FLUDARABINE INFUSION POTENTIATES ARABINOSYLCYTOSINE METABOLISM IN LYMPHOCYTES OF PATIENTS WITH CHRONIC LYMPHOCYTIC-LEUKEMIA

Our previous work has shown that incubation of K562 cells or lymphocytes from patients with advanced chronic lymphocytic leukemia (CLL) with arabinosyl-2-fluoroadenine (F-ara-A) potentiates the rate of arabinosylcytosine 5'-triphosphate (ara-CTP) synthesis during subsequent treatment with arabinosylcytosine (ara-C). To test the biochemical modulation of ara-CTP in a clinical setting, we designed a protocol to administer fludarabine (Fludara, F-ara-AMP) and ara-C in a pharmacologically directed sequence for patients with CLL refractory to conventional fludarabine therapy. ara-C was infused in seven patients with progressive CLL at a dose rate that maximizes ara-CTP accumulation (0.5 g/m2 during 2 h). Fludarabine (30 mg/m2 during 30 min) was infused 20 h later, followed by a second, identical dose of ara-C at 24 h, when the concentration of F-ara-A 5'-triphosphate (F-ara-ATP) was maximal in CLL cells. Comparison of ara-CTP pharmacokinetics in circulating CLL cells demonstrated that the ara-CFP area under the curve increased by a median of 1.5-fold (range, 1.1- to 1.7-fold) after fludarabine infusion. Plasma pharmacokinetics indicated that neither the median steady-state ara-C concentrations nor the levels of its deamination product arabinosyluracil were significantly affected by fludarabine infusion. The median rate of ara-CTP elimination was slightly faster after fludarabine treatment (t1/2, 6.7 versus 5.8 h), suggesting that catabolism of ara-CTP was not responsible for the increased ara-CTP area under the curve. The rate of ara-CTP accumulation by CLL cells after fludarabine infusion, however, was increased by a median of 1.3-fold in seven of the eight patients (range, 1.2- to 1.8-fold); the peak occurred within 1 h of the end of the infusion. In vitro incubation of leukemic lymphocytes with F-ara-A before ara-C also showed a median 1.3-fold increase in the rate of ara-CTP accumulation. Thus, infusion of fludarabine before ara-C augments ara-CTP metabolism in leukemic lymphocytes. This knowledge should be considered in the design of combination chemotherapy.