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CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine.
- Source :
-
Leukemia [Leukemia] 2007 Sep; Vol. 21 (9), pp. 1937-44. Date of Electronic Publication: 2007 Jul 05. - Publication Year :
- 2007
-
Abstract
- 5-Azacytidine, a DNA methyl transferase inhibitor, is effective in patients with myelodysplastic syndromes (MDS). Whether responses to 5-Azacytidine are achieved by demethylation of key genes or by cytotoxicity is unclear. Of 34 patients with MDS or acute myeloid leukaemia (AML) treated with 5-Azacytidine, 7 achieved complete remissions (CR) (21%) and 6 achieved haematological improvement. All six had less than 5% bone marrow (BM) blasts at the time of haematological improvements (HI) (2 had pre-existing refractory anaemia (RA), 4 had refractory anaemia with excess blasts (RAEB)). A further patient with RAEB had blast reduction to less than 5% without HI. Five of the seven (71%) complete responders had chromosome 7 abnormalities. BM CR predicted longer overall survival (OS) (median 23 versus 9 months, P=0.015). Bisulphite genomic sequencing (BGS) of the CDKN2B (p15(INK4b)) promoter showed low level, heterogeneous pretreatment methylation (mean 12.2%) in 14/17 (82%) patients analysed. Lower baseline methylation occurred in responders (9.8% versus 16.2% in non-responders P=0.07). No response was seen in patients with >24% methylation, in whom p15(INK4b) mRNA was not expressed. 5-Azacytidine reduced CDKN2B methylation by mean 6.8% in 8/17 (47%) patients, but this did not correlate with response. At 75 mg/m(2), cell death (reduced BM cellularity (P=0.001) and increased apoptosis (P=0.02)) rather than demethylation of CDKN2B correlates with response. Patients with >24% methylation may benefit from alternative dosing or combination strategies.
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic adverse effects
Apoptosis drug effects
Azacitidine adverse effects
Bone Marrow Cells pathology
DNA Methylation drug effects
Female
Genetic Markers
Humans
Injections, Subcutaneous
Male
Middle Aged
Myelodysplastic Syndromes pathology
Predictive Value of Tests
Promoter Regions, Genetic physiology
Survival Rate
Treatment Outcome
Antimetabolites, Antineoplastic administration & dosage
Azacitidine administration & dosage
Chromosome Aberrations
Chromosomes, Human, Pair 7
Cyclin-Dependent Kinase Inhibitor p15 genetics
Myelodysplastic Syndromes drug therapy
Myelodysplastic Syndromes genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0887-6924
- Volume :
- 21
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 17611569
- Full Text :
- https://doi.org/10.1038/sj.leu.2404796