manejo de los smd de riesgo bajo

Manejo de los SMD de riesgo bajo

Pierre Fenaux

Hôpital AvicenneParis 13 University

Inserm U 848France

Oviedo 3/2011

Manejo de las citopenias en SMD de riesgo bajo ?

• Anemia

• Neutropenia

• Trombopenia

0 30 60 90 120 150 180 210

Hb

(g

/dL

)

Days of treatment

8

12

14

10

4

6

Transfusion given

EPO

Blood transfusion

Quality of Life is correlated to Hb levels

Hb level (g/dl)LASA: Linear Analog Scale Assessment

Qu

alit

y o

f L

ife

(LA

SA

, m

m)

45

50

55

60

65

7 8 9 10 11 12 13 14

Crawford et al. Cancer 2002; 95: 888–95

RBC transfusions in MDS ( Bardiaux et al 2003)

MDS represent - 3% of all RBC units transfused - 24% of hospitalizations for transfusion

Mean monthly cost for transfusions: 810 euros

Como evitar trasfusiones de GR en SMD de riesgo bajo?

• Tratamiento de primera linea– ASE (EPO y darbepoetina)

• Tratamiento de secunda linea– Lenalidomida ( del 5q)– Immunosupression (ATG+/- ciclo) – Talidomidea– Lenalidomida (non del 5q)– Hipometilantes

Como evitar trasfusiones de GR en SMD de riesgo bajo?

• Tratamiento de primera linea– ASE (EPO y darbepoetina)

• Tratamiento de secunda linea– Lenalidomida ( del 5q)– Immunosupression (ATG+/- ciclo) – Talidomidea– Lenalidomida (non del 5q)– Hipometilantes

A simplified validated decision model for treatment

of the anemia in MDS with G-CSF + EPO

Predictive value of model : p<0.001

Variable value score value score

Transf. need <2 U/m 0 ≥2 U/m 1

Serum-epo <500 U/l 0 ≥500 U/l 1

Probability of response: Total score 0: 74%, score 1: 23%, score 2: 7%QoL improved in responding patients

Hellstrom-Lindberg, et al, Br J Haem, 2003

EPO +/- G-CSF in MDS: prognostic factors of response

(Park , Kelaidi,Blood 2007)

• N= 403 pts treated with EPO+/- G-CSF or Darbepoetin alpha

• Hb<10g/dl (54%transfused)• 63% response (43% major, 20% minor)• Median response duration: 24 months

Duration of response (IWG 2006) (Park, Kelaidi, Blood 2008)

Median 24 months

EPO treated versus IMRAW cohort (transfusions only):Time to AML progression (Park ,Blood 2008)

Comparison between IMRAW and French-EPO cohort restricted to IPSS LOW INT1 patients without unfavorable karyotype

(IMRAW n=447 patients, French-EPO= 284)

a) progression to AML , p= NS

EPO treated versus IMRAW cohort (transfusions

only): Overall survival (Park, Blood 2008)

EPO + ATRA (Itzykson, Leukemia, 2009)

Early introduction of ESA in low risk MDS patients may delay the need for RBC transfusion: a retrospective

analysis on 112 patients ( Park,ASH, 2009)

Causes of relapse in MDS responding to EPO

• Nordic MDS group (Jadersten, 2005)

39/48 relapses. Cause:– Overt Progression (n=7)– Discontinuation(n= 14))– No clear evolution (n=18/39)

• GFM (Park, Kelaidi 2008)

54/251 relapses. Cause:– Progression:28%– No clear evolution: 72%

Treatment of MDS with del 5q: EPO (or darbepoetin) +/- G-CSF

Serum EPO level

Response

rate

Response duration

Del 5q 287U/l 46% 12 m

No del 5q 68 U/l 64% 24 m

P value <0.001 0.01 0.019

(Kelaidi, ASH 2006, abstr n° 2678 )Park ,ASH 2006, abstr n° 522)

Como evitar trasfusiones de GR en SMD de riesgo bajo?

• Tratamiento de primera linea– ASE (EPO y darbepoetina)

• Tratamiento de secunda linea– Lenalidomida ( del 5q)– Immunosupression (ATG+/- ciclo) – Talidomidea– Lenalidomida (non del 5q)– Hipometilantes

Lenalidomide Erythroid Response:lower risk Del 5q (List, 2006)

99 (67%)

13 (9%)

112 (76%)

Erythroid Response

Transf -Indep

Minor (>50%) TI +Minor

4.6 wks

(1- 49)

Time to Response

148No . Patients

Variable ,

n (%)

Evaluable 104

Cytogenetic response*

Complete (CCR)

Minor (≥ 50%)

75%

48%

27%

Cytogenetic response in patients with del 5q

*All cytogenetic responders achieved an erythroid response.

List AF, et al. Updated data presented at ASH Annual Meeting, 2006 [Abstract 251].

Duration of major erythroid response in patients with del 5q (N = 168)

0 1 2 3 4 50

20

40

60

80

100

Time (years)

Pat

ien

ts (

%)

50% ongoing responders

73% TI response ≥ 1 year46% TI response ≥ 2 years

Median duration of TI = 2.2 yearsMedian follow-up: 1.3 years (min–max: 0.1–4.4 years)

Data cutoff 4 Dec 2006 (N = 114).

List AF, et al. Updated data presented at ASH Annual Meeting, 2006 [Abstract 251].

min–max = 0.2–4.4+ years

Censored patients who remain TI at time of data cutoff or at time of study discontinuation.

Drug-Related Adverse Events

55%**57%Neutropenia

Fatigue*

DiarrheaRashPruritus

Thrombocytopenia

Adverse Event

12%24%28%32%

58%

All Grades

2% 7%2%3%

54%*

>Grade 3 (%)

Lenalidomide in lower risk MDS with del 5q: French ATU (M Sébert, F Le Bras, ASH 2009)

• 95 pts

• 2/3 tranfusion independence (TI)

• Median TI duration not reached

• 3 deaths from cytopenias

• 7 cases of deep venous thrombosis

• 6 progressions to AML

Risk of progression in lower risk MDS with del 5q treated without lenalidomide (Germing, ASH 2009)

#xxx

•International retrospective study in IPSS low ou int-1 with del 5q : 303 patients• variable treatments, mainly ESAs•AML progression:

•7% at 2 y •18% at 5 y

•Main predictive factors of AML progression:•% marrow blasts•Cytogenetic complexity •RBC transfusion dependence

•AML risk comparable to MDS-003 and MDS-004 studies

KM Kurven AML Progression nach Transfusionsbedarf

Baseline characteristics of patients of patients treated

with or without Lenalidomide

N, %Median [Q1-Q3]

Historical controls Lenalidomide p-value

After matching N=71 N=71 Paired tests

Age, years 72.4 [64.9-78.7] 0.92

Gender male 22 (31%) 22 (31%) 1.00

Karyotype ISOLATED del 5q 57 (80%) 55 (77%) 0.84

Del5q + 1abn 10 (14%) 11 (15%) 1.00

Del 5q+2 or more abn 4 (6%) 5 (3%) 1.00

WHO 5q- syndrom 25 (35%) 28 (39%) 0.72

RAEB-1 20 (28%) 22 (31%) 0.86

RARS 4 (6%) 3 (4%) 1.00

RCMD 8 (11%) 8 (11%) 1.00

IPSS 0 30 (42%) 22 (31%)0.45 0.5 23 (32%) 32 (45%)

1 18 (25%) 17 (24%)

Overall Outcome

100

80

60

40

20

0

100

80

60

40

20

0

0 50 100 150 200 0 50 100 150 200

Times (Months) Times (Months)

Cum

. Inc

. Of A

ML

Ove

rall

Surv

ival

Control groupLenalidomide group

4 y CIR of AML 8.9% vs 15.8%; p=0.14 Median OS 150 months vs 72.8 , p= 0.10

MDS-004: study design (ASH 2009)

*Patients stratified by IPSS score and cytogenetic complexity prior to randomization.**Bone marrow assessments were performed at baseline, 12 weeks, and every 24 weeks thereafter.

LEN, orally5 mg/day for 28 days of each 28-day cycle

LEN, orally5 mg/day for 28 days of each 28-day cycle

Placebo Placebo

Responders (at least minor erythroid response at week 16):

Continued double-blind treatment for up to 52 weeks, relapse or progression

Non responders:Discontinued double-blind treatment and entered open-label treatment or withdrew

from study

STRAT IFY

RESPONSE

RANDOM IZED

LEN, orally10 mg/day for 21 days of each 28-day cycle

LEN, orally10 mg/day for 21 days of each 28-day cycle

Double-blind phase**

Planned enrollment (n = 205)

Week 0 4 8 12 16 52

*

Protocol defined (≥ 26 weeks)

IWG(≥ 8 weeks)

*P < 0.001 vs placeboBars represent 95% CI

*

41

*

56

8

*

50

*

61

66

MDS-004: RBC-TI (mITT population)

MDS-004: cytogenetic response (mITT population)

Placebo(n = 51)

LEN 5 mg(n = 46)

LEN 10 mg(n = 41)

Cytogenetic response, % Complete response (CR) Partial response (PR) CR + PR

000

10.9*6.5

17.4**

24.4**17.1

41.5***P = 0.01 vs placebo**P < 0.001 vs placebo

Assessed by standard cytogenetics and FISH.CR defined as absence of chromosome 5q31 abnormality;PR defined as reduction of abnormality by > 50%.

Como evitar trasfusiones de GR en SMD de riesgo bajo?

• Tratamiento de primera linea– ASE (EPO y darbepoetina)

• Tratamiento de secunda linea– Lenalidomida ( del 5q)– Immunosupression (ATG+/- ciclo) – Talidomidea– Lenalidomida (non del 5q)– Hipometilantes

Immunosuppression in MDS(Sloand, JCO, 2008)

129 pts

– 24% response (CR+PR) to ATG– 48% response to ATG+ CsA– 8% response to CsA

Prognostic factors of response :– Younger age (<60 y)– HLA DR 15– ATG+ CsA– IPSS low or int 1

If compared to IPSS data base: immunosuppression improves survival in younger patients

Alemtuzumab in lower risk MDS (Sloand, ASH 2009)

• IPSS int-1 et int-2, RBC transfusion dependent and/or platelets < 50 G/L and/or ANC < 0,5 G/L and predictive factors of response to immunosuppression (younger age and HLADR15+)

• Campath: 1mg IV test , then 10 mg IV/d x 10 d• 24 patients evaluable; median FU 12 months,• 20 (83%) responses, after a median of 96 d,• 16 still responders, 4 relapses• Cytogenetic response in 5 of 7 patients with anomalies ,

including monosomy 7

#116 Olnes ORAL

Should Immunosuppressive Therapy (IST) be used more often in lower risk MDS? Cereja S, Bréchignac S, Ades L, Braun T, Boehrer S, Lim EM, Hebibi Z, 2-3 gros centres du register, Sapena R Dreyfus F, Fenaux P, Gardin C

GFM database: transfusion dependent anemia: -and IPSS low or int-1: 20% (<60 y) 22% (<65 y), 24% (<70 y)

- and IPSS int-1 with <5 % marrow blasts (ie thrombocytopenia or int karyotype): 5.5% (<60 y) 6.5% (<65 y), 6.5% (<70 y)

Como evitar trasfusiones de GR en SMD de riesgo bajo?

• Tratamiento de primera linea– ASE (EPO y darbepoetina)

• Tratamiento de secunda linea– Lenalidomida ( del 5q)– Immunosupression (ATG+/- ciclo) – Talidomida– Lenalidomida (non del 5q)– Hipometilantes

Thalidomide and lower risk MDS(D Bouscary,BJH 2005; F Tamburini, Leuk Res, 2009)

• > 130pts

• 50 tp 800 mg /d

• 35 % responses

• Short and medium term side effects

Como evitar trasfusiones de GR en SMD de riesgo bajo?

• Tratamiento de primera linea– ASE (EPO y darbepoetina)

• Tratamiento de secunda linea– Lenalidomida ( del 5q)– Immunosupression (ATG+/- ciclo) – Talidomida– Lenalidomida (non del 5q)– Hipometilantes

Lenalidomide erythroid response non del 5q

4.5 [0.3–39.1]Median time to response, weeks [range]

58 (27)

36 (17)

94 (44)

Erythroid response, n (%)

major

Minor (> 50% ) major + minor

,

166

Total

n

Feature

Raza, Blood, 2008)

Duration of transfusion independence

Ongoing

Discontinued

Median follow-up: 58 weeksMedian duration TI MDS-003: > 47 weeks MDS-002: 43 weeksRange: 8.6–66+ weeks

10 20 30 40 50 60 70Time (weeks)

0

Pro

por

tion

tra

nsf

usi

on

free

0.5

Del 5q

Non del 5q

1.00.90.80.70.6

0

0.40.30.20.1

Lenalidomide (LEN) in lower-risk myelodysplastic syndromes (MDS) with karyotypes other than deletion 5q and refractory to erythropoiesis-stimulating agents (ESAs) ( ASH 2010)

David Sibon, Giovanna Cannas, Fiorenza Baracco, Thomas Prebet, Norbert Vey, Anne Banos, Caroline Besson, Selim Corm, Michel Blanc, Borhane Slama, Hervé Perrier, Pierre Fenaux, and Eric Wattel.

-31 patients-13 (42%) erythroid response (IWG 2006 criteria)- Median response duration was 12 months - erythroid responses lower patients who developed neutropenia or thrombocytopenia: 1/8 vs 12/23, p = 0.038.

Lenalidomide in lowerrisk MDS without del 5q

• Randomized GFM phase II trial Lenalidomide +/- EPO beta

In patients CLEARLY resistant to ESAs (at least 12 weeks using 60000 U/ w EPO or 250ug/w Darbepoetin)

(A Toma, F Dreyfus)

MDS 005 study (Celgene)

• Lenalidomide versus placebo

• Low and int risk MDs without del 5q

• Resistant to ESA, or having both baseline EPO> 500 U/l and RBC transfusion requirement >2 units /month

Hypomethylating agents in lower risk MDS

• 30 to 40% erythroid responses

– Azacytidine (Silverman, 2002; Lyons, 2007)

– Decitabine (Wijermans, 2005; Kantarjian, 2007)

• Italian experience with azacitidine(Musto, Cancer, 2010)– 61 patients– 41% tranfusion independence

AZA in lower risk MDS (S Boehrer, C Gardin)

• Randomized phase II trial AZA+/- EPO beta

In patients CLEARLY resistant to ESAs (at least 12 weeks using 60000 U/ w EPO or 250ug/w Darbepoetin)

Ensayo aleatorizado AZA ± EPO en SMD de riesgo bajo resistentes a EPO(analisis intermedia)

S. Boeher et al,. ASH 2010, # 1880

AZA 75 mg/m²/j 5 j/28j ± EPOβ 60 000 UI/semana

Todos AZA AZA+EPO

N 93 48 45

Edad médiana 72 72 71

Blastos >5% 12 6 6

CGR/8 semana 6 6 6

Citogénética favorable

73 NA NA

Pacientes

Todos AZA AZA+EPO p

HI-E Mayor 11 4 7 0.17

HI-E menor

9 8 1

Todas las HI-E

20(38%)

12 (40%)

8(36%)

Respuestas IWG 2000 a 6 ciclos (n=52)

Azacitidina en el registro AVIDA en EEUU (Komrokji, EHA 2010)

• N=434, 52% > 75 anos

• AZA 7d(13%) ou 5 d (52%) /4semanas, o 5-2-2 (16%)

• 68% faible riesgo bajo, 32% riesgo alto

• Numero mediano ce ciclos: 4

• 60% HI

Tratamiento de la neutropenia

• No beneficio demostrado de utilizar G-CSF a lo largo plazo

• antibioticos and antifungales profilacticos ?

• antibioticos largo spectro en caso de fiebre (Amoxicilina- acido clavulanico-ciprofloxacina)

Tratamiento de la trombopenia

• Interleukinas (3, 6,11) ?

• Androgenos (danazol)

• A veces: destruccion periferica de las plaquetas

• Agonistos de receptores de TPO

300 μg n = 6

67%

10

20

30

40

50

60

Res

po

nse

a R

ate

(%)

0700 μg n

= 111000 μg n =

111500 μg n

= 16

7064%

36%

50%

Treatment of thrombocytopenia Romiplostin (AMG 531 in lower risk MDS) (Kantarjian, JCO, in press)

a: increase from baseline in platelet count by 30 x 109/L for patients starting with >20 x 109/L platelets, or an increase from <20 x 109/L to >20 x 109/L and by at least 100%.7

• Platelet response achieved in 52% of patients overall.

Romiplostim in MDS (Kantarjian, ASH 2008)

SCREENING

Placebo

Romiplostim 750 µg

Four 28-day cycles of azacitidine

Romiplostim 500 µg

ENROLLMENT

RANDOMIZATION

Treatment Period

Stratification by pre Rx PLTs < or ≥ 50 X 109/L

Romiplostim and placebo s.c. weekly

Platelet Counts Per Azacitidine CycleNadirBaseline (Day 1)

Placebo 500 µg 750 µg

Aza Cycles 1-4

AzaCycles 1-4

AzaCycles 1-4

Placebo 500 µg 750 µg

Aza Cycles 1-4

AzaCycles 1-4

AzaCycles 1-4

0

50

100

150

200

250

300

350

0

25

50

75

100

125

150

Pla

tele

t Cou

nts

(x 1

09 /L

)

13 11 11 10 13 10 10 9 14 13 11 10 13 11 11 10 13 10 10 9 14 13 11 10

– Romiplostim 750 µg/w– Decitabine 20 mg/m²/j 5 d, 4 cycles – 29 patients

Romiplostin after Decitabine and Lenalidomide

Abs 1769 Po I-791 – PL GREENBERG et al.(1)

Abs 1770 Po I-792 – RM LYONS et al.(2)

– Romiplostim 500 µg ou 750 µg /w– Lenalidomide 10 mg/j, 4 cycles– 39 patients

Eltrombopag en SMD

• Ensayo en SMD de riesgo alto resistances al tratamiento convencional

Sobrecarga de hierro y tratamiento quelante en SMD?

200–250 mg iron

Moderate transfusion requirement: 2 units / month

24 units / year

~ 100 units / 4 years

High transfusion requirement: 4 units / month

48 units / year

~ 100 units / 2 years

Most important cause of iron overload in MDS: Transfusion therapy

100 units: ≥ 20 g iron

Normal body iron: 3-4 g

NTBI leads to organ toxicity in MDS

100%

30%

Normal: no NTBI produced Iron overload

Subsequent formation of NTBI in plasma

Fe

FeFe

FeFe

FeFe

Transferrin saturation due to frequent blood transfusions

Uncontrolled iron loading of organs, such as:

NTBI=non-transferrin bound iron.

http://oernst.f5lvg.free.fr/liver/iron.html

MRI can evaluate cardiac and liver iron overload (MRI T2*)

A

B

Normal myocardial iron

Severe myocardial overload

RA = refractory anaemia; RARS = RA with ringed sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RCMD-RS = RCMD with ringed sideroblasts. Based on Malcovati L, et al. Haematologica. 2006;91:1588-90.

RA/RARS/5q−(HR = 1.42; p < 0.001)

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

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0Serum ferritin (μg/L)

1,0001,5002,0002,500

Serum ferritin (μg/L)1,0001,5002,0002,500

Cu

mu

lati

ve p

rop

orti

on s

urv

ivin

g

0 20 40 60 80 100 120 140 160 180Survival time (months)

Cu

mu

lati

ve p

rop

orti

on s

urv

ivin

g0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1800 20 40 60 80 100 120 140 160Survival time (months)

Survival of patients with MDS according to serum ferritin level

Independent Impact of Iron Overload and Transfusion Dependency on Survival and Leukemic Evolution in

Patients with Myelodysplastic Syndrome

Sanz G, Nomdedeu B, Such E, Bernal T, Belkaid M, Ardanaz MT, Marco V, Pedro C, Ramos F, del Cañizo C, Luño E, Cobo F, Carbonell F, Gomez V, Muñoz JA, Amigo ML,

Bailen A, Bonanad B, Tormo M, Andreu R, Arrizabalaga B, Arilla MJ, Bueno J, Requena MJ, Bargay J, Sanchez J, Senent L, Arenillas L, de Paz R, Xicoy B, Duarte R, Cervera J

(Spanish Registry of MDS)

50th Annual Meeting of the American Society of HematologySan Francisco, CA, December 8, 2008

Prognostic Impact of Development of Iron Overload is Independent of WPSS Score

Overall survival Leukemia-free survival

Variable* HR P value

Iron overload 4.34 <0.001

WPSS 1.60 <0.001

Variable* HR P value

WPSS 2.24 <0.001

Iron overload 2.13 <0.001

Time from transplantation (years)

Ove

rall

su

rviv

al (

%)

p < 0.001

Serum ferritin 1st –3rd quartileSerum ferritin highest quartile

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Tre

atm

ent-

rela

ted

m

orta

lity

(%

)

p = 0.005

Serum ferritin 1st –3rd quartileSerum ferritin highest quartile

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8Time from transplantation (years)

DF

S (

%)

p < 0.001

Serum ferritin 1st –3rd quartileSerum ferritin highest quartile

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Rel

apse

(%

)p = 0.7

Serum ferritin 1st–3rd quartileSerum ferritin highest quartile

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8

Outcomes according to pre-transplant serum ferritin level in MDS patients undergoing HSCT

Armand P, et al. Blood. 2007;109:4586-8. DFS = disease-free survival.

Como puede la quelacion de hierro mejorer la supervivencia en SMD?

• Reduccion de la sobrecarga de hierro en el higado y corazon

• Mejora de la supervivencia despues de alo TPH

• (disminucion del numero de infecciones) ?• (retraso de progresion en LMA) ?

Iron chelators can induce cell differentiation in AML (Callens, J exp Med,

2010)

• Differentiation of AML cell lines (HL 60, U 937) by Desferoxamine and deferasirox

• Mechanism involving ROS modulation and activation of MAPs pathway

• Synergism with vitamin D pathways

• One AML patient succesfully treated

Iron chelation therapy and improvement of erythropoiesis?

• Deferiprone does not seem to improve transfusion requirement, but little data available

• Deferoxamine and deferasirox may improve transfusion requirements, and even yield transfusion independence in some cases– deferoxamine seems dependent on effective iron chelation therapy– deferasirox appears independent of effective iron chelation therapy;

improvement occurs very early during treatment

Del Rio Garma J, et al. Haematologica. 1997;82:639-40. Di Tucci AA, et al. Eur J Haematol. 2007;78:540-2.

Jensen PD, et al. Br J Haematol. 1996;94:288-99. Kersten MJ. Ann Hematol. 1996;73:247-52.

Messa E, et al. Acta Haematol. 2008;120:70-4.

GFM study: chelation versus no chelation in heavily transfused lower risk MDS (n= 170)

(Rose, Leuk Res 2010)

• Outpatient setting• MDS referred for RBC transfusion• 18 GFM centers

• Hematological data• Transfusion requirement• Chelation therapy• Iron overload (ferritin)

• Survival • Chelation therapy• Transfusion requirement• Iron overload• Causes of deaths

Inclusion Criteria

Prospective Survival Analysis

May15-June15 2005

Dec 15 2007

Parameters Studied

GFM study: chelation versus no chelation in heavily transfused lower risk MDS (n= 170)

(Rose, Leuk Res 2010)

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

0.00

0.25

0.50

0.75

1.00

Diagnosis to Death (Months)

0 50 100 150 200 250

chelation

No chelation

Median Survival : 63 months overall 115 versus 51 months (p< 0.0001)

Fox et al. Matched-pair analysis of 186 patients receiving iron chelation therapy or transfusion therapy only [1747] (1)

• 93 MDS patients undergoing long-term chelation therapy were matched with 93 patients receiving supportive care in the Düsseldorf MDS Registry

• All patients were iron overloaded with serum ferritin levels of >500 ng/mL

• Iron chelation therapy included:– DFO [n=54]– Deferiprone (n=5)– Deferasirox (n=32)– DFO or followed by deferasirox (n=12) – DFO + deferiprone (n=4)

• Mean duration of iron chelation therapy– Deferasirox 28 months; DFO 39 months

Aim: To assess effect of iron chelation therapy on survival in MDS using a retrospective matched-pair analysis

Fox et al. Matched-pair analysis of 186 patients receiving iron chelation therapy or transfusion therapy only [1747] (2)

Chelation therapy Supportive care P-value

Deaths 52% 58% Not reported

Median survival time 74 months 49 months 0.002

Cumulative risk of AML transformation

2 years post diagnosis 10% 12%

5 years post diagnosis 19% 18% 0.73

Guidelines Initiating iron chelation therapy Target serum ferritin level

Transfusion status Serum ferritin level MDS risk score

Canadian consensus guideline

NRM > 1,000 µg/L Life expectancy > 1 yearCandidates for SCT

NRM, reduce dose when < 2,000 µg/L; discontinue iron chelator when < 1,000 µg/L

Israeli consensus guideline

20–25 RBC units > 1,000 µg/L IPSS: Low or Int-1 Candidates for SCT

< 500 to < 1,000 µg/L

Austrian consensus recommendations

> 2 RBC units/month > 2,000 µg/L Life expectancy > 1 yearCandidates for SCT

Organopathy resulting from iron overload

NRM, continue iron chelation as long as response can be maintained, or if patient is

transfusion-dependent with high serum ferritin or severe organopathy is present

NCCN > 20–30 RBC units (≥ 5–10 g iron)

> 2,500 µg/L Low or Int-1 < 1,000 µg/L

Japanese consensus statement

> 40 Japanese RBC units

> 1,000 µg/L Life expectancy > 1 year 500–1,000 µg/L

MDS Foundation 2 RBC units/month for ≥ 1 year

> 1,000 µg/L Life expectancy > 1 yearCandidates for SCT

NRM

Spanish guidelines Transfusion-dependent anaemia

> 1,000 µg/L IPSS: Low or Int-1; WPSS: Very low, Low, Intermediate;

IPE system: Low Candidates for SCT

NRM

.

Overview of iron chelation guidelines in MDS (2008)

Quelacion de hierro en SMD

• Indicaciones:– IPSS low o int 1 (o int 2 o alto si tratamiento con impacto sobre

supervivencia)– IMPRESCINDIBLE: pacientes con > 60-70 unidades, o RMN

cardiaca anormal o antes de alo TPH

– OTROS CASOS: >20- 40 concentrates, or Ferritin > 1000-2000

• farmacos:– desferoxamina (SC, IV)– Deferiprona (oral)– Deferasirox(oral)

Abs 633 – CO – N GATTERMANN et al. (1)

Abs 634 – CO – A F LIST et al. (2)

Deferasirox in lower risk MDS

EPIC study (1) US03 study (2)

Design341 MDS already chélated 52%

, 176 MDS, 50% already chelated

Dosing 10 mg/kg/j < 2CGA/m20 mg/kg/j 2 - 4 CGA 30 mg/kg/j si > 4CGA

initial 20mg/kg/j

médian baseline Ferritine 2729 µg/L 3397 µg/L

médian Ferritine at 1 year 1903 µg/L 2501 µg/L

Abs 633 – CO – N GATTERMANN et al..

Deferasirox in lower risk MDS

0

-200

-400

-600

-800

-1000

0 3 6 9

Va

ria

tio

n m

éd

ian

e d

u t

au

x d

e f

err

itin

e p

ar

rap

po

rt à

l’i

nd

uc

tio

n (

ng

/ml)

12

21.8

Temps (mois)

< 20 mg/kg/j (n=196)> 20-<30 mg/kg/j(n=135)> 30 mg/kg/j(n=9)Tous patients (n=341)

22.4

22.7

24.818.914.4

18.3

18.5

19.5

17.1

35.5

31.3

33.2 34.0

14.515.1

Evolution of ferritin during one year of treatment

Abs 633 – CO – N GATTERMANN et al. (1)Abs 634 – CO – A F LIST et al. (2)

Deferasirox in lower risk MDS

EPIC study (1) US03 study(2)

% treatment discontinuations

48,7% 43,5%

Side effects 12,9%mainly digestive 13%mainly digestive

Increase in créatinine 25% leading to dose reduction in 5% and stop in 3%

15%

Autres 1 neutropénia, 1 hépatitis

Low or int 1 IPSS risk

Symptomatic anemia

MDS del(5q)sEPO <500 mU/mL and/or RBC

transfusion <2 U/month

Not symptomatic cytopenia

sEPO >500 mU/mL and RBC transfusion

>=2 U/month

sEPO <500 mU/mL and/or RBC

transfusion <2 U/month

rHuEPO +/- G-CSF

(Rec. A)

watchful-waiting(Rec. D)

Lenalidomide within clinical trial

(Rec. B)

rHuEPO+/- G-CSF(Rec. A)

Age <60 yrs, BM blasts<5%, normal

cytog., (hypocell. bone marrow ± HLA-DR15)

Immunosupressive therapy with ATG

(Rec. C)

RBC transfusion and iron chelation

(Rec. C)

Grupo Francofono de las Mielodisplasias

• Activa ensayos clinicos en los SMD (35 centros en Francia y Belgica Suiza, Tunisia)

• Website: www. gfmgroup.org • Registro Online de los SMD franceses • Estrecha cooperacion con: - una asociacion de pacientes con SMD - la International MDS Foundation - el European Leukemia Net

MDS Group: Hopital Avicenne (Paris 13 University) and Institut Gustave Roussy

• Clinical department (Avicenne/Paris 13)

• Claude Gardin

• Lionel Ades

• Fatiha Chermat

• Raphael Itzykson

• Sylvain Thépot

• Thorsten Braun

• Blandine Bève

• Simone Boehrer

• Pierre Fenaux

• INSERM U 848• Simone Bohrer• Sylvain Thépot• Elodie Lainé• Lionel Ades• Marie Sebert• Pierre Fenaux• Guido Kroemer

Hematology and cytogenetics lab

Avicenne/paris 13

•Hervé Roudot

•Fanny Baran-Marszak

•Virginie Eclache

•Florence Cymbalista