Clinical Responses and Mutation Clearance After Decitabine in Patients with AML and MDS

Molecular determinants of clinical responses to decitabine therapy

In a single-institution trial, patients with acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) who had cytogenetic abnormalities associated with unfavourable risk, TP53 mutations, or both achieved favourable clinical responses and robust, but incomplete, mutation clearance after treatment with decitabine. However, the responses were not durable, but they resulted in overall survival (OS) rate similar to the rate among patients with AML who had an intermediate-risk cytogenetic profile and who also received decitabine therapy. The findings are reported in The New England Journal of Medicine.

In background of the study, the authors wrote that the molecular determinants of clinical responses to decitabine in patients with AML and MDS are unclear. Therefore, they enrolled 84 adult patients to identify somatic mutations and their relationships to clinical responses to decitabine.

Decitabine was administered at a dose of 20 mg/m2 of body-surface area per day for 10 consecutive days in monthly cycles.

The study investigators performed enhanced exome or gene-panel sequencing in 67 of the patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients.

An extension cohort included 32 additional patients who received decitabine in different protocols.

Among 116 patients, 53 (46%) had bone marrow blast clearance (less than 5% blasts). Response rates were higher among patients with an unfavourable-risk cytogenetic profile than among patients with an intermediate-risk or favourable-risk cytogenetic profile (67% vs. 34%, p < 0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (100% vs. 41%, p < 0.001).

Previous studies have consistently shown that patients with an unfavourable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study neither of these risk factors was associated with a lower rate of OS than the rate of survival among study patients with intermediate-risk cytogenetic profiles. Although patients with AML and MDS who have TP53 mutations have very low response rates after standard cytotoxic therapy, all patients with a TP53 mutation had a response to serial 10-day courses of decitabine.

The authors concluded that the use of decitabine may be an important way to induce clinical remissions in patients with AML who have TP53 mutations and whose disease is resistant to induction therapy with standard cytotoxic chemotherapy. Such therapy may also provide a bridge to allogeneic stem-cell transplantation for some patients.

The study was supported by grants from the Specialized Program of Research Excellence in AML of the US National Cancer Institute and the Genomics of AML Program Project. Three patients received treatment in the trial supported by Novartis. 


Welch JS, Petti AA, Miller CA, et al. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 2016; 375:2023-2036.