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.
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.
|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|
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|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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