Treatment of refractory acute myeloid leukemia with mAMSA and VP 16-213 in combination: Results of a clinical phase I/II study

Twenty patients with refractory AML were treated with mAMSA and VP 16–213 in combination to assess the toxicity and anti‐leukemic activity of the two‐drug regimen. Refractoriness was defined according to the response to induction therapy consisting of 6‐thioguanine, cytosine arabinoside and daunorubicin (TAD9) and the duration of the preceding remission. Patients were eligible for AMSA/VP 16–213 if they were primary non‐responders against two TAD9 induction courses, had early relapses within the first six months, were non‐responders to one additional TAD9 course at later relapses or were at second or subsequent relapses. Therapy consisted of a five‐day course of mAMSA 210 mg/m2/d on days 2, 3 and 4. VP 16–213 was applied on days 1 and 5 by a 1‐h infusion of 100 mg/m2 followed by a 23 h infusion, the dosage of which was escalated in three steps from 110 mg/m2 over 200 mg/m2 to 230 mg/m2 in subsequent patients. Even at the highest dose of VP 16–213, toxicity was mild to moderate except for mucositis of grade III after two cycles and severe intrahepatic cholestasis in one case. Four of the 20 patients died within the first three weeks after the onset of treatment and were not evaluable for the assessment of antileukemic efficacy. From the remaining 16 patients five achieved partial remissions while no complete remission was obtained. Four of the five PR occurred in the eight patients with primary TAD9 resistance. These data indicate that AMSA/VP 16–213 reveals a moderate toxicity only, and that the combination may not be completely cross‐resistant with TAD9. The overall anti‐leukemic activity is limited however, and seems inferior compared to other presently available salvage regimens in refractory AML.