Increased BCR promoter DNA methylation status strongly correlates with favorable response to imatinib in chronic myeloid leukemia patients

Abstract

To define the correlation between BCR promoter DNA methylation and response to imatinib in chronic myeloid leukemia (CML), we investigated BCR promoter DNA methylation in three groups of subjects. The first group included chronic phase patients enrolled in an imatinib dose escalation trial. In the trial, patients who failed to achieve optimal response with 400 mg/day (suboptimal responders) received an escalated imatinib dose. The level of BCR promoter DNA methylation was quantitated at baseline six months after dose escalation. The second group included patients who achieved complete cytogenetic remission after receiving 400mg/day of imatinib (optimal responders), and the third group were the healthy controls. In the suboptimal responders, an increased BCR promoter DNA methylation at six months compared with the baseline was related to a rapid reduction in the BCR-ABL/ABL transcript level following dose escalation (p=0.001) and a longer time to treatment failure (TTFx) of the dose-escalated imatinib (p=0.008). When multivariate analysis was performed with regard to the baseline BCR-ABL transcript level, baseline BCR promoter DNA methylation, and a change in the BCR promoter DNA methylation following dose escalation, the increase in the BCR promoter DNA methylation following dose escalation was an independent predictive factor for TTFx of dose-escalated imatinib (hazard ratio, 0.294; p=0.015). The baseline BCR promoter DNA methylation level in the suboptimal responders was lower than that in BCR promoter DNA methylation in the optimal responders (p=0.001) and healthy controls (p<0.001). In both the optimal and suboptimal responders, BCR promoter DNA methylation had an inverse correlation with the duration of the 400 mg/day imatinib use. In conclusion, increased BCR promoter DNA methylation strongly correlates with a more favorable imatinib response in CML patients.