Comment devenir CCA en un WE ? HPN aplasie...

Comment devenir CCA en un WE ?

HPN – aplasie médullaire

Régis Peffault de Latour, MD, PhD

Saint Louis Hospital, Paris;

regis.peffaultdelatour@sls.aphp.fr

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

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)

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

O-P-O-

(a 1-2) (a 1-6)

Phospho-

ethanolamine

Glycan core

Phosphatidy-

linositol

GPI anchor

structure

Deficit in GPI-

anchored

proteins

Intracellular

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

C5 C5a C7 C8

C5b,6,7

C5b C6

C9 x 12–15

convert

Absence of CD59 allows

terminal complement complex formation

PNH, paroxysmal nocturnal haemoglobinuria

CD59 CD59

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

Eculizumab

Hemolytic PNH AA / PNH

Severe AA No Hemolysis

AA Hemolysis

Moderate AA No Hemolysis

THROMBOSIS

Eculizumab

Hemolytic PNH

AA Hemolysis

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?

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?

1 - Eculizumab

et en fer

ATG + cyclosporine

Intermediate

(n=93)

Classic

(n=113)

Hb <12g/dl and/or thrombosis

Intermediate PNH AA-PNH

Classic PNH

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)

Eculizumab n = 79

Untreated n = 30

1 2 3 4 5 6 7 8 9

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

Eculizumab

Hemolytic PNH

AA Hemolysis

THROMBOSIS

AA / PNH

Eculizumab

Hemolytic PNH

Moderate AA Hemolysis

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

1 - Eculizumab

et en fer

ATG + cyclosporine

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

1 - Eculizumab

et en fer

ATG + cyclosporine

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%

0 12 36 60 24 48

BM, 20 yrs, N = 308, 85%

PB, 20 yrs, N = 49, 73%

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

1 - Eculizumab

et en fer

ATG + cyclosporine

Mr JE. RE. 22 ans

1 - Eculizumab

et en fer

ATG + cyclosporine

Eculizumab

Hemolytic PNH

THROMBOSIS

Sib. No

AA / PNH

Eculizumab

Hemolytic PNH

AA Hemolysis

THROMBOSIS

Sib. No

AA / PNH

Eculizumab

Hemolytic PNH

AA Hemolysis

THROMBOSIS

Sib. No

AA / PNH

Eculizumab

Hemolytic PNH

THROMBOSIS

Sib. No

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.

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

Mr RE. PE.

1 - Stop anticoagulatio et poursuite

de l’ecullizumab

2 - Stop eculizumab

et anticoagulation

à vie

Intermediate PNH Aplastic anaemia–PNH

Classical PNH

10-year CI 37.9%

10 20 30

10-year CI 27.8%

10-year CI 27.3%

Thrombosis

Thrombosis risk factors RR p

Age >55 years

Thrombosis (at diagnosis)

Warfarin (prophylaxis)

Transfusions

Immunosuppressive therapy

<0.001

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.

Patients

Hazard

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

Pre-Eculizumab Treatment Eculizumab Treatment

P=0.0001

Thrombosis and Eculizumab

SFH EBMT

122 47

Non grafted SCT

Not confirmed 1

Severity ?

Date ? 2 2

F-up<6mo post Thr

MDS before 1

24 24 Matched pairs

25 20 15 10 5 0

Time since thrombosis (year)

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.

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

Eculizumab

Hemolytic PNH

THROMBOSIS

Sib. No

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

Eculizumab

Hemolytic PNH

THROMBOSIS

Sib. No

AA / PNH

Merci!

Participating centers

Centre Ref. Aplasie Médullaire

(Pr Socié)

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