Surcharge en fer post transfusionnelle et affections onco hmatologiques

C ROSE Lille

Surcharge en fer et maladies hmatologiques

Incidence (EU) Clinical Impact

Diseases Congenital
Thalassemia major Erythroblastopenia(Blackfan Diamond) Congenital Dyserythropoiesis PK and G6PD deficiency

Dyserythropoiesis

++++ + ++++ +

++ + + ++

major +++ +++ +

Acquired
Myelodysplastic syndromes Aplastic anemia Off-therapy leukemia, BMT recipients + to +++ 0 0 ++++ + ++ + +? +

Surcharge en fer et tt hmatologiques intensifs : allogreffes , leucmie aigues, autogreffe

Physiopathologie de la surcharge en fer

Surcharge en fer hpatocytaire

Transfusions
1 CE = 200mg de fer

Hme oxygnase

Surcharge en fer macrophagique

Erythrophagocytose

Fe(II)

Mtabolisme du fer et distribution dans lorganisme

Apport alimentaire 12 mg fer / j Absorption 12 mg fer/j Transferrine plasmatique
(transport)

Pertes 12 mg fer /j
desquamation des cellules muqueuses, pertes sanguines

Equilibre

75%
Hmoglobine/ rythropose

1020%

515%

Autres

Ferritine
(stockage: foie)

Contrle de labsorption, transport et stockage +++ Aucun mcanisme de rgulation pour llimination
1.Rosmurduc O. Girot R. and Cohen A. Hemochromatose. In : Cur et Mdecine Interne. Paris Estem 2002. Tome 2 2. Andrews NC. Disorders of iron metabolism. N Engl J Med. 1999;341:1986-1995

Main clinical characteristics of patients

Rose, C. et al. Haematologica 2007;92:850-853

Copyright 2007 Ferrata Storti Foundation

Main clinical characteristics of patients

Median number of RBCs was 18 (0-240) Ferritin was 532 g/L(150-4250) Liver iron content (LIC) was 117 moles/gdw Correlation : RBCs and ferritin was (r=0.81) RBCs and LIC was (r=0.84) The high ferritin group differed from normal ferritin group in terms of RBCs transfused (p<103), ALT (p<0.009)

Correlation between number of blood units transfused and liver iron concentration (LIC) estimated by MRI

Impact de la surcharge en fer pr-greffe sur la survie globale des patients greffs

100
Treatment-related mortality (%) Ferritin 1st 3rd quartile Ferritin highest quartile

100

80
Overall survival (%)

Ferritin 1st 3rd quartile Ferritin highest quartile

80

60

60

40

40

20

p = 0.003

20

p = 0.005

0 0 1 2 3 4 5 6 7 8
Years from transplantation
Armand P, et al. Blood. 2007;109:4586-8.

2 3 4 5 6 7 Years from transplantation

CAT pratique en post greffe ou post TT intensif

Surveillance ferritine avant , en cours et distance de la greffe (2ans)
augmentation de la ferritine non corrle surcharge en fer (inflammation , infection , hpatite virale ou mdicamenteuse,tt immunosuppresseurs , maladie veino occlusive du foie, GVH, andrognes, second cancer) Coefficient de saturation leve que dans les trs forte surcharge

Concentration intra hpatique (IRM) corrle au nombre de CGR reus

Attendre deux ans post greffe pour proposer dpltion

Saignes

Rythme
Saignes tous les mois 400ml Diminuer ferritine inf 100ng/ml(1)
1. Rose, C. et al. Haematologica 2007;92:850-853

Surcharge en fer et syndromes mylodysplasiques de faibles risques

Arguments

Pas dessais contrls Arguments issus des donnes du mtabolisme du fer Arguments issus des donnes biologiques et cliniques rtrospectives des patients atteints de SMD Arguments de bnfice de survie

N et al. Hematol Oncol Clin North Am 2005;19(Suppl 1):126; 2NCCN Clinical Practice Guidelines in Oncology v.2: MDS 2008; 3Bennett JM et al. Am J Hematol 2008;83(11):85861; 4Jensen PD et al. Br J Haematol 1996;94:28899; 5Jaeger M et al. Drugs Today 1992;28(Suppl A):143147; 6Kersten MJ et al. Ann Hematol 1996;73:247252; 7Porter et al. Eur J Haematol 2008;80:168176; 8List A et al. Blood 2007;110(11):abst 1470.

1Gattermann

Physiopathologie de la surcharge en fer 2 mcanismes associs

Absorption intestinale
1-2 mg fer/jour

Stimule par la dysrythropoise

Surcharge en fer hpatocytaire

Transfusions
1 CE = 200mg de fer

Hme oxygnase

Surcharge en fer macrophagique

Erythrophagocytose

Fe(II)

Consquences de la surcharge en fer : risque de lsions tissulaires

1.
Augmentation de la saturation de la transferrine

2.
Formation de fer libre plasmatique : NTBI, LPI*

3.
(non rgule)

4.

Pntration du fer libre Formation de dans les organes radicaux libres

Saturation de la transferrine ltat basal 100%

Situation de surcharge en fer : saturation > 75% Fe Fe Fe Fe Fe OH HO HO

OH

.
HO

. .

30%

Fe

HO Fe

.
OH

5.
NTBI = non-transferrin-bound iron LPI : Labile Plasma Iron

Lsions tissulaires (fibrose, mort cellulaire)

Arguments

Arguments issus des donnes biologiques et cliniques rtrospectives des patients atteints de SMD

Impact de la dysrythropose sur la surcharge en fer

Taux de ferritine moyen au diagnostic
1000 900

en fonction du score IPSS

863

Taux moyen de ferritine (ng/ml)

800 700 600 500 400 300 200 100 0

533

Low
IPSS

Int-1

Source : registre GFM

Consquences de la surcharge en fer chez les patients SMD

Manifestations cliniques (1)
Signes gnraux : altration de ltat gnral Atteinte des organes cibles : foie, cur, glandes endocrines Dlai dapparition des complications : < 4 ans

Tenir compte de lge des patients SMD et des pathologies associes (cardiopathies)

Morbidit :
Ins. Cardiaque : 16-25% Diabte : 9-10% (2, 3, 4)

Mortalit : 5 25%
Complications cardiaques : 24% (5) Complications hpatiques : 7% (5)
1. Schafer AI N Engl J Med. 1981;304:319-324 - 2. Cazzola M. Blood. 1988;71:305-312; - 3. Mathew P. Blood. 1993;81:1040-1045; 4. Jaeger M. Beitr Infusionsther. 1992;30:464-468 5. M Takatoku. EJH 2007

Arguments

Arguments issus des donnes de survie

Impact de la dpendance transfusionelle sur la survie globale des patients

Cazzola M. New Engl J Med 2005 352 p 537-538, Malcovati JCO

Impact de la surcharge en fer sur la survie globale des patients

RA/RARS/5q (HR = 1.42, p < 0.001)
1.0 Cumulative proportion surviving 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 20 40 60 80 100 120 140 160 180 Survival time (months)

RCMD/RCMD-RS (HR = 1.33, p = 0.07)

1.0 Cumulative proportion surviving 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 20 40 60 80 100 120 140 160 180 Survival time (months)

sFerr sFerr sFerr sFerr

= = = =

1,000 ng/mL 1,500 ng/mL 2,000 ng/mL 2,500 ng/mL

sFerr sFerr sFerr sFerr

= = = =

1,000 ng/mL 1,500 ng/mL 2,000 ng/mL 2,500 ng/mL

Malcovati L, et al. Haematologica. 2006;91:1588-90.

Impact de la surcharge en fer pr-greffe sur la survie globale des patients greffs
100
Treatment-related mortality (%) Ferritin 1st 3rd quartile Ferritin highest quartile

100

80
Overall survival (%)

Ferritin 1st 3rd quartile Ferritin highest quartile

80

60

60

40

40

20

p = 0.003

20

p = 0.005

0 0 1 2 3 4 5 6 7 8
Years from transplantation
Armand P, et al. Blood. 2007;109:4586-8.

2 3 4 5 6 7 Years from transplantation

Is Treatement chelation improve survival in MDS ?

Leitch HA et All (Blood 2006,108:Abst249) 178 MDs patients IPSS low Int 1 :60% Treatement by supportive care :71% Chelation in 18 patients
Ferritin >1000g :in 13 Iron overload :in 3 Transfusion more than 20U: in 2

Two factors significant for Survival IPPS (p<0.008) Iron chelation (p<0.002)

Methods - study design

Inclusion Criteria
Outpatient setting MDS referred for RBC transfusion 18 GFM centers

Prospective Survival Analysis

May15-June15 2005 Hematological data Transfusion requirement Chelation therapy Iron overload (ferritin)

May 15 2007

Survival Chelation therapy Transfusion requirement Iron overload Causes of deaths

Results : Chelation Therapy > 6 Months

Nb
No Chelation Therapy Chelation Therapy 89 76 57 41 6 5 5 19 12 7

%
53.9 46.1

1) Standard chelation therapy 5d/ w)

Deferioxamine s/c continuous (8h)(40mg/kg/d, 3

Deferasirox(20 to 30 mg/kg/d) Deferiprone (30 to 75 mg/kg/d) Deferiprone + Deferioxamine s/c

2) Low chelation therapy

Deferioxamine s/c bolus (2 to 3g/week) Deferioxamine IV

(50 to 100mg/kg/d once after RBC Transfusion)

Results: Survival (Kaplan Meier)

1.00

Median Survival : 63 months (whole group) 115 versus 51 months (p< 0.0001)
Survival Distribution Function
0.75

0.50

CT
0.25

No CT
0.00 0 50 100 150 200 250

Diagnosis to Death Time (Months)

Results: Survival according IPSS

IPSS= low
Median : not reached versus 69 months (p< 0.002)
Survival Distribution Function
1.00 1.00

IPSS= int 1
Median :Median : 115 versus 50 months (p< 0.003)

Chelation therapy

Survival Distribution Function

0.75

0.75

Chelation therapy

0.50

0.50

No Chelation therapy

0.25

0.25

No Chelation therapy

0.00 0

0.00 0 20 40 60 80 100 120 140

50

100

150

200

250

Diagnosis to Death Time (Months)

Diagnosis to Death Time (Months)

Rsultats Identique pour sexe , ge

Results: Survival -intensity of chelation

1.00

Median : 120 std versus 69 months (low)(p< 0.001)

Survival Distribution Function 0.75

0.50 Standard/High Chelation 0.25 Low Chelation No chelation 0.00 0 50 100 150 Diagnosis to Death Time (Months) 200 250

Results: Cox model: multivariates Survival analysis

Parameter Good Chelation IPSS: >1 Transf rate > 3 RBC / month IPSS int1 Y >77

P= 0.0002 0.0030 0.0757 0.3914 0.9226

Hazard Ratio 0.215 3.888 2.122 1.435 1.036

Global Test (Wald): P= 0.00012

QUI Chlat?
Consensus

SMD rgulirement transfuss Ferritine suprieure 1000-2000ng/ml ou prsence de signes clinique de surcharge en fer tissulaire IPSS faible ou int 1 AR ARSI 5qSMD non volutifs sans co morbidit majeure limitant l esprance de vie Candidat une allogreffe

N et al. Hematol Oncol Clin North Am 2005;19(Suppl 1):126; 2NCCN Clinical Practice Guidelines in Oncology v.2: MDS 2008; 3Bennett JM et al. Am J Hematol 2008;83(11):85861; .

1Gattermann

International Prognostic Scoring System (IPSS)

Score Prognostic variable Bone marrow blasts (%) Cytogenetics Cytopenias Score 0 0.51.0 1.52.0 > 2.5 0 <5 Good 0/1 IPSS subgroup Low Int-1 Int-2 High 0.5 510 Intermediate 2/3 Median survival (years) 5.7 3.5 1.2 0.4
Greenberg P, et al. Blood. 1997;89:2079-88.

1.0

1.5 1120

2.0 21-30

Poor

International MDS risk classification

AML evolution
100 90 80 70 100 90 80 70

Survival
Low 267 pts Int-1 314 pts Int-2 179 pts High 56 pts

Percent

Percent

60 50 40 30 20 10 0
0 0

Low 235 pts Int-1 295 pts Int-2 171 pts High 58 pts

60 50 40 30 20 10 0

1 2 3 4 5 6 7 8 9 101112131415161718 4 10 12 14 16 18

0 2 4 6 8 10 12 14 16 18 0 1 2 3 4 5 6 7 8 9 101112131415161718

Years

Years
Greenberg P, et al. Blood. 1997;89:2079-88.

Survival of MDS patients by WHO

1.0 5q-syndrome RARS RA RCMD RCMD-RS RAEB I p < 0.00005 RAEB II p < 0.00005 n = 1,157 (n = 1157)

Cumulative survival

0.8

0.6

0.4

0.2

0.0
0 24 48 72 96 120 144 168 192 216 240 264 288 312 360 386

Months
Germing U, et al. Haematologica. 2006;91:1596-604.

The new WHO classification-based Prognostic Scoring System (WPSS)

WHO category Variable Karyotype Transfusion requirement RA, RARS, del(5q) 0 Good No 0 (Very low) 1 (Low) WPSS risk groups 2 (Intermediate) 34 (High) 56 (Very high)
Malcovati L, et al. J Clin Oncol. 2007;23:3503-10.

RCMD, RCMD-RS 1 Intermediate Regular

RAEB-1 2 Poor

RAEB-2 3

Overall survival and AML risk assessments in MDS by WPSS (2)

Risk group Very low Low Intermediate High Very high

Risk group Very low Low Intermediate High Very high

Malcovati L, et al. J Clin Oncol. 2007;23:3503-10.

Survie des patients SMD de risque faible et intermdiaire I

Survie et transformation en leucmie en fonction de lge des patients et du score IPSS Age Ans < 60 < 70 > 70 Faible Risque mdiane 11 ans 9 ans 4 ans Risque Intermdiaire I mdiane 5 ans 4,5 ans 2,5 ans Dcs non li la leucmie (%) 70% 75% 80%

Exposition la surcharge martiale importante et patient de bon pronostic : bnfices du traitement chlateur ?
Greenberg P Blood. 1997;89:2079-2088

Comment chlat?
Caractristiques des traitements chlateurs
Proprit
Dose (mg/kg/j) Voie dadministration Demi-vie Excrtion Principaux Effets secondaires

Desferal 1,2
2560 s.c., i.v. (812 heures, 5 j/sem) 2030 minutes Urinaire, fcale Ractions locales, troubles ophtalmologiques et auditifs, retard de croissance, allergie

Deferiprone
75

3,4

Deferasirox
2030

5,6

Orale 3 prises par jour 34 heures Urinaire Effets secondaires gastro-intestinaux, agranulocytose/ neutropnie, arthralgie, augmentation des enzymes hpatiques

Orale 1 prise par jour 816 heures Fcale Effets secondaires gastrointestinaux, rash, augmentation de la cratinine (modre, non progressive), augmentation des enzymes hpatiques, vision et audition surveiller Oui

Indication dans les SMD

Oui

Non (-Thalassmie majeure uniquement)

1Olivieri NF, et al. Blood. 1997;89:739-61. 2Deferoxamine [package insert]. Novartis; 2002. 3Kushner JP, et al. Hematology. 2001;47-61. , 4Deferiprone [package insert]. Apotex Europe Ltd; 1999. 5Cappellini MD, et al. Blood. 2006;107:3455-62. 6Deferasirox [package insert]. Novartis; 2005.

deferasirox: Etudes cliniques: efficacit tolrance

Randomise (DFO/ICL670) Beta thal107 (Blood 2006) Randomise (DFO/ICL670) Drpanocytose 109 (ASH2005) british 2007) Non randomis anmies chroniques108 (Europ J Hematol 2008) Etudes ancillaires: efficacit Foie , Cur, Rythme transfusionnel, Mthodes valuation surcharge

POSO

Efficacit Deferasirox : LIC

15 Change in LIC, mg Fe/g 10 5 0 -5 -10 -15 -20 DFO DSX
DFO 0107 DFO 0109 DSX 0107 DSX 0108 DSX 0109

< 25 5

25 - 35 35 - 50 10 20 All doses in mg/kg

50 30

DFO, deferoxamine; DSX, deferasirox.

EPIC study
The efficacy and safety of deferasirox in patients with MDS was evaluated as part of the large, prospective, 1-year EPIC study including 1,744 iron overloaded patients with various transfusion dependent anemias Includes the largest group of MDS patients evaluated for any chelation therapy to date N=341 ASH 2008
AIM: To evaluate the efficacy and safety of deferasirox in a large group of patients with transfusion-dependent MDS

Discontinuations
Patients (n=341), n (%) Completed Discontinued AEs Consent withdrawal Unsatisfactory therapeutic effect Lost to follow-up Death Other 175 (51.3) 166 (48.7) 78 (22.9) 33 (9.7) 6 (1.8) 2 (0.6) 26* (7.6) 21 (6.2)

*None treatment-related as per investigators assessments; 25 patients discontinued due to gastrointestinal AEs

Conclusion EPIC

significant reduction in serum ferritin levels with appropriate dose adjustments every 3 months based on serum ferritin trends and safety markers AE profile was consistent with previously reported deferasirox data in MDS patients Discontinuation rates were higher in this subgroup than in other patient subgroups in EPIC, primarily due to AEs

1List 2List

A et al. Blood 2007;110(11):abst 1470; A et al. Haematologica 2008;93(Suppl 1):abst 0228.

Comment Surveiller SMD chlats

Suivi de la surcharge en fer
Au diagnostic, puis intervalle rgulier, selon le rythme transfusionnel En pratique :
Rythme transfusionnel Ferritinmie tous les 3 mois pour les patients rgulirement transfuss Evaluation de la surcharge organique par IRM cardiaque et hpatique Evaluation des fonctions cardiaques et hpatiques

Suivi traitement chlateur

Deferasirox (uree creat, ferritine , TGO, TGP, gamma GT,bil, proteinurie) Deferiprone (Nf Hebdomadaire)
Consensus statement on iron overload in myelodysplastic syndromes. Hematology/Oncology Clinics. 2005; S18-S25.

COMMENT FAIRE LA SURVEILLANCE : Examens AVANT ET SOUS TRAITEMENT

Avant traitement
Ferritinmie Cratininmie Cl de la cratinine

suivi hebdomadaire

Suivi mensuel X

Suivi annuel

X X* X* X X

X X X

Protinurie Transaminases

X X X

X X X

Tests audio FO

Poids, taille

COMMENT SUIVRE LEFFICACITE DU TRAITEMENT?

Avant traitement Rythme transfusionnel Clinique Ferritinmie Transaminases hpatiques IRM hep IRM cardiaque X X X X X X

Suivi mensuel X X X X

Suivi annuel X

DISCORDANCE

X X

X X

Comment valuer efficacit sur la surcharge en fer ?

Evaluation de la fonction de chaque organe Foie (fibrose, cirrhose) bilan hpatique lastomtrie Cur (fonction cardiaque et rythme) Glandes endocrine (Glycmie, TSH, Ca ,P, PTH, FSH,LH,testo) Estimation de la concentration en Fer Indirectement ( Ferritine srique) Foie (Biopsie, MRI, SQUID) Cur (indirectement MRI) Mesure de marqueurs srique de toxicit du fer?

INTERET IRM STANDARDISEE

http://www.radio.univ-rennes1.fr/Sources/FR/HemoCalc15.html http://oernst.f5lvg.free.fr/liver/iron.html

LIC< 300 mol/g dw

LIC >3OO mol/g dw up to 800

Cardiac T2*

Questions en suspens ?
Impact mortalit morbidit de la surcharge en fer parmi les dcs non leucmiques impact anmie chronique

Dcs non lis la leucmie chez les patients SMD transfuss

100

N = 467

75 Percentage
p = 0.01

51 50 31 25 8 0 Cardiac failure Infection Haemorrhage Hepatic cirrhosis Other 8 2

Malcovati L, et al. J Clin Oncol. 2005;23:7594-603.

Rle co morbidits
Frquence co morbidit et ge Risque de dcs Facteur pronostique indpendant dans certains cancers et maladies hmatologiques et MDS (ash2008) MDS et Population ge
WHO IPSS Malcovati Srie Greenberg IPSS: Srie Epo GFM: srie transfusion GFM: 467 pts 816 pts 403 pts 165 pts med med md mdi 66 ans 69 ans 74 ans 77ans

Asmis 2008 JCO Sorror 2008 Cancer

Attitude transfusionnelle et chlation Anmie et mortalit

Anmie et insuffisance rnale

Foley Rn J Am Soc Nephrol998;9; Samac Mj Circulation ,2003;108 Anomalie fonction ventriculaire gauche Mortalit

Anmie et dfaillance cardiaque (infarctus)

Wu W, N Engl J Med 2001 mortalit

Anmie sujet g > 65

Izaks Gj JAMA.1999;281;Chaves Ph J Am Geriatr Soc .2004;52 Penninx Bw J Am Geriatr Soc 004;52 ;Thomas Dr J Gerontol A Biol Sci Med Sci,2004;59 Culleton Bf,Blood2006;107 Plus hospitalisation Plus de mortalit Plus AVC Moins de qualit de vie QOL

Cardiac MRI T2* : impact MDS

-Atteinte cardiaque SMD: anmie chronique, vieillissement, ischmie, infarctus, hypertension, surcharge en fer

Cardiac MRI T2*: influenc que par le fer myocardique

Jensen PD Blood 1995 n= 14 CE= 110 CE 11/14 IRM anormale Chacko Brit J Haematol 2007n=11 - 63 CE- 10/11 T2* FE normale Konen AM J Hematol 2007 n= 10 - 90 CE - T2* normal

Di Tucci Haematologica 2008 n=22 CE >110T Projet GFM

Conclusions
-Traitement chlateur prventif indiqu pour les SMD rgulirement transfuss de faible risque -Affiner les indications au sein de ce groupe low risk (consensus MDS symposium) Rapport cout bnfice , effet II -Mieux cibler les patients pouvant tirer le meilleur bnfice du traitement chlateur -facteurs pronostiques -Co morbidits IRM - Apport des nouvelles drogues pour indpendance transfusionnelle