The long-term goal of this project is to identify the patients with acute myeloid leukemia (AML) who are the most likely to respond to decitabine therapy, and to determine the molecular mechanisms of decitabine responses. We recently reported that TP53 mutated AML and MDS patients, which have a high risk of relapse, and very poor outcomes, respond consistently to decitabine, a hypomethylating agent that can be given as an outpatient, and which is well tolerated in most patients. However, most responding patients did not have TP53 mutations, suggesting that other pathways can also influence decitabine sensitivity. The molecular mechanisms associated with decitabine responses and subsequent relapse are currently unclear. To refine and extend these findings, we propose the following specific aims:
Aim 1. We will determine the efficacy of decitabine salvage therapy in AML patients with TP53 mutations. Patients with relapsed/refractory AML and with TP53 mutations represent an ultra-high-risk population with extremely poor outcomes, representing an unmet therapeutic need. We will therefore treat 60 relapsed/refractory AML patients known to have TP53 mutations with decitabine on days 1-10 of 28-day cycles at 3 centers (Washington University, Fred Hutchinson Cancer Research Center, and the University of Iowa). Responding patients will undergo allogeneic transplantation for consolidation therapy, if possible. We will determine the overall survival at 1 year, as well as response rates, time to transplant, time to leukemia relapse, and the average number of hospital days during cycles 1 and 2.
Aim 2. We will define the genomic and epigenomic signatures associated with decitabine responses. We will use enhanced whole genome sequencing to determine whether TP53 wild-type patients have recurrent, non-genic mutations, and whether recurrent mutations are acquired at relapse, regardless of TP53 status. We will integrate whole genome bisulfite sequencing with RNA-Seq to determine whether decitabine causes specific and canonical patterns of DNA hypomethylation, whether these changes result in consistent transcriptional signatures, and whether any of these patterns correlate with clinical outcomes.
Patients with TP53 mutated, relapsed/refractory AML have two adverse risk prognostic markers and respond poorly to standard cytotoxic chemotherapy, but may respond consistently to decitabine. We will determine whether decitabine can salvage this ultra-high-risk group of patients, and whether this improves the 1-year survival rate. By integrating whole genome bisulfite sequencing and RNA-Seq with clinical outcomes, we will determine the molecular consequences of decitabine, and define molecular features that correlate with morphologic responses and outcomes.
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