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As a Registered E-Materials Service User of the EBMT Annual Meeting in Marseille March 26-29Th 2017, You Have Been Granted Permi Copyright Statement As a registered E-materials Service user of the EBMT Annual Meeting in Marseille March 26-29th 2017, you have been granted permission to access a copy of the presentation in the following pages for the purpose of scientific education. This presentation is copyrighted material and must not be copied, reproduced, transferred, distributed, leased, licensed, placed in a storage retrieval system, publicly performed or used in any way, except as specifically permitted in writing by the presenter or, as allowed under the terms and conditions under which it was received or as permitted by applicable copyright law or rules of proper citation. Any unauthorised distribution or use of this presentation, a subset of it or graphics taken from the presentation may be a direct infringement of the presenter’s rights. RACE DM training session: Immunusuppressive treatment for aplastic anemia Antonio M. Risitano, M.D., Ph.D. Head of Bone Marrow Transplantation Unit Federico II University of Naples Aplastic anemia Neutrophils for Incidence, age for SCT . Opha disease. Iidee ates peset geogaphi aiatios. to ‐fold highe ates i Asia tha Euope ad the Uited States . Gloal iidee ates age .‐. ases pe illio ihaitats. Aplasti aeia: AA • AA: hat does it ea? • Ho e do the diagosis? • Whe should e teat? • Ho e teat? Aplasti aeia: AA • AA: hat does it ea? • Ho e do the diagosis? • Whe should e teat? • Ho e teat? Aplastic anemia Normal Aplastic anemia CML AA Normal Marrow aplasia Takaku et al, Blood 2010 Takaku et al, Blood 2010 Contraction of stem cell pool Cytopenia AA: hat does it ea? (Oligo) clonal CD8+ T cells Auto-immunity = immune disorder = idiopathic AA AA: hat does it ea? Constitutionnal = inherited disorder (FA, dyskeratosis congenita) Hematopoietic stem cells in AA Hematopoietic progenitor cultures T-cell clonality in aplastic anemia A surrogate marker for Ag-driven immune response Experimental Hematology 23 (1995): 433 Establishment of a CD4+ T cell clone recognizing autologous hematopoietic progenitor cells from a patient with immune-mediated aplastic anemia. Nakao S, Takamatsu H, Yachie A, Itoh T, Yamaguchi M, Ueda M, Shiobara S, Matsuda T. Pathophysiology of aplastic anemia The immune system Hematopoietic stem cell Aplasti aeia: AA • AA: hat does it ea? • Ho e do the diagosis? • Whe should e teat? • Ho e teat? Ho e do the diagosis To eliminate something else (leukemia, lymphoma etc) Aplastic anemia Diagnosis Full lood outs: ‐ Patopeia ‐ At least ellula lies ae deeased Ho e do the diagosis: peipheal lood Ho e do the diagosis: ao saplig Ho e do the diagosis: ao iops Aplastic anemia Summary Patopeia Pesistet, ueplaied ao aplasia ‐ Heatopoiesis eplaed fat ells No speifi ake ‐ Diagosis elusio Seeit eed to e defied Aplastic anemia Cytogenetics and flow cytometry Due to hpoellula oe ao feuetl isuffiiet etaphases FISH fo hoosoes ad should e osideed isolated del faoale log‐te outoe A aoal togeeti loe does ot ipl the diagosis of MDS o AML Ctogeeti aoalities a e peset i up to % of tpial AA patiets Detetio of sall PNH loes has ipliatios fo defiig the disease. ‐ Aout % ae aplasti ith sall loes ad o heolsis. PNH loe size easueets: at pesetatio seial oitoig should e pefoed at least eal Aplastic anemia Differential diagnosis Chaateistis AA hpoplasti MDS dsethopoiesis soeties es aoal eutophil o es dsplasti egakaotes o es fiosis o oasioal ieased lasts o Soeties ALIPS CD+ ells i BM < .% soeties ieased loalit possile soeties spleoegal aset oasioal Beett et al. Se Heato ;:‐ Beett & Orazi. Haeatologia Fe; :‐‐ Haa A et al. Risho Ketsueki Aug ; :‐ Aplastic anemia Differential diagnosis Faoi aeia: ‐ Positie hoosoal eakage test MMC o DEB that still epesets the diagosti gold stadad. Seeig: teloee legth Dyskeatosis ogeita ‐ Asptoati: ‐ Feuet assoiatio ith TE‘C, TE‘T utatio ‐ % all idiopathi fos ‐ ‘ael, ith TINF gee utatio ‐ ‘eogizale pheotpe of DC: ‐ TINF, NHP, NOP, DKC utatio Aplastic anemia Severity Based o peipheal alues ad oe ao fidigs Seee AA SAA At least to of the folloig thee iteia hae to e fulfilled: ‐ ‘etiulotes </L usig a autoated aalze o < /l aual out* ‐ Platelets < /L ‐ Neutophil out <. /L Vey seee AA SAA Sae iteia of SAA hae to e fulfilled; ut the eutophil out has to e < . /l No‐ seee AA Patiets ot fulfillig the iteia fo SAA ad SAA. * The diffeet alues ae eause autoated out a oe‐estiate the outig at lo leel of etiulote outs, i.e. it eads /L ut i ealit the ae less Aplasti aeia: AA • AA: hat does it ea? • Ho e do the diagosis? • Whe should e teat? • Ho e teat? Whe should e teat? SAA Moderate Hypocellularity (<30%) and at Not all criteria for SAA 9 least 2/3 criteria: PNN >0.5x10 /L PNN <0.5x109/L Platelets <20x109/L Reticulocytes <20x109/L Transfusions? VSAA 9 PNN <0.2x10 /L Yes No Treatment Follow-up Camitta BM et al. Blood 1976;48:63–70 SAA, severe AA; VSAA, very severe AA Aplasti aeia: AA • AA: hat does it ea? • Ho e do the diagosis? • Whe should e teat? • Ho e teat? Treatment options for aplastic anemia Locasciulli et al, Haematologica 2007 Idiopathi AA: ho e teat? 1. Immunosuppressive treatment (Oligo) clonal CD8+ T cells Auto-immunity = immune disorder = idiopathic AA Idiopathi AA: ho e teat? Idiopathi AA: ho e teat? 2. Bone marrow transplantation (Oligo) clonal CD8+ T cells Auto-immunity = immune disorder = idiopathic AA Idiopathi AA: ho e teat? 2. Bone marrow as Greffon source of stem cells -8 -7 -6 -5-4 -3 -2 -1 0 +14 +40 +100 +180 3. No need for GvHD Conditionnement infections 1. Reduced intensity 4. conditioning regimen Idiopathi AA: ho e teat? Age < yeas > yeas HLA‐idetial No siligs siligs Iuosuppessie teatet BMT Iheited AA: ho e teat? Bone marrow transplantation Constitutionnal = inherited disorder (FA, dyskeratosis congenita) Colusio: AA • AA: ao epty, othig else • Diagosis is ey ipotat • Teatet if SAA o tasfusios • Iuosuppessie theapy auied o BMT auied ad iheited AA and… … supportive care Supportive care The improvement in anti-infectious management CID 2011 n=420 (174 non-responders) Group 1: 12/1989-10/1986 Infection-related mortality from 37% to 11% Group 2: 11/1986-10/2002 Incidence of IFIs from 49% to 8% Group 3: 11/2002-04/2008 The most relevant breakthrough in AA treatment was the anti-infectious supportive care: keeping AA patients alive until they recover (IST or SCT) Supportive care The role of steroids Steroids are broadly used as ancillary therapy of SAA Based on old data on potential therapeutic efficacy (Bacigalupo et al NEJM 1982) Drawn from empirical use (and possible efficacy) of steroids in other immune- mediated cytopenias (Ab-mediated) BUT No clinical evidence of efficacy Increased risk of severe infectious complications (mostly IFI) May mask ongoing/overt infections (including sepsis) Short-term toxicity (cumulative with CsA): hypertension, diabetes, fluid retention Long-term toxicity: avascular necrosis, cataracts, etc In the context of SAA, steroids should be used only as prophylaxis of serum sickness during ATG treatment, using the lowest effective dose and the faster tapering Start with 1 mg/kg/day, eventually doubled in case of serum sickness or other allergic manifestations*; then taper by 25% every 2-4 days *ATG-related allergic infusion reactions should rather considered manifestations of Complement Activation Related Pseudo-Allergy (CARPA), which eventually derive from massive activation of the classical pathway due to the exogenous antibodies and their immune-complexes AA and… … immunosuppressive treatment OUTCOME OF IMMUNOSUPPRESSION FOR SAA Improvement over the years EBMT Database N=3202 ‐ ‐ ‐ ‐ Survival improved with years, mostly due to: Better supportive therapy Better salvage treatment (SCT) Courtesy of Jakob Passweg 2003 n=112 hATG x 4 (40mg/kg) + CsA x 6 m OS 55% @7y; OR 60% @ 3m, 61% @ 6m, 58% @ 1y 3m survivors 3m survivors Hematological response is the main predictor for outcome IMPROVING ATG-BASED IMMUNOSUPPRESSION The benefit of combining ATG and cyclosporine A Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group NEJM 1991 Blood 2003 N Frickhofen, JP Kaltwasser, H Schrezenmeier, A Raghavachar, HG Vogt, F Herrmann, M Freund, P Meusers, A Salama, and H Heimpel CyA speed hematological response CyA reduces early treatment failure but without affecting survival not long-term relapse rate RELAPSES AFTER IST The role of maintenance CyA therapy Maintenance CyA is required to sustain blood counts after initial response to IST Frickhofen N. Blood. 2003 (101). 1236-1242 REASONS FOR TREATMENT FAILURE •Pathophysiology other than immune-mediated •Irreversible stem cell deficit •Insufficient immunosuppression Improve front line immunosuppressive therapies Improving IST for AA: chronicle of a failure STRATEGIES OF IMMUNOSUPPRESSION (Risitano, BJH 2010) Autoantigen IL-2 HLA TCR release IL-2 signaling APC Naive T-cell Cell-cell contact Cytokine release (IL-1, IL-6) Activated APC (HLA+Ag) triggering T-cell activation T-cell Second signals Anergy CNIs IL-2 R blockers MToR inhibitors (IL-2, IL-12, IL-23, inductors •CyA •Daclizumab •Sirolimus IL-4, IL-6, IL-17) •CTLA4-Ig •FK506 •Basiliximab •Everolimus T-cell •Anti-CD154 differentiation Anti-cytokines Anti-lymphocyte agents Effector Biologicals Cytostatics T-cell TNF-α •Etanercept Selective Broad •CTX •Infliximab •Rituximab •ATGs •MMF •Adalimumab •Visilizumab •Alemtuzumab •MTX •Zanolimumab •AZA IFN-γ Proliferation •Fontolizumab •Apolizumab Steroids •Alefacept T-cell •Efalizumab expansion Haematopoietic niche ? Haematopoietic stem cells TNF-α IFN-γ Inflammation Perforine/ Fas-L granzyme Expanded effector T-cell Inhibitory cytokines Cell-cell contact pool Marrow damage Effector mechanisms IMPROVING IMMUNOSUPPRSSIVE TREATMENT FOR AA The history of a failure 1. No benefit from the addition of a third drug over the hATG-CsA platform Mycophenolate mofetil (randomized NIH trial) Rapamicine (open-label NIH trial) 2.
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