Use of high intensity, AML-type chemotherapy (HI) in patients age > 60 with untreated high-risk MDS (International Prognostic Scoring System categories intermediate-2 or high) has yet to improve survival relative to supportive care, consequent to both a 35% rate of treatment -related mortality (TRM) and a 60% rate of """"""""resistance"""""""" to therapy. New HI {e.g. clofarabine + ara-C) may decrease resistance, thereby increasing survival in older patients. Another approach emphasizes use of lower intensity, """"""""targeted"""""""", therapies (LI) in such patients. As single agents, LIs likely produce lower short-term TRM rates than HI, but, to date, have also produced lower CR rates. This is noteworthy because, at least with HI, only patients who achieve CR achieve a potential long-term survival advantage. Thus, it is unclear whether untreated older patients with high-risk MDS should receive HI first followed at failure by LI (the two:course strategy HI, LI), or, alternatively, receive HI only after failing LI (the two-course strategy LI, HI). Our first specific aim is to compare these strategies in such patients. We will employ our recently published statistical design thai not only permits comparison of the individual treatments (Hl= clofarabine + ara-C, L11 = PKC412, LI 2= R115777, LI 3= decitabine), used either as initial or as salvage therapy, but also allows selection of the best strategy, L11, LI 2, or LI 3, followed at failure by HI, or HI followed at failure by L11, LI 2, or LI 3. Selection is based on probabilities of both response and death allowing for """"""""trade-offs"""""""" between these outcomes such that that several potential rates of response, on the one hand, and death, on the other, are considered equal. To aid in evaluation of LIs in MDS, an NCI Working Group has recently published criteria for response. These include several categories of """"""""minor response""""""""(MR, less than CR). With HI, we have demonstrated that CR prolongs survival to a much greater extent than MR. Therefore; the second specific aim of the Project is to evaluate the significance of Ll-induced MR, for both survival and """"""""quality of life"""""""". The """"""""results"""""""" of any therapy are an average of results from different patients, some of whom the therapy may have helped or harmed more than a hypothetical"""""""" average"""""""" patient. Our previous attempts at identifying such subgroups have used statistical models to assess interactions between treatment and clinical prognostic factors, e.g. cytogenetics. In contrast, the LIs used here are directed at targets that are quantifiable in the laboratory. Thus our third specific aim is to identify patient subgroups responsive to a particular LI by testing for correlations between clinical outcome and the pre-treatment status of the target or the Li's ability to modulate the target. This will be done in collaboration with Projects 2-4 and Cores A-C.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA108631-04
Application #
7726940
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$148,615
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Tothova, Zuzana; Krill-Burger, John M; Popova, Katerina D et al. (2017) Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia. Cell Stem Cell 21:547-555.e8
Ajore, Ram; Raiser, David; McConkey, Marie et al. (2017) Deletion of ribosomal protein genes is a common vulnerability in human cancer, especially in concert with TP53 mutations. EMBO Mol Med 9:498-507
Krönke, Jan; Fink, Emma C; Hollenbach, Paul W et al. (2015) Lenalidomide induces ubiquitination and degradation of CK1? in del(5q) MDS. Nature 523:183-188
Malouf, Gabriel G; Zhang, Jianping; Yuan, Ying et al. (2015) Characterization of long non-coding RNA transcriptome in clear-cell renal cell carcinoma by next-generation deep sequencing. Mol Oncol 9:32-43
Yamazaki, Jumpei; Jelinek, Jaroslav; Lu, Yue et al. (2015) TET2 Mutations Affect Non-CpG Island DNA Methylation at Enhancers and Transcription Factor-Binding Sites in Chronic Myelomonocytic Leukemia. Cancer Res 75:2833-43
Fink, Emma C; Ebert, Benjamin L (2015) The novel mechanism of lenalidomide activity. Blood 126:2366-9
Lindsley, R Coleman; Mar, Brenton G; Mazzola, Emanuele et al. (2015) Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 125:1367-76
Guirguis, Andrew A; Ebert, Benjamin L (2015) Lenalidomide: deciphering mechanisms of action in myeloma, myelodysplastic syndrome and beyond. Curr Opin Cell Biol 37:61-7
Maegawa, Shinji; Gough, Sheryl M; Watanabe-Okochi, Naoko et al. (2014) Age-related epigenetic drift in the pathogenesis of MDS and AML. Genome Res 24:580-91
Raiser, David M; Narla, Anupama; Ebert, Benjamin L (2014) The emerging importance of ribosomal dysfunction in the pathogenesis of hematologic disorders. Leuk Lymphoma 55:491-500

Showing the most recent 10 out of 77 publications