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 approximately 50% of patients with high-risk myelodysplastic syndrome (MDS). We examined the incidence and kinetics of cytogenetic responses to decitabine in these patients. Of 115 successfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities prior 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 cytogenetic 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 responses (60%) in the IPSS 'low-risk' group, 6 out of 30 with 'intermediate risk' (20%) and 10 out of 26 in the 'high-risk' group (38%). Median survival in these cytogenetic subgroups was 30, 8 and 13 months respectively. The relative 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, repeated courses of low-dose decitabine induce cytogenetic remissions in a substantial number of elderly MDS patients with pre-existing chromosomal abnormalties; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with 'high-risk' chromosomal abnormalities may particularly benefit from this treatment.
Lübbert
M
M
Department of Medicine, Division of Haematology/Oncology, University of Freiburg Medical Centre, Freiburg, Germany. luebbert@mm11.ukl.uni-freiburg.de
Wijermans
P
P
Kunzmann
R
R
Verhoef
G
G
Bosly
A
A
Ravoet
C
C
Andre
M
M
Ferrant
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000753:Anemia, Refractory / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000754:Anemia, Refractory, with Excess of Blasts / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000756:Anemia, Sideroblastic / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002869:Chromosome Aberrations; D025063:Chromosome Disorders; D000077209:Decitabine; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D012306:Risk; D015996:Survival Rate
D000964:Antimetabolites, Antineoplastic; D000077209:Decitabine; D001374:Azacitidine