The main objective of this project is to identify improved therapeufic opfions for pafients with CML. Imafinib is standard therapy for CML, but neariy 20% of patients never achieve complete cytogenetic remission, and most have residual disease by polymerase chain reacfion, and 10-15% of those who achieve remission eventually progress. More potent tyrosine kinase inhibitors (TKI) such as dasatinib and nilotinib have significant clinical activity after imatinib failure.
The first aim i s to determine whether dasatinib or nilotinib may improve the molecular response, and event-free and progression-free survival of patients with newly diagnosed chronic phase CML. Pafients will be treated in one of two parallel studies with the primary objective to improve the molecular response rate at 12 months.
The second aim i s to invesfigate whether immunotherapy, in the form of PRI vaccine, can improve molecular responses of patients with minimal residual disease on imatinib therapy. Because Interferon may improve the expression of proteinase 3 from which PRI is derived, patients with this phenotype will be randomized to receive PRI and imatinib, with or without interferon. The primary objective is to improve the molecular response with PRI vaccine. Based on data originated through this grant suggesting activation of JAK2 in Bcr-Abl-posifive cells, the third aim is to invesfigate whether JAK2 inhibition may have clinical activity in CML pafients refractory to TKI. We will conduct a phase 2 trial of INCB18424, a JAK2 inhibitor, in patients who failed at least 2 TKI. The long-term plan is to use this agent in combination with TKI.
The fourth aim deals with the problem of patients with blast phase, a group with dismal outcome with available therapy. Dasatinib induces high response rates but most patients eventually relapse. Increased methylafion is associated with progression in CML. We will thus treat patients with blast phase CML with decitabine, a hypomethylating agent, and dasafinib to determine whether this combinafion may improve the rate and durability of responses in blast phase CML. Overall, this project may lead to improved long-term outcome for patients with all phases ofthe disease and get us closer to complete eradication of CML.

Public Health Relevance

Approximately 30% of patients with CML do not have a favorable outcome with imafinib and those who respond well usually have residual disease. The treatment of those who fail therapy with one or two drugs or with advanced stage remains ineffective. Idenfifying new therapies to improve the outcome of all pafients, and markers of efficacy of the treatment as proposed in this project, will help improve the success, with the final goal to safely discontinue therapy on patients after successful therapy, and reach a cure for all pafients

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA049639-20A2
Application #
8000049
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
20
Fiscal Year
2010
Total Cost
$1,390,873
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Boddu, Prajwal; Benton, Christopher B; Wang, Wei et al. (2018) Erythroleukemia-historical perspectives and recent advances in diagnosis and management. Blood Rev 32:96-105
Ruvolo, Peter P; Ruvolo, Vivian R; Burks, Jared K et al. (2018) Role of MSC-derived galectin 3 in the AML microenvironment. Biochim Biophys Acta Mol Cell Res 1865:959-969
Cortes, Jorge E; Gambacorti-Passerini, Carlo; Deininger, Michael W et al. (2018) Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial. J Clin Oncol 36:231-237
Sasaki, Koji; Kantarjian, Hagop; O'Brien, Susan et al. (2018) Prediction for sustained deep molecular response of BCR-ABL1 levels in patients with chronic myeloid leukemia in chronic phase. Cancer 124:1160-1168
Gambacorti-Passerini, Carlo; Cortes, Jorge E; Lipton, Jeff H et al. (2018) Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study. Haematologica 103:1298-1307
Boddu, Prajwal; Shah, Abdul Rashid; Borthakur, Gautam et al. (2018) Life after ponatinib failure: outcomes of chronic and accelerated phase CML patients who discontinued ponatinib in the salvage setting. Leuk Lymphoma 59:1312-1322
Kornblau, Steven M; Ruvolo, Peter P; Wang, Rui-Yu et al. (2018) Distinct protein signatures of acute myeloid leukemia bone marrow-derived stromal cells are prognostic for patient survival. Haematologica 103:810-821
Zhang, Weiguo; Ly, Charlie; Ishizawa, Jo et al. (2018) Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial. Haematologica 103:1642-1653
Alhuraiji, Ahmad; Kantarjian, Hagop; Boddu, Prajwal et al. (2018) Prognostic significance of additional chromosomal abnormalities at the time of diagnosis in patients with chronic myeloid leukemia treated with frontline tyrosine kinase inhibitors. Am J Hematol 93:84-90
Ishizawa, Jo; Nakamaru, Kenji; Seki, Takahiko et al. (2018) Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition. Cancer Res 78:2721-2731

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