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.
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.
|Ghobadi, Armin; Choi, Jaebok; Fiala, Mark A et al. (2016) Phase I study of azacitidine following donor lymphocyte infusion for relapsed acute myeloid leukemia post allogeneic stem cell transplantation. Leuk Res 49:1-6|
|Al-Hussaini, Muneera; Rettig, Michael P; Ritchey, Julie K et al. (2016) Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 127:122-31|
|Welch, John S; Petti, Allegra A; Miller, Christopher A et al. (2016) TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 375:2023-2036|
|Rashidi, Armin; Ebadi, Maryam; Colditz, Graham A et al. (2016) Outcomes of Allogeneic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. Biol Blood Marrow Transplant 22:651-7|
|Fehniger, Todd A; Cooper, Megan A (2016) Harnessing NK Cell Memory for Cancer Immunotherapy. Trends Immunol 37:877-888|
|Wong, Terrence N; Miller, Christopher A; Klco, Jeffery M et al. (2016) Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 127:893-7|
|Rashidi, Armin; Walter, Roland B; Tallman, Martin S et al. (2016) Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials. Blood 128:763-73|
|Shirai, Cara Lunn; Ley, James N; White, Brian S et al. (2015) Mutant U2AF1 Expression Alters Hematopoiesis and Pre-mRNA Splicing In Vivo. Cancer Cell 27:631-43|
|Wong, Terrence N; Ramsingh, Giridharan; Young, Andrew L et al. (2015) Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 518:552-5|
|Uy, Geoffrey L; Hsu, Yen-Michael S; Schmidt, Amy P et al. (2015) Targeting bone marrow lymphoid niches in acute lymphoblastic leukemia. Leuk Res 39:1437-42|
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