Wolf-Karsten Hofmann, MD, PhDProfessor of MedicineDepartment of Hematology and OncologyUniversity Hospital Benjamin FranklinBerlin, Germany

European LeukemiaNet

Work-Package 8: Myelodysplastic Syndromes

Suggestions on Microarray Experiments

Microarrays in MDS: What is the need?

•Multiple microarray-data from CD34+ cells (other cells are in discussion, granulocytes?) at the time of initial diagnosis of MDS.

To correlate specific gene expression profiles with diagnosis and risk/course of the disease?

To add new prognostic parameters/gene expression profiles? To predict response to treatment?

•Central sample collection!

•Standardization of microarray protocols (e. g. Affymetrix platform)!

•Tight collaboration with WP13 (Gene Profiling: T. Haferlach, W. Hiddemann)!

Microarray Experiments in MDS

•Aims To use gene expression profiles for classification or risk-evaluation in MDS

To detect altered molecular pathways in MDS-cells

•Technique Most common: Oligonucleotide microarrays (Affymetrix) Less common: cDNA-arrays

WKH 02/2003

Erythropoiesis (CD71+)All genes (22,283)

Megakaryopoiesis (CD61+)All genes (22,283)

Time course of gene expression (normal CD34+)

MicroFluidic Cards

Application in MDS studies?

(Future) applications Hematology UMCN

• Downstream targets of WT1 in AML, MDS, and in murine transplant model

• Hematology Card, targets involved in leukemogenesis, cell cyclus, differentiation/proliferation

• ABC transporter genes in AML and MDS

• Software package for cluster analysis

Meeting of the European LeukemiaNet, WP8 (MDS): Salamanca, Nov. 2004

Interaction with AML workpackage

Listing: European, national studies recruiting both MDS

and AML (according to FAB) patients

total number of studies: >25

standard induction treatment: >80 %

non-intensive treatment: < 20 %

studies including patients aged >60 years: ca. 10

Meeting of the European LeukemiaNet, WP8 (MDS): Salamanca, Nov. 2004

Interaction with AML workpackage

Biological agents active in „overlap studies“ of MDS and AML

• farnesyl transferase inhibitors

• histone deacetylase inhibitors

• anti-angiogenic agents

• DNA methyltransferase inhibitors

• low-dose melphalan

Meeting of the European LeukemiaNet, EHA, Geneva June 10, 2004WP8: MDS

Interaction with AML workpackage

MDS and AML as a biological continuum

• blast cut-off lowered over time (50==>30==>20%)

• cytogenetics similar in high-risk MDS and sAML, tAML

• inclusion of high-risk MDS and bona fide AML patients in same studies

40

30

20

10

% BM blasts

5

3 6 9 12 months

1) indolent, „low-risk“ MDS2) evolving, „high-risk“ MDS3) acute myeloid leukemia (with or without multilineage dysplasia)

4) AML from MDS (> 6 months duration)5) „RAEB-t“ (FAB classification) = AML (WHO classification)

6) smouldering AML

33 4

6

2

5

1

Karyotype abnormalities (%)Age (years) n

no single double complex numerical Chromosome5 Chromosome 7

Rossi 2000i MDS/AML n.g.

>65

35

48

31

27

14

13

17

14

37

46

89

93

20

31

27

27

Mauritzson 1999ii MDS

AML

>65

>65

281

161

48

51

28

24

7

6

16

20

49

49

22

16

12

8

Preiss 2003iii AML median 67 (range: 16-93) 303 47 41 15 44 24 15 16

i Rossi G, Pelizzari AM, Bellotti D, Tonelli M, Barlati S: Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients. Leukemia 2000 14(4): 636-641

ii Mauritzson N, Johansson B, Albin N, Billström R, et al.: A single-center population-based consecutive series of 1500 cytogenetically investigated adult hematological malignancies: karyotypic features in relation to morphology, age and gender. Eur J

Haematol 1999;62:95-102.iii Preiss BS, Kerndrup GB, Schmidt KG, Sorensen AG, Clausen NA, Gadeberg OV, Mourits-Andersen T, Pedersen NT: Cytogenetic findings in adult de novo acute myeloid leukemia. A population-based study of 303/337 patients. Br J Haematol 2003, 123,

219-234.

Cytogenetic similarities between MDS and AMLin population-based studies of older patients

From: B. Deschler et al., „Treatment decision-making in the biological continuum of

older patients with myelodysplastic syndrome and acute myeloid leukemia“ (in prep.)

% BM blasts

Inclusion for DAC studies

AML DAC00331Study

MDS DAC 06011EORTC Study

% BM blasts Cytogenetics

poor risk

all

100

90

80

70

60

50

40

30

20

10

all except t(15;17)

Implementation and coordination of ongoing and new clinical trials

specific

• Phase I/II trials (thalidomide, farnesyltransferase inhibitors,

arsenic trioxide and others) Fenaux

• Trials with Hematopoietic growth factors/iron chelators Hellström

• Anticytokine and signal transduction modulating studies Fenaux

• DNA hypomethylating studies Lübbert

• Eradication of the myelodysplastic clone by novel intensive

cytotoxic therapy including autologous SCT Sanz/Mufti

• New forms of allogeneic stem cell transplantation Martino/De Witte

• Immunosuppression Ganser