The main objective of this project is to identify improved therapeutic options for patients with CML. Imatinib is standard therapy for CML, but nearly 20% of patients never achieve complete cytogenetic remission, and most have residual disease by polymerase chain reaction, 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. Patients 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 investigate 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-positive cells, the third aim is to investigate whether JAK2 inhibition may have clinical activity in CML patients 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 methylation is associated with progression in CML. We will thus treat patients with blast phase CML with decitabine, a hypomethylating agent, and dasatinib to determine whether this combination 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. Identifying new therapies to improve the outcome of all patients, 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 patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J)
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University of Texas MD Anderson Cancer Center
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Eiring, A M; Page, B D G; Kraft, I L et al. (2015) Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia 29:586-97
Zhang, Weiguo; Gao, Chen; Konopleva, Marina et al. (2014) Reversal of acquired drug resistance in FLT3-mutated acute myeloid leukemia cells via distinct drug combination strategies. Clin Cancer Res 20:2363-74
Tao, Wenjing; Leng, Xiaohong; Chakraborty, Sandip N et al. (2014) c-Abl activates janus kinase 2 in normal hematopoietic cells. J Biol Chem 289:21463-72
Thall, Peter F; Nguyen, Hoang Q; Zohar, Sarah et al. (2014) Optimizing Sedative Dose in Preterm Infants Undergoing Treatment for Respiratory Distress Syndrome. J Am Stat Assoc 109:931-943
Mak, P Y; Mak, D H; Mu, H et al. (2014) Apoptosis repressor with caspase recruitment domain is regulated by MAPK/PI3K and confers drug resistance and survival advantage to AML. Apoptosis 19:698-707
Jin, Ick Hoon; Liu, Suyu; Thall, Peter F et al. (2014) Using Data Augmentation to Facilitate Conduct of Phase I-II Clinical Trials with Delayed Outcomes. J Am Stat Assoc 109:525-536
Benjamini, Ohad; Kantarjian, Hagop; Rios, Mary Beth et al. (2014) Patient-driven discontinuation of tyrosine kinase inhibitors: single institution experience. Leuk Lymphoma 55:2879-86
Havelange, Violaine; Ranganathan, Parvathi; Geyer, Susan et al. (2014) Implications of the miR-10 family in chemotherapy response of NPM1-mutated AML. Blood 123:2412-5
Ohanian, Maro; Kantarjian, Hagop M; Quintas-Cardama, Alfonso et al. (2014) Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk 14:155-162.e1
Zabriskie, Matthew S; Eide, Christopher A; Tantravahi, Srinivas K et al. (2014) BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell 26:428-42

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