V. Gandhi et al., Evaluation of the combination of nelarabine and fludarabine in leukemias: Clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells, J CL ONCOL, 19(8), 2001, pp. 2142-2152
Purpose: A pilot protocol was designed to evaluate the efficacy of fludarab
ine with nelarabine (the prodrug of arabinosylguanine [ara-G]) in patients
with hematologic malignancies. The cellular pharmacokinetics was investigat
ed to seek a relationship between response and accumulation of ara-G tripho
sphate (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 m
easurements 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 fludar
abine 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; ran
ge, 18 to > 48 hours). The ratio of ara-GTP ta its normal counterpart, deox
yguanosine 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 reg
imen against leukemias. Clinical responses suggest the need for further exp
loration of nelarabine against fludarabine-refractory diseases. Determinati
on of ara-GTP levels in the target tumor population may provide a prognosti
c test for the activity of nelarabine. (C) 2001 by American Society of Clin
ical Oncology.