title: CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine.
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.
authors.affiliation: King's College London, Department of Haematological Medicine, Denmark Hill Campus, London, UK.
authors.forename: K
authors.initials: K
authors.lastname: Raj
authors.forename: A
authors.initials: A
authors.lastname: John
authors.forename: A
authors.initials: A
authors.lastname: Ho
authors.forename: C
authors.initials: C
authors.lastname: Chronis
authors.forename: S
authors.initials: S
authors.lastname: Khan
authors.forename: J
authors.initials: J
authors.lastname: Samuel
authors.forename: S
authors.initials: S
authors.lastname: Pomplun
authors.forename: N S B
authors.initials: NS
authors.lastname: Thomas
authors.forename: G J
authors.initials: GJ
authors.lastname: Mufti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects; D001854:Bone Marrow Cells / Q000473:pathology; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D005819:Genetic Markers; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000502:physiology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D005819:Genetic Markers; D001374:Azacitidine