Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2 '-deoxycytidine

Decitabine (5-aza-2'-deoxycytidine) acts as a powerful demethylating agent in vitro. Clinically, low-dose decitabine ameliorates cytopenias including induction of trilineage responses in approximate to 50% of patients with hi gh-risk myelodysplastic syndrome (MDS). We examined the incidence and kinet ics of cytogenetic responses to decitabine in these patients. Of 115 succes sfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities p rior to treatment. Major cytogenetic responses were observed in 19 patients (31% of those with abnormal cytogenetics, 17% of all patients by intention -to-treat) after a median of three courses (range, 2-6) until best cytogene tic response. Progressive decrease of the abnormal clone over time was also determined using fluorescence in situ hybridization (FISH) analysis in two patients. Median duration of cytogenetic responses was 7.5 months (range, 3-15). Analysis of response by the International Prognostic Scoring System (IPSS) cytogenetic risk groups revealed three out of five cytogenetic respo nses (60%) in the IPSS 'low-risk' group, 6 out of 30 with 'intermediate ris k' (20%) and 10 out of 26 in the 'high-risk' group (38%). Median survival i n these cytogenetic subgroups was 30, 8 and 13 months respectively. The rel ative risk of death in patients achieving a major cytogenetic response was 0.38 (95% confidence interval 0.17-0.88) compared with patients in whom the cytogenetically abnormal clone persisted (P = 0.0213). In conclusion, repe ated courses of low-dose decitabine induce cytogenetic remissions in a subs tantial number of elderly MDS patients with pre-existing chromosomal abnorm alites; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with 'high-ri sk' chromosomal abnormalities may particularly benefit from this treatment.