comment devenir cca en un we ? hpn aplasie...
TRANSCRIPT
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Comment devenir CCA en un WE ?
HPN – aplasie médullaire
Régis Peffault de Latour, MD, PhD
Saint Louis Hospital, Paris;
AIH 27 Septembre 2014
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Paroxysmal Nocturnal Hemoglobinuria (PNH):
Rare disease:
– Prevalence: 15.9 / million1
Young patients: median age early 30’s3-5
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.
Acquired hemolytic anemia
Thrombosis
+/- aplastic anaemia
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Mortality rate in PNH:
Data From French Patients
n 454 211 120 58 22 11 2 1 1
1
8
6
4
2
0
0 5 10 25 30 40 15 20 35
Time after diagnosis (years)
O/N* 10-year survival rate (SE)
96/454 0.75 (0.03)
Su
rviv
al
Peffault de Latour et al. Blood 2008; 112:3099-3106.
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Pathophysiology
Young NS et al. Hematology Am Soc
Hematol Educ Program 2000:18–38
1189 1452 982 849 716 1
6 3 5 2 4 1
Somatic
mutations
in the PIG-
A gene
Protein
C=O
NH
CH2
CH2
O
O-P-O-
O
MAN
MAN
MA
N
O
(a 1-2) (a 1-6)
O
GLU O
N
INOS
C=O
O
O=P-O
O CH2
H
C H2
C O O
C=O
Phospho-
ethanolamine
Glycan core
Phosphatidy-
linositol
GPI anchor
structure
Deficit in GPI-
anchored
proteins
Intracellular
COOH
NH2
COOH
NH2
Extracellular
PNH, paroxysmal nocturnal haemoglobinuria;
PIG-A, phosphatidylinositol glycan class A; GPI, glycosylphosphatidylinositol
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Adapted from Abbas AK et al. Cellular and Molecular Immunology, 3rd ed. WB Saunders: Philadelphia, 1991
C5b
C5 C5a C7 C8
C5b
C7
C6
C7
C6
C5b,6,7
C8
C5b C6
C5b-8
C9
C7
C8
C5b C6
C9
C7
C8
C5b C6
C9 x 12–15
C5b-9
C5
convert
ase
C5
convert
ase
Absence of CD59 allows
terminal complement complex formation
PNH, paroxysmal nocturnal haemoglobinuria
CD59 CD59
X X
GPI deficiency results in Hemolytic Anemia (lack of CD59 or CD55)
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Anemia
Reduced Red Cell Mass Free Hemoglobin
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
Complement
Activation
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.
Historically Viewed as a Hemolytic Anemia
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How best to treat PNH & AA in 2014
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH AA / PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
AA / PNH
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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
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Quelle est votre attitude?
Answ
ers
(n)
1 - Eculizumab
2 - Prophylaxie Anti-thrombotique
3 - Supplémentation en folates
et en fer
4 - Immunosuppression:
ATG + cyclosporine
5 - Greffe de moelle
0
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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
An
sw
ers
(n)
0%
0%
0%
0%
0%
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Intermediate
(n=93)
Classic
(n=113)
Hb <12g/dl and/or thrombosis
0.6
1
0.8
0.2
0.4
10 20
0
0
Intermediate PNH AA-PNH
Classic PNH
Surv
ie
30
Temps (années)
AA – PNH syndrome
(n=224)
2 or 3 lineages* *Hb10g/dl, Platelets 80 g/L, Neutrophiles 1 g/L
Socié et al, Lancet 1996; Peffault de Latour, RP et al, Blood. 2008;112(8):3099-3106.
Mortality With Best Supportive Care In
Hemolytic PNH Patients
French cohort
(n=460)
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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)
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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
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Time (years)
Cu
mu
lati
ve S
urv
ivin
g (
%)
Eculizumab n = 79
Untreated n = 30
1 2 3 4 5 6 7 8 9
20
40
60
80
100
0
Kelly RJ et al. Blood. 2011
Mortality With Eculizumab In Hemolytic
PNH Patients
Long-term follow-up needed!!
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Quelle est votre attitude? 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
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Quelle est votre attitude? 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
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
AA / PNH
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
Moderate AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
AA / PNH
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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
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Mr JE. RE. 22 ans
Answ
ers
(n)
1 - Eculizumab
2 - Prophylaxie Anti-thrombotique
3 - Supplémentation en folates
et en fer
4 - Immunosuppression:
ATG + cyclosporine
5 - Greffe de moelle
0
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Mr JE. RE. 22 ans Mr JE. RE. 22 ans
Answ
ers
(n)
1 - Eculizumab
2 - Prophylaxie Anti-thrombotique
3 - Supplémentation en folates
et en fer
4 - Immunosuppression:
ATG + cyclosporine
5 - Greffe de moelle
0%
0%
0%
0%
0%
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Severe (SAA)
Hypocellularity (<30%) &
At least 2/3 critèria:
PNN <0.5x109/L
Platelets <20x109/L
Reticulocytes <20x109/L
Very severe (vSAA)
PNN <0.2x109/L
Moderate Not all criteria for SAA
PNN >0.5x109/L
Transfusions?
Yes No
Treatment Follow-up
Camitta et al. Blood 1976
AA and treatment
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AA and sibling donor
HSCT for SAA; young patients and HLA-identical sibling Donor
Marrow
Schrezenmeier et al Blood 2007
=<20 years(RR 2.4) p=0.02
>20 years(RR 1.2) p=0.1
0 12 36 60 24 48
BM, 20 yrs, N = 307, 12%
PB, 20 yrs, N = 49, 27%
100
0
20
40
60
80
0 12 36 60 24 48
BM, 20 yrs, N = 308, 85%
PB, 20 yrs, N = 49, 73%
100
0
20
40
60
80
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AA and sibling donor
HSCT for SAA; young patients and HLA-identical sibling Donor
Marrow
Cy- ATG
Blood. 2007;109:4582-4585
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AA and sibling donor
HSCT for SAA; young patients and HLA-identical sibling Donor
Marrow
Cy- ATG
CsA + MTX
Blood. 2000;96:1690-1697
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HSCT for SAA; young patients and HLA-identical sibling Donor
Event No of Events 6yr-CI (%)
Secondary Cancer 1 2 (0-9)
Osteonecrosis 10 21 (10-36)
Cardiovascular complications
1 2 (0-9)
Endocrine dysfunctions
7 19 (9-31)
87,5 % (IC 95%, 78-97)
AA and sibling donor>BMT!
Saint Louis experience Haematologica 2012
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AA and no sibling donor
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Scheinberg P, NEJM, 2011; Marsh JC, Blood 2012
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%
AA and no sibling donor
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Mr JE. RE. 22 ans
Answ
ers
(n)
1 - Eculizumab
2 - Prophylaxie Anti-thrombotique
3 - Supplémentation en folates
et en fer
4 - Immunosuppression:
ATG + cyclosporine
5 - Greffe de moelle
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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
Answ
ers
(n)
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
Moderate AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
Sib. No
Sib.
AA / PNH
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
Sib. No
Sib.
AA / PNH
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
Sib. No
Sib.
AA / PNH
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
Moderate AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
Sib. No
Sib.
AA / PNH
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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 109/l, Plts 219 x 109/l
– 99.5% de neutros HPN
– 37% de GR HPN
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Mr RE. PE.
• Decembre 2006:
− Douleurs abdominales d’apparition aiguë
− Ascite
> Syndrome de Budd-Chiari
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Mr RE. PE.
• Unité de soins intensifs
– Feeling extremely unwell
– Encephalite
– Fièvre
– HBPM
– Antibiotiques
– TIPS (transjugular intrahepaticportosystemic shunt)
– Fin d’hospitalisation
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Mr RE. PE.
• Réhospitaliser en aout 2007 avec des douleurs
abdominles aiguës
– Ascite
– Extension de la thrombose de la veine hépatique
• Sep 2007….
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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?
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Mr RE. PE.
Answ
ers
(n)
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
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Mr RE. PE.
Answ
ers
(n)
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%
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Intermediate PNH Aplastic anaemia–PNH
Classical PNH
10-year CI 37.9%
10 20 30
Cu
mu
lati
ve
in
cid
en
ce
0.6
0.5
0.1
0.3
0.4
0.0
0 40
Years
10-year CI 27.8%
10-year CI 27.3%
Thrombosis
0.2
Thrombosis risk factors RR p
Age >55 years
Thrombosis (at diagnosis)
Warfarin (prophylaxis)
Transfusions
Immunosuppressive therapy
1.8
3.7
5.2
1.7
0.5
0.01
<0.001
<0.001
0.01
0.02
Thrombosis in PNH
55% (10/18) had a TE while on prophylactic anticoagulation1
1.Peffault de Latour, RP et al. Blood. 2008;112(8):3099-3106.
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Thrombosis is Associated With
Risk of Early Mortality
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
TE increases risk of death 15-fold over patients with no TE
(n=415)
1. Peffault de Latour R et al. Blood. 2008;112(8):3099-3106.
15.40
0
2
4
6
8
10
12
14
16
18
Patients
Hazard
Rati
o
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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
39
3
0
5
10
15
20
25
30
35
40
45
Pre-Eculizumab Treatment Eculizumab Treatment
Th
rom
bo
tic E
ven
ts (
#)
P=0.0001
N=195
Thrombosis and Eculizumab
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SFH EBMT
122 47
Non grafted SCT
Not confirmed 1
121
Severity ?
27
2
Date ? 2 2
F-up<6mo post Thr
MDS before 1
42 92
24 24 Matched pairs
25 20 15 10 5 0
80
60
20
Time since thrombosis (year)
40
100
SCT
Non Grafted
p Log Rank = .01
p Cox stratified on pairs = .007
HR SCT/non grafted = 10.0(1.3-78.1)
Overall Survival (OS)
Thrombosis and Transplantation
Peffault de Latour et al, Haematologica 2012
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Mr RE. PE.
Answ
ers
(n)
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
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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
Answ
ers
(n)
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PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
Moderate AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
Sib. No
Sib.
AA / PNH
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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
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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 post-
partum + Eculizumab
de Guibert et al, Haematologica 2010
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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 post-
partum + Eculizumab
International study on going
- Almost 80 cases
- Abstract for ASH
de Guibert et al, Haematologica 2010
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Take home messages
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
Moderate AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
Sib. No
Sib.
AA / PNH
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Merci!
Participating centers
SFH
Centre Ref. Aplasie Médullaire
(Pr Socié)