Current treatment of MDS, and perspectives

1
Current treatment of MDS, and perspectives

• Pierre FENAUX,
• Hopital Avicenne, Paris 13 University and Groupe
  Francophone des Myélodysplasies (GFM)

2
Myelodysplastic Syndromes

• Clonal disorders of multilineage hematopoietic
  progenitors characterized by
• Ineffective hematopoiesis leading to blood
  cytopenias
• Progression to acute leukemia in 35
• Median age 65 to 70 years
• Incidence3 to 5/100000 persons/year

3
FAB Classification of MDS
Subtype Blast percentage Other
features
Blood Bone
marrow Refractory Anemia (RA) lt 1
lt 5 Refractory Anemia w. ringed
lt 1 lt 5
gt 15 ringed sidero- sideroblasts
(RARS) blasts Refractory anemia w blast
lt 5 5-20excess (RAEB) Chronic
myelomonocytic lt 5
5-20 monocytosis leukemia
(CMML) (gt 1000/µl) RAEB in transformation
gt 5 21-30
(RAEB/T)
4
Greenberg P et al. Blood. 1997892079-2088.
5
MDS WHO Classification

• pure RA
• With ringed sideroblasts
• Without ringed sideroblasts
• Refractory cytopenia with multilineage dysplasia
• - With ringed sideroblasts
• Without ringed sideroblasts
• RAEB RAEB 1 (lt10 blasts
• RAEB 2 (gt 10 blasts)
• 5q syndrome
• RAEB-t AML
• CMML MPS/MDS

6
International Prognostic Scoring System
7
International MDS Risk Classification
AML Evolution
Survival
100
90
80
70
60
Percent
50
Percent
40
30
20
10
0
18
17
16
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
Greenberg P et al. Blood. 1997892079-2088.
8
MDS  Higher  vs   Lower  Risk

• Higher risk
• IPSS intermediate-2 or high
• ( Marrow blasts gt10)
• Lower risk
• IPSS low or intermediate-1
• (Marrow blasts lt5)

9
Genetic and epigenetic changes during
leukemogenesis

• genetic
• (irreversible)
• mutations
• deletions
• gene rearrangements

• Epigenetic
• (potentially reversible)
• DNA methylation
• histone deacetylation
• histone methylation

10
Rationale for hypomethylating drugs in cancer
Normal gene processing
NORMAL
inappropriate gene silencing
TUMOR Methylation
Growth-regulating gene
Helps to reverse inappropriate gene silencing
DRUG-INDUCED DEMETHYLATION
Growth-regulating gene
Adapted from Bender et al. Pharm Res
19981517587
11
Histones

• Histone proteins organize DNA into nucleosomes
• Nucleosomes consist of DNA wrapped around a
  core histone
• A histone core comprises two copies each of four
  different core proteins (H2A, H2B, H3, H4)
• Histones can be acetylated and methylated at
  N-terminal lysines

H2B
H2A
H4
H3

12
DNA methylation,Histone acetylation and Active /
inactive chromatin histone H3 and H4
HYPERACETYLATED DNA NOT METHYLATED
Gene transcription histone H3 and H4
NOT ACETYLATED DNA METHYLATED Gene
silencing
13
Treatment Objectives

• Delay disease progression
• Prolong survival
• Improve blood cell deficiencies
• Improve quality of life

14
Treatment Objectives (High risk MDS)

• Delay disease progression
• Prolong survival
• Improve blood cell deficiencies
• Improve quality of life

15
Treatment Objectives (low risk MDS)

• Delay disease progression
• Prolong survival
• Improve blood cell deficiencies
• Improve quality of life

16
Treatment of higher risk MDS
17
Treatment of higher risk MDS

• Allogeneic SCT
• Chemotherapy
• Hypomethylating agents
• New agents and combinations
• Clofarabine and cloretazine
• FTIs
• HDAC inhibitors in Combination

18
SMD allogreffe de cellules souches  classique 

• Nécessite
• Donneur HLA identique
• Age lt50 ans
• Résultats
• 50 guérison
• 25 rechûte
• 25 décès toxiques

19
Survival HLA-Identical Siblings for MDS (EBMT)
1.0
.8
.6
After 1996 (236)
Proportion
19931996 (372)
.4
Before 1993 (360)
.2
P .02
0.0
60
48
36
24
12
0
20
SMD allogreffe de cellules souches

• -Possibilité détendre lindication jusquà 65-70
  ans grâce aux  conditionnements atténués 
• Moins de toxicitémais plus de rechûtes

21
Figure 1
Standard
RIC
REL
REL
NRM
NRM
Months post-transplant
Months post-transplant
22
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23
Allogreffe dans les SMDquel conditionnement?

• Dépend de
• Age
• Comorbidités
• Risque de rechûte ( blastes, caryotype)

24
Allogreffe dans les SMD demblée ou après
réduction de la blastose ?

• Risque de rechûte très élevé si
• Greffe classique blastes gt 10
• Mini allogreffe blastes gt5
• Comment réduire la blastose ?
• Chimio intensive
• Agents hypométhylants

25
Intensive AML chemotherapy in MDS

• Restricted to patients lt 65 y
• Anthracycline-Ara C
• 50 to 60 CR
• median CR duration 10 to 12 months
• Cytogenetics major prognostic factor for CR
  achievement and CR duration
• very few long term survivors

26
Kaplan-Meier Estimate of Survivalwith Intensive
Chemotherapy
N 99
Wattel E. et al. With Permission of E Estey,
MD Br J Haematology. 199798983-991.
27
Low dose chemotherapy

• low dose AraC ( 20mg/m2/12h, 14 days/ month)
• -15 CR, 20 PR(Cheson, 1986)
• - Favorable results almost exclusively in
  patients with normal karyotype
• - myelosuppressive regimen (10 mortality)
• .

28
Clofarabine in MDS (Gandhi, ASH 2006)

• Purine analog
• Clofarabine 15 or 30 mg/m2 /d x5 IV
  OR
• 40 mg/m2/d x5 orally
• 5/ 9 CR in MDS but myelotoxic
• lower doses (25-30 mg/m2/d orally) currently
  tested

29
Cloretazine in MDS (Karp, ASCO 2006)

• Novel DNA alkylating agent that selectively
  targets the 0-6 position in Guanine
• 350 to 600mg/m2 as single infusion
• 4 CR 2 CRp in 15 high risk MDS (40 response)

30
Hypomethylating agents
Adapted from Santini et al. Ann Intern Med
200113457386
31
Irreversible inactivation of DNA
methyltransferase enzyme by azanucleosides after
their incorporation into replicating DNA


5-
azacytidine
(5-
azaCR
, Vidaza)
C
K


CK




CK
5-
azaC
MP
5-
azaC
DP

5-
azaC
TP
RNA

ca. 10 conversion by
5-
aza
-2-
deoxycytidine
(5-
azaCdR
, Decitabine)
ribonucleotide reductase
dCK
dCK





dCK
5-
aza
-
dC
MP
5-
aza
-
dC
DP
5-
aza
-
dC
TP
DNA

CK,
cytidine kinase
dCK
,
deoxycytidine kinase
32
Demethylation of p15 promoter by DAC is
associated with p15 protein reexpression
33
p15 promoter Hypomethylation by treatment of
myeloid cells with decitabine but not
cytarabine(KG1)
Berg et al. Leuk Res 200731497506
34
AzacytidineCALGB MDS Studies
35
CALGB 9221, 8921 and 8421 All Patients
Response Rates,
plt0.0001 compared to supportive care (0 CR
PR) plt 0.0001 compared to supportive care (18
CR PR ImP)
36
CALGB 9221 A Randomized Phase III study with
azacytidine
Specific Criteria
Supportive Care (N 41)
No
Supportive Care (N 92)
FAB-basedStratifiedRandomization
Azacitidine (N 51)
Yes
Azacitidine (N 99)
Patient Characteristics Median age (yrs)
67 RAEB or RAEB-T 54 Transfusion
dependent 70

37
MDS Clinical Studies Phase III
Efficacy Results Response
Note Statistical analysis does not include data
obtained after cross over 1 plt0.001 vs BSC 2
plt0.01 vs BSC
38
MDS Clinical Studies Phase III
Efficacy Results Transformation and Survival
1 p 0.1 vs BSC 2 p 0.007 vs BSC
(Silverman, JCO, May 2002)
39
Survival (ITT) RAEB and RAEB-T ? 65 Years
40
Azacitidine in RAEB and RAEB-T (gt65 years)

• Response Rate 58
• RBC Transfusion Independence 42
• Platelet Transfusion Independence 50
• Survival Additional 5.5 months
• Transformation to AML Prolonged 24.3 months

41
Other Azacitidine Studies in MDS Patients (Gryn,
2002)

• 42 MDS patients
• Median 6 cycles/patient
• 16/42 responders
• - 8 CR (2-21 months)
• 8 PR (2-36 months mean 10 months)
• 39 patients became transfusion independent
• responses similar in RAEB/RAEB-T

Leuk Res 2002, 26, 893
42
Other Azacitidine Studies in MDS Patients (Raj,
Mufti, 2005)

• 24 elderly,high-risk MDS pts
• Abnormal cytogenetics (n 17)
• monosomy 7 (n4)
• trisomy 8 (n4)
• der(7) (n2)
• Median of 5 courses (range 1-13)

Raj and Mufti et al. Submitted to 2005 ASH.
43
Response to Azacitidine in High-Risk MDS
Patients (Raj Mufti, 2005)

• CR (n 6) (25) including
• 2 with trisomy 8
• 3 with monosomy 7 1 with der(7)
• Hematologic Improvement (n11)
• Sustained responses (gt 10 months)

Raj and Mufti et al. Submitted to 2005 ASH.
44
French experience with Azacytidine (ATU)(Fabre,
ASH 2006)

• ? Sept 2004 to Oct 2006
• ? High and int 2 MDS
• ? 121 patients
• - 3 deaths before treatment
• - 116 received ? 1 cycle
• ? M / F 76 / 40
• ? median age 71 17-102

45
WHO Classification at inclusion

• ?MDS/MPD
• - CMML 4
• ? MDS
• - RARS 1
• - RA 1
• - RCMD 3
• - RAEB 1 or 2 55 (12 43)
• - Unclassified 9
• ? AML post MDS 43

46
Caryotype at onset of azacytidine
47
IPSS at onset of azacytidine
- Low 1 (0.5) - Int-1 9 (8 ) -
Int-2 52 (45 ) - High 54 (46.5 )
48
Previous treatments
? Previous treatment 67 ? Response to
previous treatment 44 - anthr
AraC 27 - LD AraC 21 - Growth
factors (G-CSF / EPO) 20 - others 13
49
Response to Azacytidine
50
Response to azacytidine
OR 55
OR 44
51
Response to azacytidine

• ? according to IPSS
• - High OR 57
• - Int-2 OR 63
• - Int-1 OR 75
• ?according to previous treatment
• - Yes OR 60
• - No OR 65

52
Cumulative analysis of 177 MDS patients treated
with low-dose decitabine within 4 Phase II
studies in Europe and the USA

• Toxic death 7
• Progressive disease 18
• Stable disease 20
• Improvement 14
• Partial response 10
• Complete response 24
• Not evaluable 7
• RESPONSE RATE 49
• Median response duration 36 weeks
• Median survival 15 months
• 2 years survival 31

(Wijermans, Lübbert et al., Ann. Hemat. 2005)
53
Decitabine in MDSResponse by FAB classification
FAB RA/RARS RAEB RAEB-t CMML
Total Total 23 66
65 23 177 Response rate
35 51 48 52
49
P Wijermans 2005
54
MDS Survival by IPSS risk score
n med. 2 year surv. surv. Int 1 45
23 48 Int 2 47 15 24 High 70
12 29
Int 1
high
Int 2
55
MDS Survival by cytogenetic risk
survival n med. 2
yr low-risk1 85 19 43
interm.-risk3 39 10 20 high-risk2 33
15 27 1normal, sole 5q-, 20q-, -Y 2chrom.
7, gt3 abnormalities 3other abnormalities
no data
normal low no metaph.
interm
high
56
Decitabine(DacogenTM) Phase III Study Design
Supportive Care DacogenTM (N 89)
RANDOMIZED

• Stratification
• IPSS Classification
• Prior Chemotherapy
• Study Center

Eligible Patient (N 170)
Supportive Care (N 81)
Antibiotics, Growth Factors and/or Transfusions
57
Response (All Patients)

• Patients that withdrew from study prior to any
  response evaluation
• Two patients had a partial response to DacogenTM
  after progressing on supportive care
• 2-sided Fishers Exact Test for equal overall
  response rate (CRPR)
• Not reflective of adjudicative data set

58
Time to AML or Death (All Patients)
DacogenTMSupportive Care
2-sided Wilcoxon test for homogeneity of survival
distributions p 0.042 2-sided Log-rank test for
homogeneity of survival distributions p
0.198 Reflects cut-off after 92 events. 3
Patients crossing over or never receiving
randomized treatment are censored Based on
treatment schema, median treatment 3 cycles
(168 days)
59
Time to AML or DeathHigh Risk Patients(n 44)
DacogenTMSupportive Care
2-sided Wilcoxon test for homogeneity of survival
distributions p lt 0.001 2-sided log-rank test for
homogeneity of survival distributions p 0.004
60
Decitabine versus intensive chemotherapy in MDS
(Jabbour, ASH 2006)
61
Azacitidine Confirmatory Trial

62
Azacytidine confirmatory trial (ASH 2007)

• 358 pts
• Survie médiane
• 24.4 mois avec AZA
• 15 mois avec le traitement  conventionnel 
• Avantage pour AZA quel que soit le bras de
  comparaison et le caryotype

63
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64
Multicenter phase II study of Tipifarnib
(Zarnestra) in high risk MDS ( Fenaux, Blood
2007 )

• 82 patients IPSS (36 high, 32 int 2, 14 int 1)
• 30 patients already treated
• 300 mg/12h
• 28 (33 ) responses 6 CR, 2 CRp, 2 PR, 18 HI
• Main toxicity myelosuppression

65
Treatment of IPSS high and int 2 MDS conclusion

• Patient eligible for allo transplant allo
  indicated
• As first line or after previous treatments?
• Classical or non myelo ablative?

66
Treatment before allo

• lt5 to 10 blasts first line transplantation
• gt 5 to 10 marrow blasts
• no unfavorable karyotype
• intensive chemotherapy
• unfavorable karyotype
• hypomethylating agents

67
Treatment of IPSS high or int 2 MDS conclusion

• No donor available  young 
• favourable karyotype intensive chemo or
  hypomethylating agents ?
• Unfavorable karyotype hypomethylating agents

68
Treatment of IPSS high or int 2 MDS conclusion

• No donor available  old 
• hypomethylating agents

69
Treatment of IPSS high or int 2 MDSperspectives

• hypomethylating agents prior to transplant
• hypomethylating agents HDAC inhibitors
• hypomethylating agents FTIs
• hypomethylating agents lenalidomide (in case of
  del 5q)

70
HDAC inhibitors
71
Gene Re-expression through Sequential
Methyltransferase and Histone Deacetylase
Inhibition
KG1a KG1a KG1a KG1a
HL60 5AC only TSA 5ACTSA
(ve control)
RT - -
- - -

72
Phase I/II Study of 5-azacytidine, Valproic Acid
and ATRA in Leukemia
Abstract 160

• Andres O Soriano, Hui Yang, Weigang Tong, Stefan
  Faderl, William Wierda, Michael Andreeff, Zeev
  Estrov, Souzanne Ouzounian, Jonathan Clavell,
  Hagop Kantarjian, Jean-Pierre Issa, and Guillermo
  Garcia-Manero
• Department of Leukemia
• University of Texas MD Anderson Cancer Center

73
5-AZA VPA ATRA in Leukemia Responses
74
Azacytidine Valproic acid ATRA (Raffoux, EHA
2007)

• 20 AML or high risk MDS
• 53 CR PR
• Response after 1 to 3 courses

ALFA group
75
Treatment of low risk MDS
76
How should we treat cytopenias in low risk MDS?

• Anemia is the most prominent cytopenia should it
  be treated just by transfusion or by trying to
  avoid it ?
• Neutropenia
• Thrombocytopenia

77
Hb level maintained versus RBC transfusions
EPO
14
Blood transfusion
12
Transfusion given
10
Hb (g/dL)
8
6
4
0
30
60
90
120
150
180
210
Days of treatment
78
Quality of Life is correlated to Hb levels
65
60
Quality of Life (LASA, mm)
55
50
45
7
8
9
10
11
12
13
14
Hb level (g/dl)
Crawford et al. Cancer 2002 95 88895
LASA Linear Analog Scale Assessment
79
RBC transfusions in MDS

• 1)MDS represent
• - 3 of all RBC units transfused
• - 24 of hospitalizations for transfusion
• Mean monthly cost for transfusions 810 euros
• ( Bardiaux et al 2003)
• 2)Also
• RBC transfusions lead to iron overload, probably
  associated to shorter survival
•  hospital dependence  for the patient

80
How to prevent anemia recurrence in MDS ?

• EPO and darbepoetin
• Thalidomide
• ATG
• Lenalidomide
• (Hypomethylating agents ?)

81
How to prevent anemia recurrence in MDS ?

• EPO and darbepoetin
• Thalidomide
• ATG
• Lenalidomide
• (Hypomethylating agents ?)

82
GFM Clinical Trial (Casadevall)

• Inclusion criteria
• Patients with RA, RARS, RAEB (lt 10 blasts)
• Hb lt 10 g/dl or transfusions (gt 2 units) during
  the last 2 months
• Serum Epo level lt 500 mU/ml

83
GFM Clinical Trial

• responders Epo alone
• ( G-CSF if relapse)
• Arm A EpoG-CSF
• non-responders Supportive care
• Randomisation (1/1)
• Arm B Supportive Care Supportive Care
• 12 weeks 9 months

84
GFM Clinical Trial-Arm A-Results

• Evaluation at week 12
• Erythroid response
• According to the IWG criteria
• 15 responders (62,5 )

85
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86
Randomized study Epo vs EpoG-CSFBalleari et al,
Ann Hematol 2006

• 30 MDS, lt10 marrow blasts
• 37 transfusion-dependent
• Randomized Epo 30 000 U/w vs Epo G-CSF 600µg/w
• Response
• Epo 40
• EpoG-CSF 73
• Addition of G-CSF to NR to Epo induced response
  in 4/9 pts
• Transformation to AML
• Epo 13
• EpoG-CSF 13

87
Darbepoetin in MDS

• Musto el al, BrH 2005, 37 MDS, Low-Int-1
• 15 (40) erythroid response
• Better response in pts with non / low transfusion
  need, S-Epo lt100 U/L
• Mannone et al, BRJ 2006, 62 MDS, lt10 blasts.
• 71 erythroid responses, few additional responses
  to G-CSF
• Median maintenance dose 300 µg / 14 days, the
  majority responded gt40 weeks
• Stasi et al, Ann Oncol 2005, 53 MDS, Low-Int-1
• 45 response (21/24 major)
• Response associated with improved QoL
• Giraldo et al, Cancer 2006. 81 MDS, retrospective
  analysis
• 30 major 25 minor responses. Responses also
  in rHuEPO refractory pts
• Most responses occurred within 8 weeks

88
Changes in QoL during Epo treatment

• Clavio et al, 2004
• 11 patients, Epo treated, 55 response. Fact-An,
  neurophysiological evaluation
• Improved QoL compared to baseline, cerebral
  improvement in 3 pts
• Stasi et al, 2005
• 53 patients. Darbepoetin treated, 45 response.
  LASA, Fact-An
• Significant improvement of QoL, responders gt
  non-responders
• Aloe Spiriti et al, 2005
• 133 patients, Epo, 68 response. Fact-An (103 pts
  at w 0, 86 at week 8)
• Significant mean increase at w 8, responders gt
  non-responders
• Balleari et al, 2006
• 30 patients, randomized Epo vs Epo G-CSF, 40
  vs 73 response. Fact-An
• Sign improvement QoL, responders gt non-responders

89
A simplified validated decision model for
treatment of the anemia in MDS with G-CSF EPO
Predictive value of model plt0.001
Variable value score value score Transf.
need lt2 U/m 0 2 U/m 1 Serum-epo lt500
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
90
EPO /- G-CSF in MDS prognostic factors of
response(Park , Kelaidi, ASH 2006)

• N 403 pts treated with EPO/- G-CSF or
  Darbepoetin alpha
• Hblt10g/dl (54transfused)
• 63 response (43 major, 20 minor)
• Median response duration 22 months

91
EPO /- G-CSF in MDS prognostic factors of
response (Park , Kelaidi,ASH, 2006)

• Significantly higher response rate
• EPO lt200 U/l
• IPSS low or int 1
• Transfusion lt 2RBC concentrates /month
• Significantly longer responses
• IPSS low or int 1
• No multilineage dysplasia

92
Treatment of MDS with del 5q EPO (or
darbepoetin) /- G-CSF
(Kelaidi, ASH 2006, abstr n 2678 )Park ,ASH
2006, abstr n 522)
93
Comparison between IMRAW and French patients
French EPO data base n 433
IMRAW data base n 816
Unclassified 10 RAEB-t4 CMML16
Unclassified 2 RAEB-t61 CMML125
N628 patients
N403 patients
IPSS not available N57
Low/ int-1 N475
Int-2 / high N153
Low/int-1 N303
Int-2 / high N43
Unfavorable karyotype n28 (including 3q26 abn
n10)
Unfavorable karyotype 18 (including 3q26 abnn2)
N284
N447
94
Time to AML progression and survival (Park,
Kelaidi)

• 5-year incidence of progression to AML 12.2 in
  the French cohort vs 16.7 in the IMRAW cohort
  (p NS)
• The 5-year OS was 64 in the French-EPO cohort
  and 47 in the IMRAW (p0.002)

95
Time to AML progression
Comparison between IMRAW and French-EPO cohort
restricted to IPSS LOW INT1 patients without
unfavorable karyotype (IMRAW n447 patients,
French-EPO 284) a) progression to AML , p NS
96
Overall survival
b) Overall survival, P0.002
97
Comparison Nordic and Italian MDS patients

• EPO-G patients (n121)
• Nordic cohort
• Inclusion criteria
• FAB 1-3
• Hblt10g/dl or transfusion dependency

• Untreated patients (n268)
• Pavia cohort
• Selection criteria
• FAB 1-3
• Hblt10g/dl or transfusion dependency

vs.
Jadersten et al, ASH 2006 abs
98
Improved survival in GE treated patients Cox
regression curves adjusted for major prognostic
variable
Survival
AML evolution
1
1
.9
.9
HR P
0.89 0.66
.8
.8
.7
.7
HR P
0.61 0.002
Probability of freedom of AML
.6
.6
Probability of survival
.5
.5
.4
.4
.3
.3
.2
.2
.1
.1
0
0
0
50
100
150
200
0
50
100
150
200
Months
Months
Untreated
EPO-G
Curves estimated from the multivariate Cox
analysis
99
How to prevent anemia recurrence in MDS ?

• EPO and darbepoetin
• Thalidomide
• ATG
• Lenalidomide
• (Hypomethylating agents ?)

100
THALIDOMIDE RESULTS
11 Erythroid (4 MR7mR) 1 Platelet (1 MR) 2
Neutrophil (2 MR)
101
Results Side Effects
side effect pts
. Sleepiness 72 . Constipation and
dizziness 45 . Cutaneous reactions 33 .
Headache 17 . Nausea 11 . Asthenia
8 . Paresthesia 7 . Worsening
granulocytopenia 5 . Dyskinesia 4 .
Oedema 2 . Others 5 . Thrombosis
0
102
THAL-SMD-2004 trial (F Tamburini, D Bouscary,
ASH 2006)
Part 1 (59 first patients) Thalidomide
200mg/d during 12 weeks
Part 2 (28 patients) Thalidomide 50mg/d
103
THAL-SMD-2004 trial (F Tamburini, D Bouscary)
SMD de faible risque AR, ASIA, AREB lt 10
32 (37) pts stopped treatment before week 12 (32
with 200 mg, 46 with 50 mg) 55 pts completed
12 weeks 22 (40, 25 of pts included) response
(12 major, 10 minor) 43.5 (28) responses after
200 mg 29 (18) after 50 mg
104
How to prevent anemia recurrence in MDS ?

• EPO and darbepoetin
• Thalidomide
• ATG
• Lenalidomide
• (Hypomethylating agents ?)

105
Sérum antilymphocytaire (ATG) in MDS (NIH)

• 61 pts, 40 response
• Prognostic factors
• Younger age
• Low cellularity
• No excess of blasts
• Normal karyotype
• Pancytopenia
• PNH clone
• HLA DR 15

106
Antithymocyte globulin in MDS

• Lim (Leukemia, 2007)
• 96 patients 40 (42) responses , during a median
  of 31 months (6-92)
• low IPSS and marrow hypocellularity favorable
  prognostic factors

107
How to prevent anemia recurrence in MDS ?

• EPO and darbepoetin
• Thalidomide
• Lenalidomide
• (Hypomethylating agents ?)

108
Lenalidomide

• Lenalidomide (CC-5013 Revlimid)
  4-amino-glutarimide thalidomide analogue
• No evidence of teratogenicity or significant
  neurotoxicity
• Potent modulator of myelosuppressive
  properties

Bartlett JB, et al. Nat Rev Cancer. 20044314-22.
109
MDS 003 Multicenter Phase II of lenalidomidein
Transfusion-Dependent Low/Int-1 MDS withdel 5 q
R E S P O N S E
R E G I S T E R
Eligibility gt2U RBC/8wks
lenalidomide 10 mg po x21
lenalidomide 10 mg po qd

110
Erythroid Response
111
Cytogenetic Response
112
Bone marrow Response
113
Drug-Related Adverse Events
114
MDS-003duration of transfusion-free periodn 99
Time (weeks)
Data cut-off 15 July 2005.
List A, et al. N Engl J Med. 20063551456-65.
115
MDS-002 lenalidomide in transfusion-dependent
non-del 5q MDS
R E S P O N S E
R E G I S T E R
Yes Continue
Lenalidomide 10 mg orally x 21 days

• Eligibility
• ? 2 U RBC/8 weeks
• 16-week pre-study documentation of transfusions
• Platelets gt 50 x 109/L
• ANC gt 500 x 109/L

Lenalidomide 10 mg orally every day
No Off study
Dose reduction 5 mg every day 5 mg every other
day
Week 0 4 8 12 16 20 24
Primary end-point transfusion independence (Hb?
? 1 g/dL) Secondary end-points cytogenetic
response, pathological response
n 215 enrolled n 116 evaluable
List AF, et al. Haematologica. 200590 Suppl
2307.
116
MDS-002erythroid response
List AF, et al. Haematologica. 200590 Suppl
2307.
117
Duration of transfusion independence
118
Phase II Lenalidomide in high and int 2 risk
MDS with del 5q (S Burcheri, ASH 2007)

• Lenalidomide 10 mg/d, 3 weeks on, 1 week off
• Endpoints response (CR,PR, HI), progression and
  survival
• 49 patients included

119
Treatment of thrombocytopenia

• Androgens
• TPO agonist receptors (AMG 531, Eltrombopag) ?

120
TPO agonist receptors

• As TPO itself is immunogeneic..
• AMG 531 (Amgen)
• Eltrombopag (GSK)

121
AMG 531 in lower risk MDS (Kantarjian, ASH 2007)

• Platelet response achieved in 52 of patients
  overall.

a increase from baseline in platelet count by
?30 x 109/L for patients starting with gt20 x
109/L platelets, or an increase from lt20 x 109/L
to gt20 x 109/L and by at least 100.7
122
Treatment of neutropenia

• early treatment of infections(Augmentin-Ciflo
  x)
• No proven effect of G-CSF (except in acute
  situations?)

123
First Line Treatment of IPSS low and int 1 MDS

• Non del 5q
• anemia(Hb lt10g/dl) and EPO level lt500 EPO or
  darbepoetin
• thrombocytopenia
• neutropenia
• Del 5q lenalidomide

124
Treatment of IPSS low and int 1 MDS

• Second line treatment
• thalidomide
• Lenalidomide?
• ATG

125
Treatment of IPSS low and int 1 MDS
perspectives

• Is there a role for hypomethylating agents, alone
  or in combination with other drugs?
• In particular with EPO

126
Chelation therapy in MDS

• IndicationIPSS low and int 1 or int2 or high
  with potentially curable treatment envisages
• modalities
• desferoxamine (SC, IV)
• Deferiprone (oral)
• ICL 670 (oral)

127
Rôle pathogène de la surcharge en fer dans les
SMD ? (Rose, ASH 2006)

• 45 SMD polytransfusés
• Anomalies de lIRM cardiaque (T2) chez les pts
  ayant reçu gt 50 culots
• Corrélé à la survenue dune insuffisance cardiaque

128
Chélation du fer et survie dans les SMD ? (Rose,
ASH 2007)

• 170 SMD de faible risque polytransfusés étudiés
  prospectivement
• Survie médiane supérieure chez les patients
  chelatés (p lt0.0001)
• Chélation facteur indépendant de la survie

129
Groupe Francophone des Myélodysplasies

• Activates clinical trials in MDS (35 centers in
  France and Belgium
• (recently) Switzerland, Tunisia, Romania
• Website www. gfmgroup.org
• Online registry of French MDS cases
• Close cooperation with
• - a patient support group
• - the International MDS Foundation