The long term goal of this project is to identify the patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) who are the most likely to respond to decitabine therapy. Decitabine is a hypomethylating agent that has efficacy in both MDS and AML. It can be given as an outpatient, and it is well tolerated in most patients. However, response rates are modest;even with modern aggressive schedules, only 4 5 % of patients achieve a complete response. The molecular basis of decitabine sensitivity and/or resistance is not yet clear.
Specific Aims :
Aim1. Wewilldefinethemolecularsignatureofdecitabineresponders.Wewillprospectivelybank125 properly consented patients treated with the current state-of-the-art decitabine protocol. We will comprehensively define patient-specific molecular signatures through exome sequencing and expression profiling, using both mRNA and miRNA based arrays. We will correlate genotyping and expression results with clinical features, including responsiveness to decitabine therapy. These studies will correlate genomic signatures of DNMT3A, I D H I , IDH2, and TET2 with outcomes. In addition, comprehensive, unbiased analysis will determine whether specific molecular signatures are associated with decitabine responses.
Aim 2. We will determine whether the rate of AML clearance and persistence of AML-associated subclones corresponds tddrug metabolism, molecular, and/or clinical features of AML in each case. We will assess the velocity of patient-specific mutation clearance on day 0, 10, and 28, and the persistence of AML-associated subclones despite blast clearance. W e will correlate this with steiady-state decitabine drug levels, the reduction of methylcytosine in the total marrow sample (a biomarker of effective dosing), and with clinical response rates and event-free survival.

Public Health Relevance

Many patients do not respond to decitabine therapy for AML or MDS. The causes of sensitivity and resistance are unknown. In this study we will optimize a pipeline for comprehensive molecular characterization of patient-specific mutations, expression profiles, and pharmacologic outcomes. We will determine whether molecular signatures predict response or resistance to decitabine.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Saint Louis
United States
Zip Code
White, Brian S; DiPersio, John F (2014) Genomic tools in acute myeloid leukemia: From the bench to the bedside. Cancer 120:1134-44
Mesa, Ruben A; Kiladjian, Jean-Jacques; Verstovsek, Srdan et al. (2014) Comparison of placebo and best available therapy for the treatment of myelofibrosis in the phase 3 COMFORT studies. Haematologica 99:292-8
Hopman, Rusudan K; DiPersio, John F (2014) Advances in stem cell mobilization. Blood Rev 28:31-40
Welch, John S (2014) Mutation position within evolutionary subclonal architecture in AML. Semin Hematol 51:273-81
Ramsingh, Giridharan; Westervelt, Peter; McBride, Ali et al. (2014) Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. Int J Hematol 99:272-8
Giralt, Sergio; Costa, Luciano; Schriber, Jeffrey et al. (2014) Optimizing Autologous Stem Cell Mobilization Strategies to Improve Patient Outcomes: Consensus Guidelines and Recommendations. Biol Blood Marrow Transplant 20:295-308
Anthony, Bryan A; Link, Daniel C (2014) Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol 35:32-7
Welch, John S; Niu, Haixia; Uy, Geoffrey L et al. (2014) A phase I dose escalation study of oral bexarotene in combination with intravenous decitabine in patients with AML. Am J Hematol 89:E103-8
Calvi, Laura M; Link, Daniel C (2014) Cellular complexity of the bone marrow hematopoietic stem cell niche. Calcif Tissue Int 94:112-24
Jacoby, Meagan A; Martin, Michael G; Uy, Geoffrey L et al. (2014) Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia. Am J Hematol 89:487-92

Showing the most recent 10 out of 12 publications