Evaluation of the combination of nelarabine and fludarabine in leukemias: Clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells

Purpose: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the prodrug 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 foiled prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one herd chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m(2)) was infused on days 1, 3, and 5. On days 3 and 5, fludarabine (30 mg/m(2)) 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 mu mol/L, n = 6) and nonresponders (30 mu mol/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 wets slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP ta 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. (C) 2001 by American Society of Clinical Oncology.