Post on 15-Dec-2015
MDSs in 2010 EHA
• 1 education session :
1. THE BIOLOGICAL BASIS OF MYELODYSPLASTIC SYNDROMES
2. EPIGENETIC THERAPY OF MYELODYSPLSATIC SYNDROMES : AN UPDATE
3. MANAGEMENT OF MYELODYSPLASTIC SYNDROMES
• 3 scientific sessions : (26 Abst)
Contents
• Update on epigenetic abnormalities in MDS
• Update on prognosis and diagnosis of MDS – emerging prognostic factors– analysis of patient registries
• Management of MDS
• Lenalidomide in patients with MDS
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Myelodysplastic Syndromes Myelodysplastic Syndromes FAB (French, American and British) system 1982FAB (French, American and British) system 1982::
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2008:2008:
-RCUD includes: RA, RN, RT-RCUD includes: RA, RN, RT -chromosomal abnormalities confirm -chromosomal abnormalities confirm MDS in absence of morphologyMDS in absence of morphology
-Merge RCMD-RS and RCMDMerge RCMD-RS and RCMD
-RCC: refractory cytopenia of childhoodRCC: refractory cytopenia of childhood
-t-MDS/t-AMLt-MDS/t-AML
-Ring sideroblast not ringedRing sideroblast not ringed
Myelodysplastic Syndromes Classification of MDS Myelodysplastic Syndromes Classification of MDS 2001 WHO Classification2001 WHO Classification
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Myelodysplastic Syndromes Myelodysplastic Syndromes 1997- 1997- International Prognostic Scoring System (IPSS)International Prognostic Scoring System (IPSS)
IPSS assessment criteria:IPSS assessment criteria:-Percentage of blasts in bone marrowPercentage of blasts in bone marrow-Chromosomal abnormalitiesChromosomal abnormalities-Number of cytopeniasNumber of cytopenias
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IPSS defects:-cytopenia severity-transfusion dependency-limited number of cytogenetic abnormalities-fibrosis, LDH, beta2 microglobulin, co-morbidities do not account
Myelodysplastic Syndromes : Myelodysplastic Syndromes : Prognosis and survival using IPSSPrognosis and survival using IPSS
Normal40%
810%
11(q23)1%
Abn58%
Abn78%
Abn5&715%
-Y7%
Abn17p7%
Del(20q)4%
Relative % of Various Cytogenetic Abnormalities in De Novo MDS
++
Analysis of patient registeries: a new cytogenetic scoring system for primary MDS
Schanz J, et al. Oral presentation at EHA 2010, Barcelona, Spain. Abstract 0535
New system based on reclassification of double (2 cytogenetic aberrations) and complex (≥3 cytogenetic aberrations) abnormalities
Very good
Good Int Poor Very poor
Singledel(11q)–Y
Normal
Singleder(1;7)del(5q)del(12q)del(20q)
DoubleDouble incl. del(5q)
Single–7/7q–+8+19+21iso(17q)Any others
DoubleAny other
Singleder(3)(q21)/ (3)(q26)
DoubleIncl. –7/7q–
Complex3 abnorm.
Complex>3 abnorm.
A total of 2,901 untreated patients (GA = 1,192, IMRAW = 816, GCECGH = 849, ICWG = 44); median observation time = 19 (0.1–326) months
GA = German/Austrian; IMRAW = International MDS Risk Analysis Workshop; GCECGH = Spanish Cytogenetics Working Group; ICWG = International Cytogenetics Working Group
Risk category
Schanz J, et al. Oral presentation at EHA 2010, Barcelona, Spain. Abstract 0535
0
10
20
30
40
50
60
70
OS
(m
on
ths)
Very good
Good Int Poor Very poor
60.8
48.5
25.0
15.0
5.7
Analysis of patient registeries: a new cytogenetic scoring system for primary MDS, cont’d
New scoring system predicted survival in 2,799 evaluable patients with MDS
Risk
Prognosis Patients, n (%)
Very good 80 (2.9)
Good 1,844 (65.9)
Int 578 (20.7)
Poor 101 (3.6)
Very poor 196 (7.0)
OS
DNA methylation predicts survival in patients with MDS1,2
1. Santini V. Oral presentation at EHA 2010, Barcelona, Spain2. Shen L, et al. J Clin Oncol 2009;28:605–13
Methylation analysis of a panel of 10 genes in 317 patients with MDS from three independent studies
OS PFS
Methylation measured by combined z score
Genome-wide methylation analysis of CD34+ cells from patients with MDS
Figueroa M. Oral presentation at EHA 2010, Barcelona, Spain
Sta
tist
ica
l si
gn
ific
anc
e
Normal CD34+ cells
More methylated in MDS
Less methylated in MDS
Genome-wide methylation was greater in CD34+ cells from BM of patients with MDS versus normal controls
The aberrant methylation pattern in patients with MDS
– was transmitted to CD34– progeny cells
– occurred preferentially within certain chromosomal regions
– strongly affected genes in the WNT, PTEN and PI3K/Akt signalling pathways
Aberrant methylation was more pronounced in patients with MDS than in patients with de novo AML
Azacitidine30–50mg/m2/day2
Genome-wide methylation assessed in patients who completed at least 4 cycles
Day 0 Day 15 Day 29
Entinostat
Treatment regimen (28–29-day cycles)
Day 10
Treatment significantly reduced genome-wide methylation vs baseline Demethylation was sustained throughout each cycle There was a trend towards greater genome-wide demethylation in responders
versus non-responders
1. Figueroa M. Oral presentation at EHA 2010, Barcelona, Spain2. Fandy TE, et al. Blood 2009;114:2764–73
Epigenetic therapy induced profound and sustained hypomethylation in the BM of patients with MDS
Genome-wide methylation analysis of CD34+ cells from patients with MDS: response to therapy1
Emerging prognostic factors in MDS: severity of anaemia
Ambaglio I, et al. Poster presentation at EHA 2010, Barcelona, Spain. Abstract 0310
A single-centre study of 920 patients with MDS*IPSS low/int-1/int-2/high, n = 211/264/122/31; TD, % patients = 31
OS in patients with anaemia OS according to transfusion dependence
Anaemia (<9g/dL in males and <8g/dL in females) was an independent unfavourable prognostic indicator of survival in patients with MDS
TI patientsTD patients0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 24 48 72 96 120
Time (months)144 168 192 216 240
No, mild or moderate anaemiaSevere anaemia
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0.9
1.0
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 24 48 72 96 120 144 168 192 216 240
Time (months)
*Patients who received HSCT or chemotherapy were censored at time of procedure
Cu
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Emerging prognostic factors in MDS: transfusion dependence and iron overload
Transfusion independencyTransfusion dependency
Cu
mu
lati
ve
su
rviv
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1.0
0.8
0.6
0.4
0.2
0.00 5 10 15 20
Survival, years
RR = 5.8; p < 0.001
Ferritin <1,000 ng/mLFerritin >1,000 ng/mL
Cu
mu
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rviv
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1.0
0.8
0.6
0.4
0.2
0.00 5 10 15 20
Survival, years
RR = 2.1; p < 0.025
Arnan M, et al. Poster presentation at EHA 2010Barcelona, Spain. Abstract 0314
Single-centre retrospective study of 639 patients with de novo MDS
TD and iron overload were strongly associated with worse OS
OS stratified by RBC transfusion dependence
OS stratified by serum ferritin levels (indicative of iron overload)
RR = response rate
• TD at baseline: 43%– median 2.03 (range 0.5–13.2) RBC packs/month
Emerging prognostic factors in MDS: TP53 mutations in patients with low-risk del(5q) MDS
Saft L, et al. Poster presentation at EHA 2010, Barcelona, Spain. Abstract 0313
Assessment• BM samples– stained for p53 protein
• Mutational analysis of TP53
Study of 56 patients with low-risk del(5q) MDS in two centresTD = 52%
Mutation of TP53 in patients with low-risk del(5q) MDS was associated with disease progression in this set of 56 patients
• Patients with TP53 mutation pre-progression, n (%): 10 (18)
• TP53 mutations were associated with overexpression of p53 protein
Progression to AML Disease progression* OS
*to >10% blasts or complex karyotype
Higher Risk MDS
• CHEMOTHERAPY Intensive
Low dose Ara C
Newer chemotherapeutic agents
• ALLOGENEIC SCT
• HYPOMETHYLATING AGENTS
Higher Risk MDS
• CHEMOTHERAPY Intensive
Low dose Ara C
Newer chemotherapeutic agents
• ALLOGENEIC SCT
• HYPOMETHYLATING AGENTS
Higher Risk MDS
• CHEMOTHERAPY Intensive
Low dose Ara C
Newer chemotherapeutic agents
• ALLOGENEIC SCT
• HYPOMETHYLATING AGENTS
Higher Risk MDS
• CHEMOTHERAPY Intensive
Low dose Ara C
Newer chemotherapeutic agents
• ALLOGENEIC SCT
• HYPOMETHYLATING AGENTS
Higher Risk MDS
• CHEMOTHERAPY Intensive
Low dose Ara C
Newer chemotherapeutic agents
• ALLOGENEIC SCT
• HYPOMETHYLATING AGENTS
Higher Risk MDS
• CHEMOTHERAPY Intensive
Low dose Ara C
Newer chemotherapeutic agents
• ALLOGENEIC SCT
• HYPOMETHYLATING AGENTS
Treatment of Lower Risk MDS
• Erythropoiesis stimulating agents
• Thalidomide
• Hypomethylating agents
• Immunosuppressive drug
Conclusions• MDS classifications and prognosis are in transitional
phase : FAB, WHO, IPSS, WPSS, fibrosis, immunophenotyping…
• Hypomethylating agents are a back stone in the treatment of MDS
• Lenalidomide shows a very promising result in MDS with del 5q