Comment devenir CCA en un WE ? HPN aplasie médullairecluster013.ovh.net/~aihemato/AIH/documents/journeesAIH2014/Aplasie... · Comment devenir CCA en un WE ? HPN – aplasie médullaire

Comment devenir CCA en un WE ?

HPN – aplasie médullaire

Régis Peffault de Latour, MD, PhD

Saint Louis Hospital, Paris;

[email protected]

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

Eculizumab

Hemolytic PNH


IST

AA 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



et en fer


ATG + cyclosporine


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



et en fer


ATG + cyclosporine


Quelle est votre attitude? Quelle est votre attitude?

1 - Eculizumab



et en fer


ATG + cyclosporine



PNH

Eculizumab

Hemolytic PNH


IST

AA Hemolysis


SCT

THROMBOSIS

AA / PNH


PNH

Eculizumab

Hemolytic PNH


IST

Moderate AA 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



et en fer


ATG + cyclosporine


0

Mr JE. RE. 22 ans Mr JE. RE. 22 ans

Answ

ers

(n)

1 - Eculizumab



et en fer


ATG + cyclosporine


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



Marrow

Cy- ATG

Blood. 2007;109:4582-4585



Marrow

Cy- ATG

CsA + MTX

Blood. 2000;96:1690-1697


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



et en fer


ATG + cyclosporine


Mr JE. RE. 22 ans

1 - Eculizumab



et en fer


ATG + cyclosporine


Answ

ers

(n)


PNH

Eculizumab

Hemolytic PNH


IST



SCT

THROMBOSIS

Sib. No

Sib.

AA / PNH


PNH

Eculizumab

Hemolytic PNH


IST

AA Hemolysis


SCT

THROMBOSIS

Sib. No

Sib.

AA / PNH


PNH

Eculizumab

Hemolytic PNH


IST

AA Hemolysis


SCT

THROMBOSIS

Sib. No

Sib.

AA / PNH


PNH

Eculizumab

Hemolytic PNH


IST



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


0

Mr RE. PE.

Answ

ers

(n)

1 - Stop anticoagulatio et poursuite

de l’ecullizumab

2 - Stop eculizumab

et anticoagulation


à vie




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


à vie




Mr RE. PE.

1 - Stop anticoagulatio

et poursuite de l’ecullizumab

2 - Stop eculizumab

et anticoagulation


à vie




Answ

ers

(n)


PNH

Eculizumab

Hemolytic PNH


IST



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







Guidelines

- Low weight heparin from 6 months to 3 months post-

partum + Eculizumab








Guidelines

- Low weight heparin from 6 months to 3 months post-

partum + Eculizumab

International study on going

- Almost 80 cases

- Abstract for ASH


Take home messages

PNH

Eculizumab

Hemolytic PNH


IST



SCT

THROMBOSIS

Sib. No

Sib.

AA / PNH

Merci!

Participating centers

SFH

Centre Ref. Aplasie Médullaire

(Pr Socié)

Documents

Comment devenir CCA en un WE ? HPN aplasie médullairecluster013.ovh.net/~aihemato/AIH/documents/journeesAIH2014/Aplasie... · Comment devenir CCA en un WE ? HPN – aplasie médullaire