The past 30 years have seen tremendous advances in the treatment of pediatric leukemia. What was once an invariably fatal diagnosis is now quite curable in close to 80% of cases. Unfortunately for children with acute myelogenous leukemia (AML), most of these developments have been in the treatment of acute lymphoblastic leukemia (ALL); even today, nearly half of all children diagnosed with AML will die of the disease.
In their excellent and comprehensive article, Loeb and Arceci review the current state of therapies for pediatric AML throughout the world, summarizing the approaches taken by the various major cooperative groups. In essence, these strategies have involved the intensification of either the dosages or timing of the few chemotherapeutic agents active against AML.
Distinct Disease Entities
Several themes running through the review are worth emphasizing. First, it has become increasingly clear that, despite their common CD34-positive hematopoietic stem cell origin, AML and ALL are biologically quite distinct, and the successful treatment of AML hinges upon differing treatment strategies than those used for ALL. While ALL initially responds rapidly to a number of agents, even when they are used alone, AML is resistant to all but a few drugs. Whereas regimens involving intensive but short remission induction and consolidation phases and prolonged low-intensity maintenance cycles have been effective in the treatment of ALL, this approach has not been successful in the treatment of AML.
Rather, it was found in early Children’s Cancer Group (CCG) studies that survival was significantly improved by intensive but short courses of therapy, when directly compared against prolonged ALL-style maintenance treatments. In fact, it was later shown in the Medical Research Council (MRC) AML9 study that extended maintenance therapy might be detrimental to survival because of protracted periods of immunosuppression.
Timed Sequential Therapy
In contrast to the rapid proliferation characteristic of ALL blasts, the percentage of AML cells in cycle is typically quite low because of the presence of a secreted hematopoietic inhibitory factor. This factor is no longer present following a single cycle of chemotherapy but is replaced by a factor that stimulates proliferation. These insights into the biology of AML led the CCG to adopt "timed sequential therapy" as its overall strategy in the treatment of AML, the second major theme of this review.