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)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
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
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

Showing the most recent 10 out of 375 publications