Fetal hemoglobin induction during decitabine treatment of elderly patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: a potential dynamic biomarker of outcome
Julia Stomper,
Gabriele Ihorst,
Stefan Suciu,
Philipp N. Sander,
Heiko Becker,
Pierre W. Wijermans,
Christoph Plass,
Dieter Weichenhan,
Emmanuel Bissé,
Rainer Claus,
Michael Lübbert
Affiliations
Julia Stomper
Department of Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine and Medical Center, University of Freiburg, Germany
Gabriele Ihorst
Clinical Trials Unit, Faculty of Medicine and Medical Center, University of Freiburg, Germany
Stefan Suciu
EORTC Headquarters, Brussels, Belgium
Philipp N. Sander
Department of Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine and Medical Center, University of Freiburg, Germany;Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA
Heiko Becker
Department of Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine and Medical Center, University of Freiburg, Germany
Pierre W. Wijermans
Department of Hematology, Haga Hospital, The Hague, the Netherlands
Christoph Plass
DKFZ Heidelberg, Division of Epigenomics and Cancer Risk Factors, Heidelberg, Germany;German Cancer Research Consortium (DKTK), Heidelberg, Germany
Dieter Weichenhan
DKFZ Heidelberg, Division of Epigenomics and Cancer Risk Factors, Heidelberg, Germany
Emmanuel Bissé
Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Germany
Rainer Claus
Department of Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine and Medical Center, University of Freiburg, Germany;Department of Internal Medicine II, Hematology/Oncology, Augsburg Medical Center, Germany
Michael Lübbert
Department of Hematology, Oncology, and Stem Cell Transplantation, Faculty of Medicine and Medical Center, University of Freiburg, Germany;German Cancer Research Consortium (DKTK), Freiburg, Germany
Hematologic responses to hypomethylating agents are often delayed in patients with myelodysplastic syndrome or acute myeloid leukemia. Fetal hemoglobin is a potential novel bio-marker of response: recently, we demonstrated that a high fetal hemoglobin level prior to decitabine treatment was associated with superior outcome. Here we investigated whether early fetal hemoglobin induction during decitabine treatment also had prognostic value, and studied the potential of decitabine to induce erythroid differentiation and fetal hemoglobin expression in vitro. Fetal hemoglobin levels were measured by high-performance liquid chromatography in patients with higher-risk myelodysplastic syndrome (n=16) and acute myeloid leukemia (n=37) before treatment and after each course of decitabine. Levels above 1.0% were considered induced. Patients achieving complete or partial remission as best response had attained a median fetal hemoglobin of 1.9% after two courses of treatment, whereas the median value in patients who did not reach complete or partial remission was 0.8% (P=0.015). Fetal hemoglobin induction after two courses of decitabine treatment was associated with early platelet doubling (P=0.006), and its subsequent decrease with hematologic relapse. In patients with myelodysplastic syndrome, induction of fetal hemoglobin after course 2 of treatment was associated with longer overall survival: median of 22.9 versus 7.3 months in patients with or without induction of fetal hemoglobin, respectively [hazard ratio=0.2 (95% confidence interval: 0.1–0.9); P=0.03]. In vitro decitabine treatment of two bi-potential myeloid leukemia cell lines (K562 and HEL) resulted in induction of an erythroid (not megakaryocytic) differentiation program, and of fetal hemoglobin mRNA and protein, associated with GATA1 gene demethylation and upregulation. In conclusion, fetal hemoglobin may provide a useful dynamic biomarker during hypomethylating agent therapy in patients with myelodysplastic syndrome or acute myeloid leukemia.
