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 #
5P01CA049639-22
Application #
8380187
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
1997-02-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
22
Fiscal Year
2012
Total Cost
$1,367,891
Indirect Cost
$1,189,691
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Kanagal-Shamanna, Rashmi; Jain, Preetesh; Takahashi, Koichi et al. (2017) TP53 mutation does not confer a poor outcome in adult patients with acute lymphoblastic leukemia who are treated with frontline hyper-CVAD-based regimens. Cancer 123:3717-3724
Jain, Preetesh; Burger, Jan A; Khoury, Joseph D (2017) CLL progression after one cycle of FCR: Richter's transformation versus EBV-associated lympho-proliferation. Am J Hematol 92:1113-1114
Zhou, H; Mak, P Y; Mu, H et al. (2017) Combined inhibition of ?-catenin and Bcr-Abl synergistically targets tyrosine kinase inhibitor-resistant blast crisis chronic myeloid leukemia blasts and progenitors in vitro and in vivo. Leukemia 31:2065-2074
Peters, Haley L; Tripathi, Satyendra C; Kerros, Celine et al. (2017) Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells. Cancer Immunol Res 5:319-329
Andersson, B S; Thall, P F; Valdez, B C et al. (2017) Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transplant 52:580-587
Issa, Ghayas C; Kantarjian, Hagop M; Gonzalez, Graciela Nogueras et al. (2017) Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment. Blood 130:2084-2091
Jain, Preetesh; Kantarjian, Hagop M; Ghorab, Ahmad et al. (2017) Prognostic factors and survival outcomes in patients with chronic myeloid leukemia in blast phase in the tyrosine kinase inhibitor era: Cohort study of 477 patients. Cancer 123:4391-4402
Raynal, Noël J-M; Da Costa, Elodie M; Lee, Justin T et al. (2017) Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome. Mol Cancer Ther 16:397-407
Ciurea, Stefan O; Schafer, Jolie R; Bassett, Roland et al. (2017) Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 130:1857-1868
Jain, Preetesh; Kantarjian, Hagop; Jain, Nitin et al. (2017) Clinical characteristics and outcomes of previously untreated patients with adult onset T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma with hyper-CVAD based regimens. Am J Hematol 92:E595-E597

Showing the most recent 10 out of 360 publications