Transcript Genetics and molecular genetics in MDS

Manejo de los SMD de riesgo bajo
Pierre Fenaux
Hôpital Avicenne
Paris 13 University
Inserm U 848
France
Oviedo 3/2011
Manejo de las citopenias en SMD
de riesgo bajo ?
• Anemia
• Neutropenia
• Trombopenia
EPO
14
Blood transfusion
12
Transfusion
given
Hb (g/dL)
10
8
6
4
0
30
60
90
120
Days of treatment
150
180
210
Quality of Life is correlated to Hb levels
Quality of Life (LASA,
mm)
65
60
55
50
45
7
8
9
LASA: Linear Analog Scale Assessment
10
11
Hb level (g/dl)
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
Serum-epo
<500 U/l 0
≥500 U/l 1
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
Duration of response
(IWG 2006) (Park, Kelaidi, Blood 2008)
110
100
90
80
70
60
50
40
30
20
10
0
0
10
20
30
40
months
Median 24 months
50
60
70
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)
-inclusion criteria : lower risk MDS
EPO > 500 UI
or previous failure of EPO
-59 pts evaluable
- Erythroid response
overall:
49 % (IWG 2000)
36% (IWG 2006)
EPO resistant: 43%
32%
EPO> 500
11%,
> 2CGR/month: 43%
19%
39%
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
Response
duration
Del 5q
Serum EPO Response
level
rate
287U/l
46%
No del 5q
68 U/l
64%
24 m
P value
<0.001
0.01
0.019
12 m
(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)
No . Patients
148
Erythroid Response
Transf -Indep
Minor (>50%)
TI +Minor
99 (67%)
13 (9%)
112 (76%)
Time to Response
4.6 wks
(1- 49)
Cytogenetic response
in patients with del 5q
Variable
,
n (%)
Evaluable
104
Cytogenetic response*
Complete (CCR)
Minor (≥ 50%)
75%
48%
27%
*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)
100
Median duration of TI = 2.2 years
Patients (%)
80
Median follow-up: 1.3 years (min–max: 0.1–4.4 years)
60
40
min–max = 0.2–4.4+ years
73% TI response ≥ 1 year
46% TI response ≥ 2 years
50% ongoing responders
20
0
0
1
2
3
4
5
Time (years)
Data cutoff 4 Dec 2006 (N = 114).
Censored patients who remain TI at time of data cutoff or at time of study discontinuation.
List AF, et al. Updated data presented at
ASH Annual Meeting, 2006 [Abstract 251].
Drug-Related Adverse Events
Adverse Event
Thrombocytopenia
Neutropenia
Pruritus
Rash
Diarrhea
Fatigue
*
All Grades
>Grade 3 (%)
58%
57%
32%
28%
24%
12%
54%*
55%**
2%
7%
2%
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)
•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
#xxx
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]
Gender
Karyotype
WHO
IPSS
0.92
male
22 (31%)
22 (31%)
1.00
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
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
0
30 (42%)
22 (31%)
0.5
23 (32%)
32 (45%)
1
18 (25%)
17 (24%)
0.45
Overall Outcome
100
100
80
80
Overall Survival
Cum. Inc. Of AML
Control group
Lenalidomide group
60
40
20
60
40
20
0
0
0
50 100 150 200
Times (Months)
4 y CIR of AML 8.9% vs 15.8%; p=0.14
0
50 100 150 200
Times (Months)
Median OS 150 months vs 72.8 , p= 0.10
MDS-004: study design (ASH 2009)
Planned enrollment
(n = 205)
Double-blind phase**
*
S
T
R
A
T
I
F
Y
LEN, orally
5 mg/day for 28 days
of each 28-day cycle
R
A
N
D
O
M
I
Z
E
D
R
E
S
P
O
N
S
E
LEN, orally
10 mg/day for 21 days
of each 28-day cycle
Placebo
Week
0
4
8
12
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
16
*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.
52
MDS-004: RBC-TI (mITT population)
*
*
*
*
56
50
41
6
Protocol defined
(≥ 26 weeks)
61
8
IWG
(≥ 8 weeks)
*P < 0.001 vs placebo
Bars represent 95% CI
MDS-004: cytogenetic response
(mITT population)
Cytogenetic response, %
Complete response (CR)
Partial response (PR)
CR + PR
*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%.
Placebo
(n = 51)
LEN 5 mg
(n = 46)
LEN 10 mg
(n = 41)
0
0
0
10.9*
6.5
17.4**
24.4**
17.1
41.5**
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
Feature
Total
n
166
Erythroid response, n (%)
major
Minor (> 50% )
major + minor
,
Median time to response, weeks [range]
58 (27)
36 (17)
94 (44)
4.5 [0.3–39.1]
Raza, Blood, 2008)
Duration of transfusion independence
Proportion transfusion
free
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Del 5q
Non del 5q
Median follow-up: 58 weeks
Median duration TI
MDS-003: > 47 weeks
MDS-002: 43 weeks
Range: 8.6–66+ weeks
0
10
20
30
40
Time (weeks)
Ongoing
Discontinued
50
60
70
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 lower
risk MDS without del 5q
(A Toma, F Dreyfus)
• 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)
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)

AZA 75 mg/m²/j 5 j/28j ± EPOβ 60 000 UI/semana
Pacientes
Respuestas IWG 2000 a 6 ciclos (n=52)
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
Todos
AZA
AZA+EPO
p
HI-E Mayor
11
4
7
0.17
HI-E menor
9
8
1
20
(38%)
12
(40%)
8
(36%)
Todas las
HI-E
S. Boeher et al,. ASH 2010, # 1880
Azacitidina en el registro AVIDA en EEUU
(Komrokji, EHA 2010)
• N=434, 52% > 75 anos
• AZA 7d(13%) ou 5 d (52%) /4semanas, o 52-2 (16%)
• 68% faible riesgo bajo, 32% riesgo alto
• Numero mediano ce ciclos: 4
• 60% HI
Tratamiento de la neutropenia
• No beneficio demostrado de utilizar GCSF a lo largo plazo
• antibioticos and antifungales
profilacticos ?
• antibioticos largo spectro en caso de
fiebre (Amoxicilina- acido clavulanicociprofloxacina)
Tratamiento de la trombopenia
• Interleukinas (3, 6,11) ?
• Androgenos (danazol)
• A veces: destruccion periferica de las
plaquetas
• Agonistos de receptores de TPO
Treatment of thrombocytopenia
Romiplostin (AMG 531 in lower risk MDS) (Kantarjian,
JCO, in press)
70
67%
64%
Responsea Rate (%)
60
50%
50
36%
40
30
20
10
0
300 μg
n=6
700 μg
= 11
n 1000 μg
11
n =1500 μg
= 16
n
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
a:
• Platelet
response achieved in 52% of patients overall.
Romiplostim in MDS (Kantarjian, ASH 2008)
Treatment Period
S
C
R
E
E
N
I
N
G
E
N
R
O
L
L
M
E
N
T
Four 28-day cycles
of azacitidine
Placebo
R
A
N
D
Romiplostim 500 µg
O
M
I
Z
Romiplostim 750 µg
A
T
I
O
N
Stratification by pre Rx PLTs <
or ≥ 50 X 109/L
Romiplostim and placebo s.c. weekly
Platelet Counts Per Azacitidine Cycle
Nadir
Platelet Counts (x 109/L)
Baseline (Day 1)
350
150
300
125
250
100
200
75
150
50
100
25
50
0
13 11 11 10
Aza
Cycles 1-4
Placebo
13 10 10 9
Aza
Cycles 1-4
500 µg
14 13 11 10
Aza
Cycles 1-4
750 µg
0
13 11 11 10
Aza
Cycles 1-4
Placebo
13 10 10 9
Aza
Cycles 1-4
500 µg
14 13 11 10
Aza
Cycles 1-4
750 µg
Romiplostin after Decitabine and Lenalidomide
–
–
–
Romiplostim 750 µg/w
Decitabine 20 mg/m²/j 5 d, 4 cycles
29 patients
–
–
–
Romiplostim 500 µg ou 750 µg /w
Lenalidomide 10 mg/j, 4 cycles
39 patients
Abs 1769 Po I-791 – PL GREENBERG et al.(1)
Abs 1770 Po I-792 – RM LYONS et al.(2)
Eltrombopag en SMD
• Ensayo en SMD de riesgo alto resistances
al tratamiento convencional
Sobrecarga de hierro y tratamiento
quelante en SMD?
Most important cause of iron overload in MDS: Transfusion therapy
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
100 units: ≥ 20 g iron
Normal body iron: 3-4 g
200–250 mg
iron
NTBI leads to organ toxicity in MDS
Transferrin saturation due
to frequent blood
transfusions
Normal: no NTBI
produced
Subsequent formation
of NTBI in plasma
Iron overload
100%
Fe
Fe
Fe
Fe
Fe
Fe
30%
NTBI=non-transferrin bound iron.
Fe
Uncontrolled iron
loading of organs, such
as:
MRI can evaluate cardiac
and liver iron overload (MRI T2*)
A
B
Normal myocardial iron
Severe myocardial overload
http://oernst.f5lvg.free.fr/liver/iron.html
Survival of patients with MDS according to
serum ferritin level
RA/RARS/5q−
(HR = 1.42; p < 0.001)
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Serum ferritin (μg/L)
1,000
1,500
2,000
2,500
1.0
Cumulative proportion surviving
Serum ferritin (μg/L)
1,000
1,500
2,000
2,500
1.0
Cumulative proportion surviving
RCMD/RCMD-RS
(HR = 1.33; p = 0.07)
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0
0
20
40
60
80 100 120 140 160 180
Survival time (months)
RA = refractory anaemia; RARS = RA with ringed sideroblasts;
RCMD = refractory cytopenia with multilineage dysplasia;
RCMD-RS = RCMD with ringed sideroblasts.
0
20
40
60
80 100 120 140 160 180
Survival time (months)
Based on Malcovati L, et al. Haematologica. 2006;91:1588-90.
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 Hematology
San 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
Variable*
HR
P value
Iron overload
4.34
<0.001
WPSS
2.24
<0.001
WPSS
1.60
<0.001
Iron overload
2.13
<0.001
Serum ferritin 1st –3rd quartile
Serum ferritin highest quartile
100
80
60
60
40
0
p < 0.001
0
1
2
3
4
5
6
7
p < 0.001
20
0
1
2
3
4
5
6
7
8
Serum ferritin 1st–3rd quartile
Serum ferritin highest quartile
100
80
80
60
40
p = 0.005
20
0
40
0
8
Serum ferritin 1st –3rd quartile
Serum ferritin highest quartile
100
Treatment-related
mortality (%)
DFS (%)
80
20
Serum ferritin 1st –3rd quartile
Serum ferritin highest quartile
100
Relapse (%)
Overall survival (%)
Outcomes according to
pre-transplant serum ferritin level in
MDS patients undergoing HSCT
0
1
2
3
4
5
6
Time from transplantation (years)
DFS = disease-free survival.
7
8
60
40
20
0
p = 0.7
0
1
2
3
4
5
6
Time from transplantation (years)
7
8
Armand P, et al. Blood. 2007;109:4586-8.
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)
Inclusion Criteria
• Outpatient setting
• MDS referred for RBC
transfusion
• 18 GFM centers
Prospective Survival
Analysis
May15-June15
2005
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Hematological data
Transfusion requirement
Chelation therapy
Iron overload (ferritin)
Dec 15 2007
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Survival
Chelation therapy
Transfusion requirement
Iron overload
Causes of deaths
GFM study: chelation versus no chelation in
heavily transfused lower risk MDS (n= 170)
(Rose, Leuk Res 2010)
1.00
Survival Distribution Function
Median Survival : 63 months overall
115 versus 51 months (p< 0.0001)
0.75
0.50
chelation
0.25
No chelation
0.00
0
50
100
Diagnosis to Death (Months)
150
200
250
Fox et al. Matched-pair analysis of 186 patients receiving iron
chelation therapy or transfusion therapy only [1747] (1)
Aim: To assess effect of iron chelation therapy on survival in MDS using a retrospective
matched-pair analysis
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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
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
52%
58%
Not reported
74 months
49 months
0.002
2 years post diagnosis
10%
12%
5 years post diagnosis
19%
18%
Deaths
Median survival time
Cumulative risk of AML transformation
0.73
Overview of iron chelation guidelines in MDS
(2008)
Guidelines
Initiating iron chelation therapy
Target serum
ferritin level
Transfusion status
Serum ferritin level
MDS risk score
NRM
> 1,000 µg/L
Life expectancy > 1 year
Candidates for SCT
NRM, reduce dose when
< 2,000 µg/L; discontinue iron
chelator when < 1,000 µg/L
20–25 RBC units
> 1,000 µg/L
IPSS: Low or Int-1
Candidates for SCT
< 500 to < 1,000 µg/L
> 2 RBC units/month
> 2,000 µg/L
Life expectancy > 1 year
Candidates 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 year
Candidates 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
Canadian
consensus guideline
Israeli consensus
guideline
Austrian consensus
recommendations
.
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)
Deferasirox in lower risk MDS
EPIC study (1)
Design
341 MDS
already chélated 52%
US03 study (2)
,
176 MDS,
50% already chelated
Dosing
10 mg/kg/j < 2CGA/m
20 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. (1)
Abs 634 – CO – A F LIST et al. (2)
Deferasirox in lower risk MDS
Evolution of ferritin during one year of treatment
Variation médiane du taux de ferritine par
rapport à l’induction (ng/ml)
Temps (mois)
0
0
-200
3
6
21.8
19.5
-400
12
9
17.1
22.4
18.5
22.7
18.3
15.1
14.5
35.5
-600
24.8
18.9
14.4
31.3
-800
< 20 mg/kg/j (n=196)
> 20-<30 mg/kg/j(n=135)
> 30 mg/kg/j(n=9)
Tous patients (n=341)
33.2
34.0
-1000
Abs 633 – CO – N GATTERMANN et al..
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
Abs 633 – CO – N GATTERMANN et al. (1)
Abs 634 – CO – A F LIST et al. (2)
Low or int 1
IPSS risk
Symptomatic anemia
Not symptomatic
cytopenia
watchful-waiting
(Rec. D)
sEPO <500 mU/mL
and/or RBC
transfusion <2
U/month
rHuEPO +/G-CSF
(Rec. A)
Age <60 yrs, BM
blasts<5%, normal
cytog., (hypocell. bone
marrow ± HLADR15)
MDS del(5q)
sEPO >500 mU/mL
and RBC transfusion
>=2 U/month
sEPO <500 mU/mL
and/or RBC
transfusion <2
U/month
Lenalidomide within clinical
trial
(Rec. B)
rHuEPO+/G-CSF
(Rec. A)
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
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Clinical department
(Avicenne/Paris 13)
Claude Gardin
Lionel Ades
Fatiha Chermat
Raphael Itzykson
Sylvain Thépot
Thorsten Braun
Blandine Bève
Simone Boehrer
Pierre Fenaux
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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