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

K Raj, A John, A Ho, C Chronis, S Khan, J Samuel, S Pomplun, N S B Thomas, G J Mufti

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    143 Citations (Scopus)

    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 424% 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 75mg/ 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 424% methylation may benefit from alternative dosing or combination strategies
    Original languageEnglish
    Pages (from-to)1937 - 1944
    Number of pages8
    JournalLeukemia
    Volume21
    Issue number9
    DOIs
    Publication statusPublished - Sept 2007

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