LY335979, DAUNORUBICIN, CYTARABINE IN MYELOGENOUS LEUKEM

Indiana Univ-Purdue Univ At Indianapolis, Indianapolis IN

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Abstract

Acute myelogenous leukemia (AML) is a clonal disorder of hematopoiesis characterized by the progression of abnormal myeloblast with an impaired ability to differentiate and loss of normal polyclonal hematopoesis. Untreated, AML is a uniformly fatal disease due to the infectious or hemorrhagic complications of neutropenia and thrombocytopenia, respectively. The treatment of AML is divided into induction and post-remission phases. The goal of the induction phase is to eradicate morphologic evidence of the leukemia and to restore normal hematopoiesis, a complete remission (CR). The likelihood of achieving a CR decreases with increasing age at the time of diagnosis. The failure to achieve a CR is related in large part to two factors, death during the induction period and resistance of the leukemia to chemotherapy. Conventional induction chemotherapy for AML uses one or more courses of cytarabine (also known as: Cytosar-U, arabinosyl cytosine, ara-C, or cytosine arabinoside) and anthracycycline derivative. Converted to cytarabine triphosphate (Ara-CTP), it is a competitive inhibitor of deoxyribonucleic acid (DNA) polymerase. Cytarabine is incorporated into cellular DNA and ribonucleic acid (RNA), and is active against cells in S-phase and is considered phase specific. The dose of cytarabine is 100 or 200mg/m2 as a continuous intravenous infusion over 24 hours for 7 days. The traditional anthracycline is daunorubicin (also know as: daunomycin, rubidomycin, or cerubidine) administered at a dose of 30 to 60 mg/m2 as a brief intravenous infusion daily for 3 days. Randomized trials of modifications of conventional induction therapy such as an alternative anthracycline, the addition of etoposide, or the substitution of high dose cytarabine have not demonstrated consistent improvement in the rate of CR or the disease-free surivial. Thus, novel agents or strategies need to be developed if the outcome of individuals with AML is to be improved.