Comment devenir CCA en un WE? HPN aplasie médullaire

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1 Comment devenir CCA en un WE? HPN aplasie médullaire Régis Peffault de Latour, MD, PhD Saint Louis Hospital, Paris; AIH 27 Septembre 2014

2 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 Hillmen P et al. N Engl J Med. 1995;333: Nishimura JI, et al. Medicine. 2004;83: Socié G et al. Lancet. 1996;348: Peffault de Latour et al. Blood; 112:

3 Survival Mortality rate in PNH: Data From French Patients 1 8 O/N* 96/ (0.03) 10-year survival rate (SE) Time after diagnosis (years) n Peffault de Latour et al. Blood 2008; 112:

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

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;

4 Pathophysiology 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

5 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 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

terminal complement inhibitors Without this protective

destroyed Complement Activation Intact RBC Reduced Free

International PNH Interest Group. Blood. 2005;106:3699-3709.

In: Hematology - Basic Principles and Practices. 4th ed.

Philadelphia, PA: Elsevier Churchill Livingstone; 2005;

6 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: 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; Rother RP et al. JAMA. 2005;293: Socie G et al. Lancet. 1996;348: Hill A et al. Br J Haematol. 2007;137:

7 How best to treat PNH & AA in 2014

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

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

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

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

12 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%

13 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) AA-PNH Intermediate PNH Classic PNH 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):

14 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

Transplantation - GvHD - Acute, CI = 65% - Chronic, CI = 45% - Causes of

15 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

16 Cumulative Surviving (%) Mortality With Eculizumab In Hemolytic PNH Patients 100 Eculizumab n = Untreated n = Long-term follow-up needed!! Time (years) Kelly RJ et al. Blood. 2011

17 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

18 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

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

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

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

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

23 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%

24 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

1 100 80 60 40 20 0 100 80 60 40 BM, 20 yrs, N = 308, 85% PB, 20 yrs, N = 49, 73% 0

25 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= BM, 20 yrs, N = 308, 85% PB, 20 yrs, N = 49, 73% PB, 20 yrs, N = 49, 27% 20 0 BM, 20 yrs, N = 307, 12% Schrezenmeier et al Blood 2007

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

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

28 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 (10-36) Cardiovascular complications Endocrine dysfunctions 1 2 (0-9) 7 19 (9-31) Saint Louis experience Haematologica 2012

29 AA and no sibling donor

30 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

31 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

32 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

33 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

34 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

35 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

36 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

37 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

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

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

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

41 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?

42 Answers (n) Mr RE. PE 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

43 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%

44 Cumulative incidence Thrombosis in PNH Thrombosis risk factors RR p Thrombosis 10-year CI 37.9% Age >55 years year CI 27.3% Thrombosis (at diagnosis) Warfarin (prophylaxis) Transfusions Immunosuppressive therapy <0.001 < year CI 27.8% Aplastic anaemia PNH Intermediate PNH Classical PNH Years 55% (10/18) had a TE while on prophylactic anticoagulation 1 1.Peffault de Latour, RP et al. Blood. 2008;112(8):

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.

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

46 Thrombotic Events (#) Thrombosis and Eculizumab Pre-Eculizumab Treatment N=195 P= 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

47 Thrombosis and Transplantation SFH EBMT Non grafted SCT Not confirmed 2 Date? 2 Severity? 2 F-up<6mo post Thr MDS before 1 24 Matched pairs Overall Survival (OS) 10 Non Grafted SCT p Log Rank =.01 p Cox stratified on pairs =.007 HR SCT/non grafted = 10.0( ) Time since thrombosis (year) Peffault de Latour et al, Haematologica 2012

48 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

49 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

50 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

51 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% de Guibert et al, Haematologica 2010

52 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

53 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 International study on going - Almost 80 cases - Abstract for ASH de Guibert et al, Haematologica 2010

54 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

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

Pathophysiology 7/18/2012 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Pathophysiology 7/18/2012 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA PAROXYSMAL NOCTURNAL HEMOGLOBINURIA OUTLINE OF DISCUSSION WHAT IS IT WHO GETS IT NATURAL HISTORY TYPES RISKS COURSE TREATMENTS SYMPTOMS PREGNANCY Pathophysiology Acquired hematopoietic stem cell disorder