TY - JOUR
T1 - Patient-specific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia
AU - Heinemann, V.
AU - Estey, E.
AU - Keating, M. J.
AU - Plunkett, W.
PY - 1989
Y1 - 1989
N2 - We hypothesized that the stead-state concentration of intracellular cytarabine 5'-triphosphate (ara-CTP(ss)) in leukemia cells is proportional to the dose rate of cytarabine (ara-C) during continuous infusion. To evaluate this possibility, patients with acute myelogenous leukemia in relapse were treated with two sequential schedules of serially increasing ara-C dose rates over a total of 36 hours. Schedule I consisted of serial infusions of 250, 500, and 750 mg/m2 each over 12 hours. Subsequently, patients entered on schedule II received 500, 1,000, and 1,500 mg/m2 serially, each over 12 hours. Steady-state levels of ara-CTP were achieved within four hours after beginning ara-C infusion and, in separate studies of a single ara-C dose rate, were shown to be maintained beyond 36 hours. Four patients treated with schedule I and two patients treated with schedule II showed a linear dose rate-dependent increase of ara-CTP(ss) at all three dose rates. The cells of one patient on schedule I and two patients on schedule II had a dose rate-dependent ara-CTP(ss) increase only over the first two dose levels, while no increase or lower ara-CTP(ss) was observed at the third dose rate. The ara-CTP(ss) of one patient on schedule II did not change. These results suggest that there is a proportionality between the continuous infusion dose rate of ara-C and the ara-CTP(ss) in circulating leukemia cells within the dose range of 250 to 1,000 mg/m2 over 12 hours. This opens the possibility that pharmacologic determinations may be used to redirect the ara-C dose rate to achieve a desired ara-CTP(ss) level in leukemia blasts during therapy.
AB - We hypothesized that the stead-state concentration of intracellular cytarabine 5'-triphosphate (ara-CTP(ss)) in leukemia cells is proportional to the dose rate of cytarabine (ara-C) during continuous infusion. To evaluate this possibility, patients with acute myelogenous leukemia in relapse were treated with two sequential schedules of serially increasing ara-C dose rates over a total of 36 hours. Schedule I consisted of serial infusions of 250, 500, and 750 mg/m2 each over 12 hours. Subsequently, patients entered on schedule II received 500, 1,000, and 1,500 mg/m2 serially, each over 12 hours. Steady-state levels of ara-CTP were achieved within four hours after beginning ara-C infusion and, in separate studies of a single ara-C dose rate, were shown to be maintained beyond 36 hours. Four patients treated with schedule I and two patients treated with schedule II showed a linear dose rate-dependent increase of ara-CTP(ss) at all three dose rates. The cells of one patient on schedule I and two patients on schedule II had a dose rate-dependent ara-CTP(ss) increase only over the first two dose levels, while no increase or lower ara-CTP(ss) was observed at the third dose rate. The ara-CTP(ss) of one patient on schedule II did not change. These results suggest that there is a proportionality between the continuous infusion dose rate of ara-C and the ara-CTP(ss) in circulating leukemia cells within the dose range of 250 to 1,000 mg/m2 over 12 hours. This opens the possibility that pharmacologic determinations may be used to redirect the ara-C dose rate to achieve a desired ara-CTP(ss) level in leukemia blasts during therapy.
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U2 - 10.1200/JCO.1989.7.5.622
DO - 10.1200/JCO.1989.7.5.622
M3 - Article
C2 - 2709090
AN - SCOPUS:0024594372
SN - 0732-183X
VL - 7
SP - 622
EP - 628
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 5
ER -