EHA highlightsNews in MDSJULY31, TYR ,LEBANON

MARCEL MASSOUD, M.D.

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

Update on prognosis and diagnosis of MDS and AML: analysis of patient registries

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

Update on epigenetic abnormalities in MDS and AML

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

Update on prognosis and diagnosis of MDS and AML

Update on prognosis and diagnosis of MDS and AML: emerging prognostic factors

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

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Emerging prognostic factors in MDS: transfusion dependence and iron overload

Transfusion independencyTransfusion dependency

Cu

mu

lati

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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

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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

Management of myelodysplastic syndromes

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

Special case of MDS with del 5q

• Higher risk MDS with del 5 q

• Lower risk MDS with del 5q

Special case of MDS with del 5q

• Higher risk MDS with del 5 q

• Lower risk MDS with del 5q

Special case of MDS with del 5q

• Higher risk MDS with del 5 q

• Lower risk MDS with del 5q

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

Thank you