1068PD - Favorable impact on mainly intermediate cytogenetic risk AML can be predicted by gene expression profiling- results of a phase I/II trial of belinos...

Date 01 October 2012
Event ESMO Congress 2012
Session Hematological malignancies
Topics Leukaemia
Biomarkers
Presenter Lars Bullinger
Authors L. Bullinger1, S. Knudsen2, H. Dombret3, M. Dennis4, A. Neubauer5, M.G.M. Pfreundschuh6, J. Rossi7, P. Knoblauch8, J. Tjørnelund8, R.F. Schlenk9
  • 1University Hospital of Ulm, 89081 - Ulm/DE
  • 2Devlopment, MPI, Hørsholm/DK
  • 3Haematology, Hospital Saint Louis, Paris/FR
  • 4Hematology, Oncology, Immunology, Christie Hospital NHS Trust, Manchester/UK
  • 5Hematology / Oncology, University Hospital of MarburgKlinik fuer Innere Medizin,, DE-35043 - Marburg/DE
  • 6Internal Medicine I, University Hospital of Saarland, Homburg/Saar/DE
  • 7Hematology And Oncology, CHU Lapeyronie, Montpellier/FR
  • 8Clinical Pharmacology, Topotarget, Copenhagen/DK
  • 9Internal Medicin Iii, University Hospital of Ulm, 89081 - Ulm/DE

 

Abstract

Belinostat (Bel), a histone deacetylase inhibitor (HDACi), has demonstrated effective cell killing in leukemic cells and shows a synergistic effect in combination with anthracyclines in vitro. A favorable impact on the dismal clinical course of acute myeloid leukemia (AML) was suggested (Schlenk et al. ASH 2008). Recently, a phase I/II trial assessing the efficacy and safety of two schedules of Bel in patients unfit for intensive induction therapy has shown anti-leukemic effect both of Bel alone and in combination with idarubicin (ClinicalTrials.gov ID: NCT00878722).

We evaluated the role of cytogenetic aberrations on response to Bel therapy in 41 patients (pts), of whom cases with intermediate risk cytogenetics in trend responded better to Bel than patients with high risk cytogenetics (p = 0.14). Five complete remissions (CR) and 2 partial remissions (PR) were observed in 25 pts (28%) AML cases with low/intermediate risk cytogenetic aberrations, whereas no CR and 2 PR were seen in 16 pts (13%) high risk AML cases.

Gene expression profiling based on 13 pts (4 CR + PR and 9 PD) revealed a strong gene expression pattern associated with the response to Bel. MLL, a gene well known to be involved in epigenetic deregulation, was among the top 20 strongest correlations. Furthermore, differential expression of TP53 was also of special interest as histone deacetylases have been shown to modulate p53 transcriptional activity. In accordance, gene ontology class comparison analysis showed a significant enrichment of categories associated with epigenetic regulation such as “histone methyltransferase activity” and “histone deacetylase activity”. In addition, the respective gene expression pattern harbored predictive information as based on an in vitro cell line derived predictor and a blinded Bel response prediction was feasible.

A trend indicating the potential association of Bel response and intermediate risk cytogenetics AML has been found. High risk AML cases might also benefit from an epigenetic treatment approach with a HDACi. Further randomized studies are warranted to explore the benefit of Bel in pts with AML.

Disclosure

S. Knudsen: MPI Employee

J. Tjørnelund: Employment Topotarget.

All other authors have declared no conflicts of interest.