le point sur l’hémoglobinurie paroxystique nocturne u 728
TRANSCRIPT
Le point sur l’Hémoglobinurie
Paroxystique Nocturne
U 728
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
(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
AA PNH
MDS
AA
MDS
PNH
1/3 previously considered idiopathic AA = AA/PNH (GPI-; PIG-A mutated)
Physiopathologie
Phosphoethanolamine
P
I
O OC=O
C-C-C
P
C=O
NH 2
Protein
I
Mannose
Glucosamine
Phosphoinositol
Monocytes B Cells T Cells NK 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
HematopoieticStem Cell
CD59 CD109CD90
CD55, CD59
(Cromer Ag)
CD58, PrPc,
AChE
(Cartwrigt-Ag)
CDw108
(John-Milton
- Hagen Ag)
Dombroch
residue
Holley Gregory AG
Bessler 2003
Physiopathologie
PIGSPIGTPIGUPIGK
PIGL
DPM1DPM2DPM3MPDU1
PIGN PIGBPIGMPIGX
PIGW
PIGV
PIGFPIGOGPI7
PIGAPIGCPIGHGPI1GPIP
DMP2
GPIY
GAA1
Phosphoethanolamine
P
I
O OC=O
C-C-C
P
C=O
NH2
Protein
I
Mannose
Glucosamine
Phosphoinositol
UDP
COOH COOH
NH2
NH2
DG
GDP
Dol-P
Dol-P
Ac
Ac
UDPacetate
acyl-CoA
Dol-PDol-P
DG
Endoplasmic reticulum
Dol-PDol-P
Dol-PDG
GDP
Defective in PNHPIG-A; X p22-1
Physiopathologie
Somatic mutations in PIG-A gene
COCOO
CHCH2
O POO
O
OCH2
INOS
GLUMAN
OO
O
(a 1-2)(a 1-6)
( 1-4)
CO
N
CH2
CH2
NH
O P OO
O
MANO
PHOSPHATIDYL-INOSITOL
GLYCAN COREPHOSPHO-ETHANOLAMINE
PROTEIN
MAN
1189 1452982849716
6633 555522 44
1
11
Impaired synthesis
of GPI-anchor
Lack of surface GPI-
Anchored Proteins
Cytoplasm
COOH
NH2
COOH
NH2
Extracellularspace
Physiopathologie
Physiopathologie
?
Physiopathologie
APC C3 convertaseC3bBbP
APC C5 convertase[C3b]2BbP
MACC5b-9
CD55DAF-
CD59-
Chute du pH nocturne; pas de régulation = HémolyseMAIS …
Physiopathologie de la thrombose
Activation plaquettaireActivation endothéliale
Hypo-fibrinolyseGénération de thrombine
Hémoglobine libre Déficit en NO
Dystonie
Vasoconstriction
Complément
Microvésicules
Phospholipides
THROMBOSE
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 RBCHemoglobin in
the Blood from Destroyed PNH RBCs
ComplementActivation
Anemia
Physiopathologie
R3
R3
R4 R5
A
B (iii)
(iii)
(iv)
(ii)
(ii)
(i)
(i)
Normal
GPI – Blood Cells in Pat ients with Aplastic Anemia (AA) Schubert
(1994)
Schrezenmeier
(1995)
Griscelli
(1995)
Yamaguchi
(2000)
Tooze
(1995)
Dunn
(1999)
Azenishi
(1999)
Mukhina
(2001)
Maciejewski
(2001)
Meletis (2001)
29 52 37 21 70 115 73 23 115 21 No of pat ients % of pat ients with GPI- cells 41 52 35 29 23 22 28 16 32 33
GPI – Blood Cells in Pat ients with Myelodysplast ic Syndrome (MDS)
Dunn
(1999)
Yamaguchi
(2000)
Meletis
(2001)
Maciejewski
(2001)
Mukhina
(2001)
Wang
(2002)
No of pat ients 39 18 133 120 9 119 % of pat ients with
GPI- cells 23 28 17 18 0 18
Diagnostic
CD59CD55
CTRL isoCtrl neg
TémoinCtrl pos
Patient
Analyse sur FC 500
Hématies HPN
Hématies HPN
Hématies normales
Hématies normales
PN NeutroClone « PNH »
PN Eosino
Analyse des leucocytes
PN Neutro
Analyse sur FC 500
CD24
CD16
FLAER aerolysin (Aeromonas Hydrophila)
toxin (Clostridium septicum)
Peghini et al. Cytometry 2005
Shin et al. BBRC 2004
Toxines bactériennes
AA (aplasie médullaire) et HPN
Nakao et al.2005
Patients (n=460)
• Gender F (%): 54.3
• Median age at diagnosis: 34.2 years
0
20
40
60
80
100
120
140
160
180
1950 1960 1970 1980 1990 2000
CMF-CMF+
15 new patients / year
210
33
20
18
21
15
15
Diagnostic
Characteristics n (%)
Previous AA* 106 / 23.0%
Thrombosis 33 / 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%
40 / 8.9%
92 / 20.2%
26 / 5.7%
§Antithymoglobuline Cyclosporine*Aplastic anemia
Survie globale
Years after diagnosis
Sur
viva
l1
0.8
0.2
0.4
0.6
010 20 30 400
Median follow-up: 6.0 +/- 0.5 years
Median survival time : 22.0 +/- 2.5 years
> 96 deaths / 455 patients with follow up
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)
Complications
ThrombosisThrombosis 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
<.001
.01
.02
10-year CI* (%): 5.2 (2.9-7.6) 10-year CI* (%): 2.4 (0.7-4.0)
MyelodysplasiaAcute leukemia
Cumulative incidence (CI); death and SCT as competing events
*Cumulative Incidence (Confidence Interval)
Complications
Facteurs Pronostiques (Survie)
Overall population
Period ≤ 1995
Age > 40 yearsHb < 10 g/dlNeutropenia
No treatment (first year)
Aplastic anemia (evolution)Thrombosis (evolution)MDS/AML (evolution)
RR
2.7
2.22.81.8
2.3
4.618.210.0
p
0.01
0.0010.0080.02
<.001
<.001<.001<.001
Formes Cliniques
Classical
(n=113)
Hb.<12g/dl and/or thrombosis
Neutrophils>1.5 and Pt>120
AA – PNH syndrome
(n=224)*Hb10g/dl, Platelets 80G/L, Neutrophils 1 G/L
2 or 3 lineages*
Unclassified
(n=93)
Parker C, Blood 2005
0.6
Sur
viva
l1
0.8
0.2
0.4
Years10 20 30 40
0
0
Unclassified PNH
AA-PNH
Classical PNH
Survie globale
Complications : Thromboses
0.6
0.5
10 20 30 400
0
0.4
0.3
0.2
0.1 Unclassified PNH
AA-PNH
Classical PNH
Years
Cum
ulat
ive
Inci
denc
e
10-year CI:27.8%
10-year CI:27.3%
10-year CI:37.9%
Complications : Pancytopénie
Years
Cum
ulat
ive
Inci
denc
e0.5
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 20 30 400
Facteurs Pronostiques (Survie)
Period ≤ 1985
Age:> 40 years> 55 years
No thrombocytopeniaNo Andro/Dan (first year)No ISTTransfusions
Aplastic anemia (evolution)Thrombosis (evolution)MDS/AML (evolution)
ClassicalPNH
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)
UnclassifiedPNH
5.7 (.05)
5.7 (.02)6.4 (.007)
17.6 (<10-3)38.5 (.003)
HPN :Traitement
Key issue ; 1. Will RIC reduced TRM ?2. Unrelated SCT; When and how ?
0.0
0.3
0.5
0.8
1.0
0.0 730.0 1460.0 2190.0 2920.0 3650.0
time after treatment (days)
Surv
ival
n = 121 patients
0.56 (0.46-0.66)
Survival at 10 years
0.0
0.3
0.5
0.8
1.0
0.0 730.0 1460.0 2190.0 2920.0 3650.0
time after treatment (days)
Surv
ival
1980-1993, n=33
1993-1997, n=34
1998-2002, n=18
HPN :Traitement
Time (months)
4000
3000
2000
1000
0
%
1,00
,90
,80
,70
,60
,50
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 lineTt failure or relapse
Key issue ;1. No efficacious Tt in Hemolytic form2. AA/PNH respond to IST
CH1CH1
CH
3C
H2
Hinge Hinge
CLCL
Human Framework RegionsHuman Framework Regions
Human IgG2 Heavy ChainHuman IgG2 Heavy ChainConstant Region 1 and HingeConstant Region 1 and Hinge
SolirisTM (eculizumab) Anti - C5 Antibody
TRIUMPH SHEPHERD
ParameterPlaceboN = 44
EculizumabN = 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 months 17.0 18.0 8.0
Mean Hgb setpoint 7.7 (0.75) 7.8 (0.79) N/A
Pre-treatment LDH levels 2,234.5 2,032.0 2,051.0
Free Hemoglobin at baseline 46.2 40.5 34.9
TRIUMPH and SHEPHERD Demographics
Change in Lactate DehydrogenaseDuring Eculizumab Treatment Over 52 Weeks