Daunorubicin-Induced Cell Kill with 1-Hour Versus 24-Hour Infusions: A Randomized Comparison in Children with Newly Diagnosed Acute Lymphoblastic Leukemia

Abstract

Daunorubicin (DNR) is one of the most important drugs in treatment of acute lymphoblastic leukemia (ALL). Prolonged infusions of anthracyclines are less cardiotoxic but it has not been investigated whether the in vivo leukemic cell kill is equivalent to short-term infusions. In the cooperative treatment study COALL-92 for childhood ALL 178 patients were randomized to receive in a therapeutic window a single dose of 36 mg/m (2) DNR either as a 1-h (85 patients) or 24-h infusion (93 patients). Daily measurements of white blood cell count (WBC) and peripheral blood smears for seven days could be evaluated centrally in 101 patients (1-h: 43 patients, 24-h: 58 patients). The proportional decline of blasts at day 7 after DNR infusion showed no statistically significant difference between the two treatment arms. At day 3 the median percentage of blasts was less than 10%, at day 7 less than 2% for either the 1-h or 24-h infusion. Twelve patients (1-h: 5 patients, 24-h: 7 patients) had an absolute number of more than 1000 blasts per mul peripheral blood (PB) at day 7 after DNR infusion (DNR poor responders). Kaplan-Meier analysis showed an equal probability of EFS for the short- and long-term infusion group (24-h: 83%+/-5; 1-h: 81+/-6) after a median observation time of 12.3 years. We conclude that in children with ALL a 24-h infusion of DNR has the same in vivo cytotoxicity for leukemic cells as a 1-h infusion. This offers the possibility to use prolonged infusions with hopefully less cardiotoxicity without loss of efficacy.