Project 2. Advancing Stem Cell Transplantation for CML- Chemosensitization and Enhancing Graft-vs.-Leukemia Effects, Richard Champlin, M.D., Project Leader Allogeneic stem cell transplantafion is a potentially curative treatment for CML, and remains the only effective treatment for pafients resistant to tyrosine kinase inhibitors. This project advances therapeutic concepts and preclinical studies from the projects into human clinical trials involving stem cell transplantafion. The goal of this project is to improve the safety and effectiveness of reduced intensity preparafive regimens and cellular therapy involving NK cells or antigen specific T-cells, post transplant therapy with hypomethylating agents (collaboration with project 6), and chemosensitization of the leukemia by interference with supportive interactions with the bone marrow microenvironment (collaborafion with Project 3). The primary goal is to enhance the rate of molecular complete remission induced by nonmyeloablative stem cell transplantation which is a prerequisite for cure ofthe disease.
The Specific Aims are the following: 1. Test the hypothesis that addition of haploidentical alloreactive NK cells to the busulfan fludarabine nonmyeloablative preparative regimen will increase the rate of molecular complete remission. Correlative studies will examine KIR:KIR ligand expression and NK cell cytotoxicity against CML cells in vitro. 2. Test the hypothesis that post transplant hypomethylating therapy with 5-azacitidine can increase the rate of molecular complete remission in patients with CML in collaboration with Dr. Issa in project 6. Correlative studies include pharmacodynamic studies of hypomethylation and effects on immune reconstitution. 3. Test the hypothesis that PRI speciflc cytotoxic T-cells can induce molecular complete remission in pafients with CML and residual or recurrent disease post transplant. Correlafive studies will examine anfileukemic immune response and persistence ofthe transferred cells. 4. Test the hypothesis that interference with CXCR4-SDF-1 interacfions using systemic G-CSF and plerixafor treatment will enhance antileukemia effects of busulfan-fludarabine and stem cell transplantafion, in collaboration with Drs. Andreeff and Konopleva in Project 3. Correlative studies will examine the biologic effects on leukemia cells.

Public Health Relevance

Despite treatment with tyrosine kinase inhibitors, most patients have detectable disease and overt resistance may develop. Allogeneic stem cell transplant Is a potenfially curafive option. This project evaluates innovative strategies to Increase the efficacy and reduce the risks of non-myeloablative allogeneic stem cell transplantafion.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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University of Texas MD Anderson Cancer Center
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Qazilbash, M H; Wieder, E; Thall, P F et al. (2016) PR1 peptide vaccine induces specific immunity with clinical responses in myeloid malignancies. Leukemia :
Jain, Preetesh; Kantarjian, Hagop; Sasaki, Koji et al. (2016) Analysis of 2013 European LeukaemiaNet (ELN) responses in chronic phase CML across four frontline TKI modalities and impact on clinical outcomes. Br J Haematol 173:114-26
Tripathi, Satyendra C; Peters, Haley L; Taguchi, Ayumu et al. (2016) Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc Natl Acad Sci U S A 113:E1555-64
Andreeff, Michael; Kelly, Kevin R; Yee, Karen et al. (2016) Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. Clin Cancer Res 22:868-76
Jain, Preetesh; Kantarjian, Hagop; Patel, Keyur P et al. (2016) Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors. Blood 127:1269-75
Chen, Z; Cortes, J E; Jorgensen, J L et al. (2016) Differential impact of additional chromosomal abnormalities in myeloid vs lymphoid blast phase of chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Leukemia 30:1606-9
Hoehn, Daniela; Cortes, Jorge E; Medeiros, L Jeffrey et al. (2016) Multiparameter Analysis of Off-Target Effects of Dasatinib on Bone Homeostasis in Patients With Newly Diagnosed Chronic Myelogenous Leukemia. Clin Lymphoma Myeloma Leuk 16 Suppl:S86-92
Lee, Dean A; Denman, Cecele J; Rondon, Gabriela et al. (2016) Haploidentical Natural Killer Cells Infused before Allogeneic Stem Cell Transplantation for Myeloid Malignancies: A Phase I Trial. Biol Blood Marrow Transplant 22:1290-8
Cortes, Jorge E; Lipton, Jeffrey H; Miller, Carole B et al. (2016) Evaluating the Impact of a Switch to Nilotinib on Imatinib-Related Chronic Low-Grade Adverse Events in Patients With CML-CP: The ENRICH Study. Clin Lymphoma Myeloma Leuk 16:286-96
Khorashad, J S; Tantravahi, S K; Yan, D et al. (2016) Rapid conversion of chronic myeloid leukemia to chronic myelomonocytic leukemia in a patient on imatinib therapy. Leukemia 30:2275-2279

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