Abstract
BACKGROUND
General and site‐specific DNA methylation is associated with tumor progression and resistance in several cancers, including chronic myelogenous leukemia (CML). Decitabine is a hypomethylating agent that has shown encouraging preliminary anti‐CML activity. This study evaluated the activity and toxicity of decitabine in different phases of CML.
METHODS
One hundred and thirty patients with CML were treated: 123 with Philadelphia chromosome (Ph)‐positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph‐negative CML. Decitabine was given at 100 mg/m^2^ over 6 hours every 12 hours × 5 days (1000 mg/m^2^ per course) in the first 13 patients, 75 mg/m^2^ in the subsequent 33 patients, and 50 mg/m^2^ in the remaining 84 patients.
RESULTS
A total of 552 courses were given to the 130 patients. Only four patients (3%) died during the first course from myelosuppressive complications (three patients) or progressive disease (one patient). Of 64 patients in the CML blastic phase, 18 patients (28%) achieved objective responses. Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP). Five patients (8%) had cytogenetic responses. Among 51 patients in the accelerated phase, 28 patients (55%) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP). Seven patients (14%) had cytogenetic responses. Among eight patients treated in the chronic phase, five (63%) had objective responses. Of seven patients treated for Ph‐negative CML, four (57%) had objective responses. There was no evidence of a dose‐response effect. The estimated 3‐year survival rate was less than 5% in the blastic phase and 27% in the accelerated phase. The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose dependent. With decitabine 50–75 mg/m^2^, the median time to granulocyte recovery above 0.5 × 10^9^/L was about 4 weeks. Myelosuppression‐associated complications included febrile episodes in 37% and documented infections in 34%.
CONCLUSIONS
Decitabine appears to have significant anti‐CML activity. Future studies should evaluate lower‐dose, longer‐exposure decitabine schedules alone in imatinib‐resistant CML, as well as combinations of decitabine and imatinib in different CML phases. Cancer 2003;98:522–8. © 2003 American Cancer Society.
DOI 10.1002/cncr.11543