Treatment of Newly Diagnosed AML
The anthracycline that has been most used in induction regimens for children with AML is daunorubicin,[3,6,7] though idarubicin and the anthracenedione mitoxantrone have also been used.[9,10] Randomized trials have attempted to determine whether any other anthracycline or anthracenedione is superior to daunorubicin as a component of induction therapy for children with AML. The German Berlin-Frankfurt-Munster (BFM) Group AML-BFM 93 study evaluated cytarabine plus etoposide with either daunorubicin or idarubicin (ADE or AIE) and observed similar EFS and OS for both induction treatments.[7,9] The MRC-LEUK-AML12 clinical trial studied induction with cytarabine, mitoxantrone, and etoposide (MAE) in children and adults with AML compared to a similar regimen using daunorubicin (ADE).[10,11] For all patients, MAE showed a reduction in relapse risk, but the increased rate of treatment-related mortality observed for patients receiving MAE led to no significant difference in disease-free survival or OS in comparison to ADE. Similar results were noted when analyses were restricted to pediatric patients. In the absence of convincing data that another anthracycline or mitoxantrone produces superior outcome to daunorubicin when given at an equitoxic dose, daunorubicin remains the anthracycline most commonly used during induction therapy for children with AML in the United States.
The intensity of induction therapy influences the overall outcome of therapy. The CCG-2891 study demonstrated that intensively timed induction therapy (4-day treatment courses separated by only 6 days) produced better EFS than standard-timing induction therapy (4-day treatment courses separated by 2 weeks or longer). The MRC has intensified induction therapy by prolonging the duration of cytarabine treatment to 10 days. Another way of intensifying induction therapy is by the use of high-dose cytarabine. While studies in nonelderly adults suggest an advantage for intensifying induction therapy with high-dose cytarabine (2–3 g/m2 /dose) compared with standard-dose cytarabine,[12,13] a benefit for the use of high-dose cytarabine compared with standard-dose cytarabine in children was not observed using a cytarabine dose of 1 g/m2 given twice daily for 7 days with daunorubicin and thioguanine. A second pediatric study also failed to detect a benefit for high-dose cytarabine over standard-dose cytarabine when used during induction therapy.