Modulation of AraC by Fludarabine: Results of Salvage Therapy by AMLCG

Fludarabine was shown to increase the intracellular formation of AraCTP during treatment with AraC both in vitro and in vivo and had significant activity in patients with advanced acute myeloid leukemia (AML) when used in combination with AraC in phase II studies. However, the efficacy of fludarabin as chemo-modulatior of the AraC metabolism has not yet been assessed in phase III studies. Based on the S-HAI salvage regimen comprizing high-dose AraC q 12 hours on days 1,2,8, and 9 and idarubicin on days 3,4,10, and 11, the German AML Cooperative Group initiated a prospective randomized comparison between fludarabine q 12 hours on days 1, 2, 8, and 9 in addition to S-HAI as compared with S-HAI alone. Of 91 patients having entered the ongoing study 66 are fully evaluable at the present time (median age 54 years, range 20-75). Twenty-five patients had refractory disease or early relapses, 39 patients had relapses after a preceding CR of more than six months duration and one patient had a second relapse. Thirty patients achieved a remission (CR, 45%; PR, 3%) while the non-response rate was 32% and 20% suffered from early death. The application of fludarabine resulted in a longer duration of neutropenia (38 versus 32 days). Severe non-hematologic toxicity (WHO III/IV°) consisted mainly of nausea/vomiting (26% versus 13%), diarrhea (23% versus 10%), mucositis (14% versus 19%), and bleeding (11% versus 0%) and infectious complications included pneumonia (57% versus 39%), FUO (60% versus 45%), and bacteremia (49% versus 16%). The sequential test has not yet decided for either superiority of fludarabine or equality of both study arms.