl. < 4 ml/min. LVEF < 45%; uncontrolled arhythmia; cardiac tamponade infection, etc. previous treatment with CYCLO: >5 gr iv, >3 mths po

12 3/ 22 /2 3/ 22 / Pa Le ris Nij iden me Flo gen Am ren ste ce rd am He Ba rne sel Tu Trie Str bin g r as en bo u Le rg e Vie ds n Ma na rs Gr eil le en Fre oble i To bur g ulo Wu us rz e Bo bur rde g Cle a rm ux F Fe err r Fra rara nk Le furt uv en Mo Lille Mo nt re Th ntpe al es l li e sa r lon Mi iki dd les Mi la bro n ug h date 3/ 22 /2 3/ 22 /2 3/ 22 /2 3/ 22 /2 3/ 22 /2 3/ 22 /2 3/ 22 /2 number of patients Accrual ASTIS trial Accrual per centre SSc: 79 SCT+77 controls in 27 centers France: 49; Netherlands: 54 Germany: 2; Italy: 16 Switzerland: 7, UK: 5 Austria:3, Belgium :1 Canada: 1Greece: 1

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14 HSCT in MS: ACHIEVEMENTS and PRESENT Most of pts are SP (~5-7%) in EBMT registry PFS survival around 5% at 5 yrs Low incidence of clinical relapses Efficacy on MRI parameters A minority of pts in prospective studies Lack of comparative trials Lack of clinical details on long-term survivors Non interventional study : active RRand SP-MS with failure of 1st line tt - efficacy and mechanism of action - acceptance by neurologists - further evidence to support AHSCT as treatment option in these pts. PARIS EBMT

15 VOLTARELLI J C JAMA 27; 297: 1568 Patients continuously insulin-free since AHSCT AHSCT in newly diagnosed T1D, n = 15 3 Patient number COURI C et al JAMA 29; 31: 1573 C Peptid levels and Ins Independence after AHSCT in newly diagnosed T1D, n = Mean 52.4 mo Time free from insulin (months) 13 Patients transiently free from insulin along the follow-up Sitagliptin only Sitagliptin only,2 IU/Kg/day (basal +pranial) + sitagliptin,5 IU/Kg/day (basal + prandial) + sitagliptin Patient number,2 IU/Kg/day (only prandial insulin) + sitagliptin Lost follow-up,2 IU/Kg/day (only prandial insulin)+sitagliptin Period free from insulin Period using insulin,3 IU/Kg/day (only basal insulin) + sitagliptin,15 IU/Kg/day (only basal insulin) + sitagliptin,3 IU/Kg/day (only basal insulin) + sitagliptin Total: 13 patients All patients without previous DKA,15 IU/Kg/day (only basal insulin) + sitagliptin,15 IU/Kg/day (only basal insulin) + sitagliptin,14 IU/Kg/day (only basal insulin) + sitagliptin Courtesy of J Voltarelli

16 IMMUNE RECONSTITUTION YES WE CAN INDUCE RESET OF TOLERANCE Radbruch A Ann Rheum Dis 24 Hugle T Daikeler T Hematological 21

17 After AHSCT: renewal of the immune repertoire Muraro, Douek 26 immunophenotyping, TREC (Thymic output), CDR3 spectratyping / nucleotide sequencing Type I : replacement of mature T/B memory repertoire with naïve, non-pathogenic cells Type II : reinstalement of Immune Regulation nb and / or function of regulatory cells Naïve Memory Senescent T regulatory cells Foxp3 naive B cells after HSCT CD4+CD25highFoxP3 regulatory T cells CD8+FoxP3 suppressive function Multiple Sclerosis Herman Blood 25 (mice) P Murao J. Exp. Med. 25 (n = 7) Systemic Sclerosis Farge et al Arthritis Rhum 28 (n = 7) Early IDD Yanting W 28 Biochem. Biophys. Res. Commun. Rheumatoid Arthrtitis de Kleer I Blood 26 Systemic Lupus Erythematosus Alexander Blood 29, Zhang Blood 29 (n = 15)

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