Comment devenir CCA en un WE ?
HPN – aplasie médullaire
Régis Peffault de Latour, MD, PhD
Saint Louis Hospital, Paris;
AIH 27 Septembre 2014
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
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.
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
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)
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
How best to treat PNH & AA in 2014
PNH management in 2014
PNH
Eculizumab
Hemolytic PNH AA / PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
AA / PNH
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
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
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%
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)
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)
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
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!!
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
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
PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
AA / PNH
PNH management in 2014
PNH
Eculizumab
Hemolytic PNH
Severe AA No Hemolysis
IST
Moderate AA Hemolysis
Moderate AA No Hemolysis
SCT
THROMBOSIS
AA / PNH
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
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
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%
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
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
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
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
AA and no sibling donor
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
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
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)
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
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
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
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
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
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?
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
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%
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.
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
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
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
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
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)
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
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
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
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
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
Merci!
Participating centers
SFH
Centre Ref. Aplasie Médullaire
(Pr Socié)