FLUDARABINE AND ARABINOSYLCYTOSINE THERAPY OF REFRACTORY AND RELAPSEDACUTE MYELOGENOUS LEUKEMIA

There is a strong association between ability of leukemia blasts to ac cumulate ara-CTP, the active metabolite of ara-C, and response to ara- C in patients with relapsed or refractory AML. Ara-C dose rates in exc ess of 0.5 g/m2/h do not produce further ara-CTP formation. In contras t, when given 4 h prior to ara-C at this dose rate, fludarabine, at do ses that are free of neurotoxicity in CLL, enhances ara-CTP accumulati on. This led us to administer fludarabine and ara-C to 59 patients wit h AML in relapse or unresponsive to initial therapy. Fludarabine was g iven at 30 mg/m2 once daily for 5 doses and ara-C at 0.5 g/m2/h for 2- 6 h daily for 6 doses. Doses of fludarabine preceded those of ara-C by 4 h. Results with fludarabine and ara-C (FA) were compared with those of patients treated at M.D. Anderson with high-dose ara-C (HDAC) or i ntermediate-dose ara-C (IDAC). The complete remission rate with FA was 21/59 (36%) and the actuarial median CR duration 39 weeks. FA produce d significantly higher remission rates than HDAC or IDAC in patients w ith initial remissions > 1 yr (14/20 vs 9/23 vs 6/18, p < 0.05). Respo nse rates were similar for all three treatments in patients with initi al remissions < 1 yr or with primary refractory disease. The regimen w as well tolerated; one patient developed peripheral neuropathy. This l ow level of toxicity encourages combination with other antileukemia ag ents.