Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine

Abstract

A phase II clinical trial with single-agent decitabine was conducted in older patients (>or=60 years) with previously untreated acute myeloid leukemia (AML) who were not candidates for or who refused intensive chemotherapy. Subjects received low-dose decitabine at 20 mg/m(2) i.v. over 1 h on days 1 to 10. Fifty-three subjects enrolled with a median age of 74 years (range, 60-85). Nineteen (36%) had antecedent hematologic disorder or therapy-related AML; 16 had complex karyotypes (>or=3 abnormalities). The complete remission rate was 47% (n = 25), achieved after a median of three cycles of therapy. Nine additional subjects had no morphologic evidence of disease with incomplete count recovery, for an overall response rate of 64% (n = 34). Complete remission was achieved in 52% of subjects presenting with normal karyotype and in 50% of those with complex karyotypes. Median overall and disease-free survival durations were 55 and 46 weeks, respectively. Death within 30 days of initiation of treatment occurred in one subject (2%), death within 8 weeks in 15% of subjects. Given the DNA hypomethylating effect of decitabine, we examined the relationship of clinical response and pretreatment level of miR-29b, previously shown to target DNA methyltransferases. Higher levels of miR-29b were associated with clinical response (P = 0.02). In conclusion, this schedule of decitabine was highly active and well tolerated in this poor-risk cohort of older AML patients. Levels of miR-29b should be validated as a predictive factor for stratification of older AML patients to decitabine treatment.

Trial registration: ClinicalTrials.gov NCT00492401.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Response rates for all patients and for selected subsets. Percent response is noted by each bar graph. CR is noted in black, and additional patients with incomplete CR are noted in white. Shown are response rates for all patients, patients below or above the median age of 74 years, and selected cytogenetic subsets, respectively.

Fig. 2.

Survival results. (A) Overall survival and (B) disease-free survival. Vertical marks reflect last follow-up times for censored observations.

Fig. 3.

Cycle intensity and number of cycles administered for patients achieving CR. Numerated in the column on the left is each individual CR patient (n = 25). Each color-coded bar graph shows the number of treatment courses received. In blue are cycles of 10 d of decitabine therapy, in purple 5-d cycles, in yellow 4-d cycles, and in green 3-d cycles.

Fig. 4.

Difference in baseline miR-29b expression levels in decitabine between responders vs. nonresponders. Individual patient data are shown as the points in the figure, with the overlaid boxplots showing differences in the distribution of these data. In the boxplots, the thick middle line in the box represents the median baseline miR-29b expression value for that group; the top and bottom edges of the box itself represent the 75th and 25th percentiles, respectively; and the length of the box represents the interquartile range (difference between the 75th and 25th percentile as a measure of spread of the distribution). The P value is from a comparison of the continuous baseline miR-29b expression levels between responders and nonresponders using the nonparametric Wilcoxon rank-sum test.