A Critical Risk-Benefit Assessment Argues Against the Use of Anthracyclines in Induction Regimens for Newly Diagnosed Childhood Acute Lymphoblastic Leukemia

Abstract

Although anthracyclines are associated with significant cardiac toxicity and their benefit remains unclear, they are included in nearly all current protocols for the treatment of childhood acute lymphoblastic leukemia (ALL). Currently open trials from most major groups use anthracyclines in the induction phase for all high-risk patients and in the delayed intensification phase for all patients regardless of risk classification. Our review of published randomized studies reveals no benefit for the addition of anthracyclines to induction phase of childhood ALL regimens consisting of vincristine, prednisone, and L-asparaginase (WL), with or without a delayed intensification phase. No randomized studies have evaluated the use of anthracyclines in the delayed intensification phase of therapy. Furthemore, studies of relapsed patients indicated no benefit for the addition anthracyclines to maintenance regimens. Recent evidence from preclinical studies suggests that a combination of VPL with an anti-CD 19 immunotoxin is more effective than VPL plus anthracyclines combination. Accumulated evidence exists that anthracyclines are associated with late-onset cardiac morbidity in about 25% of childhood ALL and other cancer survivors, and about 5% develop overt heart failure, with some requiring cardiac transplantation. Anthracycline-induced cardiotoxicity in children has no safe dose threshold and all doses are likely to cause significant myocardial damage. New data suggests that a unique cardiac mitochondrial exogenous NADH dehydro-genase is responsible for the anthracycline-induced oxygen radicals damage to the heart, and that chelators currently evaluated may not prevent late-onset cardiotoxicity in children. In view of these findings we urge extreme caution in using anthracyclines as part of multimoda-lity ALL treatment programs, and strongly recommend reevaluation of what should be considered the best induction regimen for high-risk childhood ALL.