TY - JOUR
T1 - Evaluation of the combination of nelarabine and fludarabine in leukemias
T2 - Clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells
AU - Gandhi, V.
AU - Plunkett, W.
AU - Weller, S.
AU - Du, M.
AU - Ayres, M.
AU - Rodriguez, Jr
AU - Ramakrishna, P.
AU - Rosner, G. L.
AU - Hodge, J. P.
AU - O'Brien, S.
AU - Keating, M. J.
PY - 2001/4/15
Y1 - 2001/4/15
N2 - Purpose: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the pro-drug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. Patients and Methods: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m2) was infused on days 1,3, and 5. On days 3 and 5, fludarabine (30 mg/m2) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days. Results: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P = .001) in responders (890 μmol/L, n = 6) and nonresponders (30 μmol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27). Conclusion: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.
AB - Purpose: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the pro-drug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. Patients and Methods: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m2) was infused on days 1,3, and 5. On days 3 and 5, fludarabine (30 mg/m2) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days. Results: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P = .001) in responders (890 μmol/L, n = 6) and nonresponders (30 μmol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27). Conclusion: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.
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U2 - 10.1200/JCO.2001.19.8.2142
DO - 10.1200/JCO.2001.19.8.2142
M3 - Article
C2 - 11304766
AN - SCOPUS:0035871440
SN - 0732-183X
VL - 19
SP - 2142
EP - 2152
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 8
ER -