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
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