Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic cells, characterized by the proliferation of abnormal blast cells and impaired hematopoiesis. While younger patients with favorable cytogenetics have increasingly favorable outcomes with dose intensive chemotherapy, they represent a distinct minority of patients with this disease. Patients with unfavorable cytogenetics, advanced age (>=60), and antecedent hematologic disorders have a decreased incidence of complete remission; even in those who achieve an initial remission, the majority relapse and survival is poor. Clearly this is a patient population for whom novel therapies are needed. Studies from our laboratory have demonstrated that the combination of the proteasome inhibitor, bortezomib, with the anthracycline, idarubicin, at concentrations readily achievable in vivo can rapidly induce apoptosis in primary human AML cells in vitro. Studies from our laboratory have demonstrated that apoptosis induced in this fashion correlates with several specific changes in primary AML cells. Following treatment with bortezomib and idarubicin strong inhibition of NF-kappaB is rapidly observed, indicating inhibition of important survival signals. In addition, levels of p53 protein are strongly increased in treated AML cells, suggesting p53 mediated changes in gene expression might be involved in the apoptosis induced by this combination. Based on our observations we propose a phase I and II clinical trial with the novel agent, bortezomib, and idarubicin given to newly diagnosed, elderly or relapsed AML patients. Monitoring for in vivo induction of apoptosis, as well as, important correlative studies assaying for inhibition of NF-kappaB and increased p53 expression are proposed. We anticipate that with this novel treatment regimen we will observe potent anti-leukemic activity and complete clinical remissions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA108162-01A1
Application #
6887118
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Wu, Roy S
Project Start
2004-09-20
Project End
2006-08-31
Budget Start
2004-09-20
Budget End
2005-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$257,563
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Howard, Dianna S; Liesveld, Jane; Phillips 2nd, Gordon L et al. (2013) A phase I study using bortezomib with weekly idarubicin for treatment of elderly patients with acute myeloid leukemia. Leuk Res 37:1502-8