Abstract
Patients with refractory or relapsed acute myeloid leukemia (AML) are often treated with regimens containing high-dose cytosine arabinoside (ARA-C), resulting in complete response rates of approximately 30% to 50%, with a median remission duration of approximately 4 months [1]. Likewise, patients with the myeloid blast crisis of chronic myeloid leukemia (CML) are often treated with high dose ARA-C, with re-establishment of a short-lived stable phase in only about 20% of cases [2]. An important reason for treatment failure in these high-risk patients is likely to be pharmacologic resistance to ARA-C, which may be due to multiple mechanisms including decreased intracellular levels of deoxycytidine kinase and decreased intracellular uptake of ARA-C. Since ARA-C is a cell-cycle-specific drug, another potential mechanism of resistance may be related to the observation that a large fraction of leukemic clonogenic cells is not in S phase at the time of ARA-C exposure [3]. We have attempted to overcome kinetic resistance to ARA-C in vitro by recruiting leukemic cells into S phase through the use of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), a humoral factor which supports the in vitro proliferation of clonogenic cells from the majority of patients with AML [4]. We have previously shown in tissue culture that this agent is able to effectively increase the fraction of leukemic clonogenic cells in S phase, and that this effect is associated with a significant increase in ARA-C-mediated cytotoxicity [5]. Since rhGM-CSF is biologically active and well-tolerated when administered to patients with normal bone marrow function [6–8], we chose to study the in vivo kinetic and therapeutic effects of combined rhGM-CSF and high dose ARA-C treatment in a population of high risk patients with myeloid leukemia. We now report the results of this treatment strategy in six patients with relapsed or refractory AML, and in two patients with the myeloid blast crisis of CML.
Supported in part by Public Health Service Grants No CA 36167, CA 42802, and CA 34183, Biomedical Research Support Grant No SO7RR05526-26, and by the U.S. Cancer Research Council.
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Cannistra, S.A. et al. (1992). Simultaneous Administration of Granulocyte-Macrophage Colony-Stimulating Factor and Cytosine Arabinoside for the Treatment of High-Risk Myeloid Leukemia. In: Hiddemann, W., Büchner, T., Wörmann, B., Plunkett, W., Keating, M., Andreeff, M. (eds) Acute Leukemias. Haematology and Blood Transfusion / Hämatologie und Bluttransfusion, vol 34. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-76591-9_18
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DOI: https://doi.org/10.1007/978-3-642-76591-9_18
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