title: Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5-aza-2'-deoxycytidine (Decitabine).
abstract: Although azanucleoside DNA-hypomethylating agents (HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), very few outcome predictors have been established. Expression of the β-like globin gene locus is tightly regulated by DNA methylation, is HMA-sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine (DAC). Pre-treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/AML patients, respectively. Elevated pre-treatment HbF was associated with longer median overall survival (OS): 26·6 vs. 8·6 months for MDS (hazard ratio [HR] 8·56, 95% confidence interval [CI] 1·74-42·49, P = 0·008, with similarly longer progression-free and AML-free survival), and 10·0 vs. 2·9 months OS for AML (HR 3·01, 95% CI 1·26-7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time-dependent Cox models revealed that the prognostic value of treatment-induced HbF induction was inferior to that of pre-treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/AML, and demonstrate prognostic value of elevated pre-treatment HbF, warranting prospective, randomized studies.
authors.affiliation: Division of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Clinical Trials Unit, University of Freiburg Medical Centre, Freiburg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ihorst
authors.affiliation: Division of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Philipp N
authors.initials: PN
authors.lastname: Sander
authors.affiliation: Division of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Institute for Medical Biometry and Statistics, Faculty of Medicine and Medical Centre - University of Freiburg, Freiburg, Germany.
authors.forename: Ljudmila
authors.initials: L
authors.lastname: Bogatyreva
authors.affiliation: Division of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Becker
authors.affiliation: Department of Haematology, Haga Hospital, The Hague, The Netherlands.
authors.forename: Pierre W
authors.initials: PW
authors.lastname: Wijermans
authors.affiliation: EORTC Headquarters, Brussels, Belgium.
authors.forename: Stefan
authors.initials: S
authors.lastname: Suciu
authors.affiliation: Institute for Laboratory Diagnostics, University of Freiburg, Freiburg, Germany.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bissé
authors.affiliation: Division of Haematology, Oncology and Stem Cell Transplantation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Claus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018572:Disease-Free Survival; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis* / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D000077209:Decitabine; D005319:Fetal Hemoglobin; D001374:Azacitidine
keywords: biomarker; decitabine; fetal haemoglobin; methylation; myelodysplastic syndrome