Comment devenir CCA en un WE? HPN aplasie médullaire

Comment devenir CCA en un WE? HPN aplasie médullaire Régis Peffault de Latour, MD, PhD Saint Louis Hospital, Paris; regis.peffaultdelatour@sls.aphp.fr AIH 27 Septembre 2014

Paroxysmal Nocturnal Hemoglobinuria (PNH): Acquired hemolytic anemia Thrombosis +/- aplastic anaemia Rare disease: Prevalence: 15.9 / million 1 Young patients: median age early 30 s 3-5 Severe disease: median overall survival 22 years 1. Hill A et al. Blood. 2006;108(11):290a. Abstract 985. 2. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 3. Nishimura JI, et al. Medicine. 2004;83:193-207. 4. Socié G et al. Lancet. 1996;348:573-577. 5. Peffault de Latour et al. Blood; 112:3099-3106.

Survival Mortality rate in PNH: Data From French Patients 1 8 O/N* 96/454 0.75 (0.03) 10-year survival rate (SE) 6 4 2 0 0 5 10 15 20 25 30 35 40 Time after diagnosis (years) n 454 211 120 58 22 11 2 1 1 Peffault de Latour et al. Blood 2008; 112:3099-3106.

Pathophysiology 1 716 849 982 1189 1452 1 2 3 4 5 6 Somatic mutations in the PIG- A gene Protein NH 2 NH 2 Phosphoethanolamine Glycan core O (a 1-6) O MA N (a 1-2) C=O NH CH 2 CH 2 O O-P-O- O MAN Extracellular COOH Phosphatidylinositol GPI anchor structure H 2 C O H C O O O=P-O CH O 2 O C=O GLU N C=O INOS MAN COOH Deficit in GPIanchored proteins Intracellular PNH, paroxysmal nocturnal haemoglobinuria; PIG-A, phosphatidylinositol glycan class A; GPI, glycosylphosphatidylinositol Young NS et al. Hematology Am Soc Hematol Educ Program 2000:18 38

GPI deficiency results in Hemolytic Anemia (lack of CD59 or CD55) C5 convertase C5 convertase Absence of CD59 allows terminal complement complex formation C9 C9 x 12 15 C5 C5a C6 C7 C5b C6 C5b C8 C6 C5b X C6 C5b X C6 C5b C7 C7 CD59 C7 CD59 C7 C8 C8 C9 C8 C5b-9 C5b,6,7 C5b-8 PNH, paroxysmal nocturnal haemoglobinuria Adapted from Abbas AK et al. Cellular and Molecular Immunology, 3rd ed. WB Saunders: Philadelphia, 1991

Historically Viewed as a Hemolytic Anemia Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Without this protective complement inhibitor shield, PNH red blood cells are destroyed Complement Activation Intact RBC Reduced Free Hemoglobin Red Cell Mass Anemia 1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; 419-427. 3. Rother RP et al. JAMA. 2005;293:1653-1662. 4. Socie G et al. Lancet. 1996;348:573-577. 5. Hill A et al. Br J Haematol. 2007;137:181-192.

How best to treat PNH & AA in 2014

PNH management in 2014 PNH Hemolytic PNH AA / PNH AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST SCT THROMBOSIS

Mr FE. CA. 31 ans 2011: Premier episode de douleurs abdominales Une taille de clone de 30% sur les globules rouges 2011-2012: Crises hémolytiques & transfusions mensuelles Nausées et vomissements Fatigue Difficulté à se concentrer 2400 olynucléaires & 123 000 plaquettes Son frère est HLA identique

Answers (n) Quelle est votre attitude? 0 1 - Eculizumab 2 - Prophylaxie Anti-thrombotique 3 - Supplémentation en folates et en fer 4 - Immunosuppression: ATG + cyclosporine 5 - Greffe de moelle

Answers (n) Quelle est votre attitude? 1 - Eculizumab 0% 2 - Prophylaxie Anti-thrombotique 0% 3 - Supplémentation en folates et en fer 0% 4 - Immunosuppression: ATG + cyclosporine 0% 5 - Greffe de moelle 0%

Survie Mortality With Best Supportive Care In Hemolytic PNH Patients 1 Intermediate (n=93) Classic Hb <12g/dl and/or thrombosis (n=113) French cohort (n=460) 0.8 0.6 0.4 0.2 0 0 AA-PNH Intermediate PNH Classic PNH 10 20 Temps (années) 30 AA PNH syndrome 2 or 3 lineages* *Hb 10g/dl, Platelets 80 g/l, Neutrophiles 1 g/l (n=224) Socié et al, Lancet 1996; Peffault de Latour, RP et al, Blood. 2008;112(8):3099-3106.

Mortality With Transplantation In Hemolytic PNH Patients EBMT cohort (n=211) - Hemolytic (n=64) - Aplastic anemia (n=100) - Thrombosis (n=47) Peffault de Latour, et al. Haematologica. 2012

Mortality With Transplantation In Hemolytic PNH Patients EBMT cohort (n=211) - Hemolytic (n=64) - Aplastic anemia (n=100) - Thrombosis (n=47) Transplantation - GvHD - Acute, CI = 65% - Chronic, CI = 45% - Causes of death (n=64) - GvHD - Infections Peffault de Latour, et al. Haematologica. 2012

Cumulative Surviving (%) Mortality With Eculizumab In Hemolytic PNH Patients 100 Eculizumab n = 79 80 Untreated n = 30 60 40 Long-term follow-up needed!! 20 0 1 2 3 4 5 6 7 8 9 Time (years) Kelly RJ et al. Blood. 2011

Quelle est votre attitude? 1 - Eculizumab 2 - Prophylaxie Anti-thrombotique 3 - Supplémentation en folates et en fer 4 - Immunosuppression: ATG + cyclosporine 5 - Greffe de moelle

PNH management in 2014 PNH Hemolytic PNH AA / PNH AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST SCT THROMBOSIS

PNH management in 2014 PNH Hemolytic PNH AA / PNH Moderate AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST SCT THROMBOSIS

Mr JE. RE. 22 ans 2011: Aplasie médullaire modérée non transfusé Une taille de clone de 13% sur les globules rouges 2011-2012: Transfusé de plus en plus souvent en plaquettes Clone augmente 50% (LDH normales) Pas de donneur familial HAL compatible

Answers (n) Mr JE. RE. 22 ans 0 1 - Eculizumab 2 - Prophylaxie Anti-thrombotique 3 - Supplémentation en folates et en fer 4 - Immunosuppression: ATG + cyclosporine 5 - Greffe de moelle

Answers (n) Mr JE. RE. 22 ans 1 - Eculizumab 0% 2 - Prophylaxie Anti-thrombotique 0% 3 - Supplémentation en folates et en fer 4 - Immunosuppression: ATG + cyclosporine 5 - Greffe de moelle 0% 0% 0%

AA and treatment Severe (SAA) Hypocellularity (<30%) & At least 2/3 critèria: PNN <0.5x10 9 /L Platelets <20x10 9 /L Reticulocytes <20x10 9 /L Very severe (vsaa) PNN <0.2x10 9 /L Moderate Not all criteria for SAA PNN >0.5x10 9 /L Yes Transfusions? No Treatment Follow-up Camitta et al. Blood 1976

AA and sibling donor HSCT for SAA; young patients and HLA-identical sibling Donor Marrow =<20 years(rr 2.4) p=0.02 >20 years(rr 1.2) p=0.1 100 80 60 40 20 0 100 80 60 40 BM, 20 yrs, N = 308, 85% PB, 20 yrs, N = 49, 73% 0 12 24 36 48 60 PB, 20 yrs, N = 49, 27% 20 0 BM, 20 yrs, N = 307, 12% 0 12 24 36 48 60 Schrezenmeier et al Blood 2007

AA and sibling donor HSCT for SAA; young patients and HLA-identical sibling Donor Marrow Cy- ATG Blood. 2007;109:4582-4585

AA and sibling donor HSCT for SAA; young patients and HLA-identical sibling Donor Marrow Cy- ATG CsA + MTX Blood. 2000;96:1690-1697

AA and sibling donor>bmt! HSCT for SAA; young patients and HLA-identical sibling Donor Event No of Events 6yr-CI (%) Secondary Cancer 1 2 (0-9) 87,5 % (IC 95%, 78-97) Osteonecrosis 10 21 (10-36) Cardiovascular complications Endocrine dysfunctions 1 2 (0-9) 7 19 (9-31) Saint Louis experience Haematologica 2012

AA and no sibling donor

AA and no sibling donor Phase III prospective randomized study First-line treatment hatg + CyA (n=60) vs ratg + CyA (n=60) OR at 6m 68% vs 37% (p<0.001) Phase II prospective study First-line treatment ratg + CyA (n=35) OR at 6m 40% Scheinberg P, NEJM, 2011; Marsh JC, Blood 2012

Answers (n) Mr JE. RE. 22 ans 1 - Eculizumab 2 - Prophylaxie Anti-thrombotique 3 - Supplémentation en folates et en fer 4 - Immunosuppression: ATG + cyclosporine 5 - Greffe de moelle

PNH management in 2014 PNH Hemolytic PNH AA / PNH Moderate AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST No Sib. SCT Sib. THROMBOSIS

PNH management in 2014 PNH Hemolytic PNH AA / PNH AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST No Sib. SCT Sib. THROMBOSIS

PNH management in 2014 PNH Hemolytic PNH AA / PNH Moderate AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST No Sib. SCT Sib. THROMBOSIS

Mr RE. PE. Homme de 31 ans Avril 1998: Le diagnostic d HPN est fait Urine foncée Dysphagie Pas de transfusions Hb 9 g/dl, GB 5.3 x 10 9 /l, Plts 219 x 10 9 /l 99.5% de neutros HPN 37% de GR HPN

Mr RE. PE. Decembre 2006: Douleurs abdominales d apparition aiguë Ascite > Syndrome de Budd-Chiari

Mr RE. PE. Unité de soins intensifs Feeling extremely unwell Encephalite Fièvre HBPM Antibiotiques TIPS (transjugular intrahepaticportosystemic shunt) Fin d hospitalisation

Mr RE. PE. Réhospitaliser en aout 2007 avec des douleurs abdominles aiguës Ascite Extension de la thrombose de la veine hépatique Sep 2007.

Mr RE. PE. Eculizumab a été débuté. Schéma posologique classique. Transformé! Aujourd hui: Toujours sous eculizumab Suivi régulier toutes les 2 semaines Que faire de l anticoagulation?

Answers (n) Mr RE. PE. 0 1 - Stop anticoagulatio et poursuite de l ecullizumab 2 - Stop eculizumab et anticoagulation 3 - Eculizumab et anticoagulation à vie 4 - Augmentation eculizumab à 1200mg et anticoagulation à vie 5 - Greffe de moelle

Answers (n) Mr RE. PE. 1 - Stop anticoagulatio et poursuite de l ecullizumab 2 - Stop eculizumab et anticoagulation 3 - Eculizumab et anticoagulation à vie 4 - Augmentation eculizumab à 1200mg et anticoagulation à vie 5 - Greffe de moelle 0% 0% 0% 0% 0%

Cumulative incidence Thrombosis in PNH Thrombosis risk factors RR p 0.6 0.5 Thrombosis 10-year CI 37.9% Age >55 years 1.8 0.01 0.4 10-year CI 27.3% Thrombosis (at diagnosis) Warfarin (prophylaxis) Transfusions Immunosuppressive therapy 3.7 5.2 1.7 0.5 <0.001 <0.001 0.01 0.02 0.3 0.2 0.1 0.0 10-year CI 27.8% Aplastic anaemia PNH Intermediate PNH Classical PNH 0 10 20 30 40 Years 55% (10/18) had a TE while on prophylactic anticoagulation 1 1.Peffault de Latour, RP et al. Blood. 2008;112(8):3099-3106.

Hazard Ratio Thrombosis is Associated With Risk of Early Mortality TE increases risk of death 15-fold over patients with no TE 18 16 14 12 10 8 6 4 2 0 15.40 Patients (n=415) TE was an independent prognostic factor related to poor survival (HR 15.4; 95% CI 9.3-25.4; P<0.001) in a large cohort of French PNH patients 1. Peffault de Latour R et al. Blood. 2008;112(8):3099-3106.

Thrombotic Events (#) Thrombosis and Eculizumab 45 40 35 30 25 20 15 10 5 0 39 Pre-Eculizumab Treatment N=195 P=0.0001 3 Eculizumab Treatment 63% of patients received concomitant anticoagulants Both venous and arterial sites There were fewer thrombotic events with Eculizumab treatment than during the same period of time prior to treatment Brodsky R et al. Blood. 2008

Thrombosis and Transplantation SFH EBMT 122 47 Non grafted SCT 121 92 1 27 Not confirmed 2 Date? 2 Severity? 2 F-up<6mo post Thr MDS before 1 24 Matched pairs 24 42 100 80 60 40 20 0 5 Overall Survival (OS) 10 Non Grafted SCT p Log Rank =.01 p Cox stratified on pairs =.007 HR SCT/non grafted = 10.0(1.3-78.1) 15 20 25 Time since thrombosis (year) Peffault de Latour et al, Haematologica 2012

PNH management in 2014 PNH Hemolytic PNH AA / PNH Moderate AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST No Sib. SCT Sib. THROMBOSIS

And what about pregnancy & PNH French experience (26 pregnancies/20 patients) - Cytopenia during pregnancy (90%) - Thrombosis at time of delivery and in the post-partum (4 severe complications/20 with 2 deaths!!) - Prematurity in 30% Guidelines - Low weight heparin from 6 months to 3 months postpartum + Eculizumab de Guibert et al, Haematologica 2010

Take home messages PNH Hemolytic PNH AA / PNH Moderate AA Hemolysis Moderate AA No Hemolysis Severe AA No Hemolysis Eculizumab IST No Sib. SCT Sib. THROMBOSIS

Merci! Centre Ref. Aplasie Médullaire (Pr Socié) SFH Participating centers