Kein Folientitel

1
European LeukemiaNet Work-Package 8
Myelodysplastic Syndromes Suggestions on
Microarray Experiments
Wolf-Karsten Hofmann, MD, PhD Professor of
Medicine Department of Hematology and
Oncology University Hospital Benjamin
Franklin Berlin, Germany
2
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)!

3
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

4
Time course of gene expression (normal CD34)
Erythropoiesis (CD71) All genes (22,283)
Megakaryopoiesis (CD61) All genes (22,283)
WKH 02/2003
5
MicroFluidic Cards Application in MDS studies?
6
(No Transcript)
7
(No Transcript)
8
(No Transcript)
9

• (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/proli
  feration
• ABC transporter genes in AML and MDS
• Software package for cluster analysis

10
Meeting of the European LeukemiaNet, WP8 (MDS)
Salamanca, Nov. 2004Interaction with AML
workpackage

• Listing European, national studies recruiting
  both MDS
• and AML (according to FAB) patients
• total number of studies gt25
• standard induction treatment gt80
• non-intensive treatment lt 20
• studies including patients aged gt60 years ca.
  10

11
Meeting of the European LeukemiaNet, WP8 (MDS)
Salamanca, Nov. 2004Interaction 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

12
Meeting of the European LeukemiaNet, EHA, Geneva
June 10, 2004WP8 MDSInteraction with AML
workpackage

• MDS and AML as a biological continuum
• blast cut-off lowered over time (50gt30gt20)
• cytogenetics similar in high-risk MDS and sAML,
  tAML
• inclusion of high-risk MDS and bona fide AML
  patients in same studies

13
BM blasts
3
3
4
6
40
30
2
5
20
10
5
1
months
3
6
9
12
1) indolent, low-risk MDS
2) evolving, high-risk MDS
3) acute myeloid leukemia (with or without
multilineage dysplasia)
4) AML from MDS (gt 6 months duration)
5) RAEB-t (FAB classification) AML (WHO
classification)
6) smouldering AML
14
From B. Deschler et al., Treatment
decision-making in the biological continuum of
older patients with myelodysplastic syndrome and
acute myeloid leukemia (in prep.)
15
Inclusion for DAC studies
BM blasts
BM blasts Cytogenetics
100 90 80 70 60 50 40 30 20 10
AML DAC 00331 Study
all except t(1517)
MDS DAC 06011 EORTC Study
all
poor risk
16
Implementation and coordination of ongoing and
new clinical trialsspecific

• 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