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Le point sur l’Hémoglobinurie Paroxystique Nocturne U 728.

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Presentation on theme: "Le point sur l’Hémoglobinurie Paroxystique Nocturne U 728."— Presentation transcript:

1 Le point sur l’Hémoglobinurie Paroxystique Nocturne U 728

2 British Journal of Hematology 2000;108:470-9 Lack of expression of the GPI-anchored proteins on hematopoietic cells Disease of the hematopoietic stem cell Coexistence of a mutated (GPI-) and “normal” (GPI +) hematopoiesis Acquired somatic mutation of the PIG-A gene Linked to other hematological disorders; SAA & MDS Hémoglobinurie Paroxystique Nocturne Acquired hemolytic anemia +/- aplastic anemia thrombosis

3 (1/3 of patients with AA will have a + Ham’s test) 1/3 of patient with AA have GPI- cells at diagnosis PIG-A mutations, in AA with GPI- cells = those with de novo PNH Definition AAPNH MDS AA MDS PNH 1/3 previously considered idiopathic AA = AA/PNH (GPI-; PIG-A mutated)

4 Physiopathologie Phosphoethanolamine P I O C=O C-C-C P C=O NH 2 Protein I Mannose Glucosamine Phosphoinositol

5 MonocytesB CellsT CellsNK CellsGranulocytesRed CellsPlatelets CD55 CD58 CD59 CD109 (Gova/b-Ag) PrPc GP500 CD55 CD58 CD59 CD14 CD16 CD24 (NAB1- Ag) CD48 CD66b CD66c CD87 CD109 CD157 LAP NB1 PrPc ADP-RT p50-80 GPI-80 CD55 CD58 CD59 CD14 {CD16} CD48 CDw52 CD87 CD109 CD157 Group-8 PrPc GPI-80 CD55 CD58 CD59 CD24 CD48 CDw52 {CD73} {CDw108} PrPc CD55 CD58 CD59 {CD16 } CD48 CDw52 {CD73} CD87 {CD90} CDw108 {CD109} PrPc ADP-RT CD55 CD58 CD59 CD16 CD48 CDw52 PrPc Hematopoietic Stem Cell CD59 CD109 CD90 CD55, CD59 (Cromer Ag) CD58,PrPc, AChE (Cartwrigt-Ag) CDw108 (John-Milton - Hagen Ag) Dombroch residue Holley Gregory AG Bessler 2003 Physiopathologie

6 PIGS PIGT PIGU PIGK PIGL DPM1 DPM2 DPM3 MPDU1 PIGN PIGB PIGM PIGX PIGW PIGV PIGF PIGO GPI7 PIGA PIGC PIGH GPI1 GPIP DMP2 GPIY GAA1 Phosphoethanolamine P I O C=O C-C-C P C=O NH 2 Protein I Mannose Glucosamine Phosphoinositol Defective in PNH PIG-A; X p22-1 Physiopathologie

7 Somatic mutations in PIG-A gene CO CO O CH CH 2 OP O O O O INOS GLU MAN O O O (a 1-2) (a 1-6) (  1-4) CO N CH 2 NH OPO O O MAN O PHOSPHATIDYL -INOSITOL GLYCAN CORE PHOSPHO- ETHANOLAMINE PROTEIN MAN 11891452982849716 6 6 3 355 2 2 4 4 1 1 1 Impaired synthesis of GPI- anchor Lack of surface GPI- Anchored Proteins Cytoplasm COOH NH 2 COOH NH 2 Extracellular space Physiopathologie

8 ?

9 APC C3 convertase C3bBbP APC C5 convertase [C3b] 2 BbP MAC C5b-9 CD55 DAF - CD59 - Chute du pH nocturne; pas de régulation = Hémolyse MAIS …

10 Physiopathologie de la thrombose Activation plaquettaire Activation endothéliale Hypo-fibrinolyse Génération de thrombine Hémoglobine libreDéficit en NO Dystonie Vasoconstriction Complément Microvésicules Phospholipides THROMBOSE

11 Hemoglobinuria Thrombosis Fatigue Renal Failure Significant Impact on Quality of Life Significant Impact on Survival Smooth Muscle Dystonias including Dysphagia, Abdominal Pain, and Male ED Pulmonary Hypertension 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 Intact RBC Hemoglobin in the Blood from Destroyed PNH RBCs Complement Activation Anemia Physiopathologie

12 Normal

13 Diagnostic

14 CD59 CD55 CTRL iso Ctrl neg Témoin Ctrl pos Patient Analyse sur FC 500 Hématies HPN Hématies HPN Hématies normales

15 PN Neutro Clone « PNH » PN Eosino Analyse des leucocytes PN Neutro Analyse sur FC 500 CD24 CD16

16 FLAER aerolysin (Aeromonas Hydrophila)  toxin (Clostridium septicum) Peghini et al. Cytometry 2005 Shin et al. BBRC 2004 Toxines bactériennes

17 AA (aplasie médullaire) et HPN Nakao et al.2005

18 Patients (n=460) Gender F (%): 54.3 Median age at diagnosis: 34.2 years CMF- CMF+  15 new patients / year 210 33 20 18 21 15

19 Diagnostic Characteristics n (%) Previous AA*106 / 23.0% Thrombosis33 / 7.2% Anemia (<12 g/dl) Pancytopenia 414 / 91.4% 175 / 39.1% Initial treatment:  Androgens  Danazole  Steroids alone  Immunosuppressive therapy §  Transplantation 73 / 16.2% 40 / 8.9% 92 / 20.2% 26 / 5.7% § Antithymoglobuline  Cyclosporine *Aplastic anemia

20 Survie globale Years after diagnosis Survival 1 0.8 0.2 0.4 0.6 0 102030400 Median follow-up: 6.0 +/- 0.5 years Median survival time : 22.0 +/- 2.5 years > 96 deaths / 455 patients with follow up

21 Complications Aplastic anemia Thrombosis 10-year CI* (%): 19.8 (15.2-24.3)10-year CI* (%): 30.7 (25.4-35.9) Cumulative incidence (CI); death and SCT as competing events *Cumulative Incidence (Confidence Interval)

22 Complications Thrombosis Thrombosis Risk Factors RR p 10-year CI* (%): 30.7 (25.4-35.9) Cumulative incidence (CI); death and SCT as competing events *Cumulative Incidence (Confidence Interval) Age >55 Thrombosis (DG) Warfarin (prophylaxis) Transfusions IST 1.8 3.7 5.2 1.7 0.5.01 <.001.01.02

23 10-year CI* (%): 5.2 (2.9-7.6)10-year CI* (%): 2.4 (0.7-4.0) Myelodysplasia Acute leukemia Cumulative incidence (CI); death and SCT as competing events *Cumulative Incidence (Confidence Interval) Complications

24 Facteurs Pronostiques (Survie) Overall population Period ≤ 1995 Age > 40 years Hb < 10 g/dl Neutropenia No treatment (first year) Aplastic anemia (evolution) Thrombosis (evolution) MDS/AML (evolution) RR 2.7 2.2 2.8 1.8 2.3 4.6 18.2 10.0 p 0.01 0.001 0.008 0.02 <.001

25 Formes Cliniques Classical (n=113) Hb.<12g/dl and/or thrombosis Neutrophils>1.5 and Pt>120 AA – PNH syndrome (n=224) *Hb  10g/dl, Platelets  80G/L, Neutrophils  1 G/L 2 or 3 lineages* Unclassified (n=93) Parker C, Blood 2005

26 0.6 Survival 1 0.8 0.2 0.4 Years 10203040 0 0 Unclassified PNH AA-PNH Classical PNH Survie globale

27 Complications : Thromboses 0.6 0.5 10 2030 40 0 0 0.4 0.3 0.2 0.1 Unclassified PNH AA-PNH Classical PNH Years Cumulative Incidence 10-year CI:27.8% 10-year CI:27.3% 10-year CI:37.9%

28 Complications : Pancytopénie Years Cumulative Incidence 0.5 0 0.4 0.3 0.2 0.1 Unclassified PNH AA-PNH Classical PNH 10-year CI:20.5% 10-year CI:19.1% 10-year CI:20.4% 10 2030 400

29 Facteurs Pronostiques (Survie) Period ≤ 1985 Age: > 40 years > 55 years No thrombocytopenia No Andro/Dan (first year) No IST Transfusions Aplastic anemia (evolution) Thrombosis (evolution) MDS/AML (evolution) Classical PNH 3.6 (.01) 5.4 (<10 -3 ) 21.4 (<10 -3 ) 6.0 (.01) 8.5 (.03) 7.3 (<10 -3 ) 7.8 (<10 -3 ) AA / PNH 2.8 (.04) 2.9 (.005) 9.9 (<10 -3 ) 43.4 (<10 -3 ) 59.4 (<10 -3 ) Unclassified PNH 5.7 (.05) 5.7 (.02) 6.4 (.007) 17.6 (<10 -3 ) 38.5 (.003)

30 HPN :Traitement Key issue ; 1.Will RIC reduced TRM ? 2.Unrelated SCT; When and how ? n = 121 patients 0.56 (0.46-0.66) Survival at 10 years 1980-1993, n=33 1993-1997, n=34 1998-2002, n=18

31 HPN :Traitement N = 38 49% hemolysis 66% pancytopenia Treatment: 29 Transfused 28 First line Tt including: Steroids (LD); 18% CSA ; 21% CSA+ATG; 26% Danazole;8% 16 (58%) 2nd line Tt failure or relapse Key issue ; 1. No efficacious Tt in Hemolytic form 2. AA/PNH respond to IST

32 CH1 CH3 CH2 Hinge CL Human Framework Regions Human IgG2 Heavy Chain Constant Region 1 and Hinge Soliris TM (eculizumab) Anti - C5 Antibody

33 TRIUMPHSHEPHERD Parameter Placebo N = 44 Eculizumab N = 43 Eculizumab N = 97 Mean Age (SD) 38.4 (13.4)42.1 (15.5)41.1 (14.4) Gender - Female (%) 29 (65.9)23 (53.5)49 (50.5) History of AA or MDS (%) 12 (27.3)8 (18.7)29 (29.9) Concomitant Anticoagulants(%) 20 (45.5)24 (55.8)59 (61) Concomitant Steroids/IST (%) 16 (36.4)14 (32.6)46 (47.4) Median PRBC in previous 12 months17.018.08.0 Mean Hgb setpoint7.7 (0.75)7.8 (0.79)N/A Pre-treatment LDH levels2,234.52,032.02,051.0 Free Hemoglobin at baseline46.240.534.9 TRIUMPH and SHEPHERD Demographics

34 Change in Lactate Dehydrogenase During Eculizumab Treatment Over 52 Weeks

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