CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine

Leukemia. 2007 Sep;21(9):1937-44. doi: 10.1038/sj.leu.2404796. Epub 2007 Jul 5.


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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / adverse effects
  • Apoptosis / drug effects
  • Azacitidine / administration & dosage*
  • Azacitidine / adverse effects
  • Bone Marrow Cells / pathology
  • Chromosome Aberrations*
  • Chromosomes, Human, Pair 7*
  • Cyclin-Dependent Kinase Inhibitor p15 / genetics*
  • DNA Methylation / drug effects
  • Female
  • Genetic Markers
  • Humans
  • Injections, Subcutaneous
  • Male
  • Middle Aged
  • Myelodysplastic Syndromes / drug therapy*
  • Myelodysplastic Syndromes / genetics*
  • Myelodysplastic Syndromes / pathology
  • Predictive Value of Tests
  • Promoter Regions, Genetic / physiology
  • Survival Rate
  • Treatment Outcome


  • Antimetabolites, Antineoplastic
  • CDKN2B protein, human
  • Cyclin-Dependent Kinase Inhibitor p15
  • Genetic Markers
  • Azacitidine