The optimal treatment of acute myeloid leukemia (AML) in children is not yet defined. Results of contemporary treatment regimens, including those that employ bone marrow transplantation, have shown that the long-term prognosis of children and adolescents with AML, while improving, remains poor. In studies conducted at the applicant's institution it has been shown that 2-chlorodeoxyadenosine (cladribine, 2-CDA) is effective as a single agent for inducing hematologic remissions in pediatric patients with AML. Although analysis of these studies is still in progress, the overall clinical result is that about 25% of previously untreated patients show complete hematologic remission after one course of treatment with 2-CDA alone, and about 50% after two courses. For the real potential of 2-CDA for the treatment of AML to be realized, however, it is essential that a combination of 2-CDA with another drug or drugs be discovered in which the combination has the maximum additive antileukemic effect while toxicity is held to an acceptable level. In the proposed research two combinations of 2-CDA with another therapeutic agent will be investigated. One is a study of the combination of 2-CDA with cytarabine (araC) in the therapy of previously untreated patients, and the other a Phase I study of the combination of 2-CDA with topotecan. The primary objectives of the former study are: 1) to evaluate the activity and toxicity of the combination of 2-CDA plus araC; and 2) to determine the influence of 2-CDA on cytarabine triphosphate levels. Preliminary clinical results of this study are encouraging. In regard to the second combination, studies in adults with topotecan alone suggest that this might be a suitable drug to pair with 2-CDA, and preclinical results using human myeloid cells in culture indicate additive cytotoxic effects of 2-CDA and topotecan when scheduling is appropriate. The initial clinical study with 2-CDA and topotecan will be a phase I investigation in relapsed pediatric AML patients for whom no other therapy is currently available, and the objectives will be: 1) to determine the maximum tolerated doses of 2-CDA and topotecan in combination; and 2) to determine the limiting hematologic and non-hematologic toxicity. When these objectives have been met, and particularly if clinical responses are observed, a phase II trial will be designed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA080735-01
Application #
2815961
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
1999-04-09
Project End
2001-03-31
Budget Start
1999-04-09
Budget End
2000-03-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105