A major challenge in the treatment of children with acute myeloid leukemia (AML) is to prolong the duration of the initial remission with additional chemotherapy or hematopoietic stem cell transplantation (HSCT). In practice, most patients are treated with intensive chemotherapy after remission is achieved, as only a small subset have a matched-family donor (MFD). Such therapy includes the drugs used in induction and often includes high-dose cytarabine. Studies in adults with AML have demonstrated that consolidation with a high-dose cytarabine regimen improves outcome compared with consolidation with a standard-dose cytarabine regimen, particularly in patients with inv(16) and t(8;21) AML subtypes.[1,2] Randomized studies evaluating the contribution of high-dose cytarabine to postremission therapy have not been conducted in children, but studies employing historical controls suggest that consolidation with a high-dose cytarabine regimen improves outcome compared with less intensive consolidation therapies.[3,4,5] The optimal number of postremission courses of therapy remains unclear, but appears to require at least three courses of intensive therapy, including the induction course. A United Kingdom Medical Research Council (MRC) study randomly assigned adult and pediatric patients to four versus five courses of intensive therapy, but five courses did not show an advantage in relapse-free and overall survival.[Level of evidence: 1iiA]
The use of HSCT in first remission has been under evaluation since the late 1970s, and an evidence-based appraisal concerning indications for autologous and allogeneic HSCT has been published. Prospective trials of transplantation in children with AML suggest that 60% to 70% of children with HLA-matched donors available who undergo allogeneic HSCT during their first remission experience long-term remissions.[9,10] Prospective trials of allogeneic HSCT compared with chemotherapy and/or autologous HSCT have demonstrated a superior outcome for patients who were assigned to allogeneic transplantation based on availability of a family 6/6 or 5/6 HLA-matched donor.[9,10,11,12,13,14] In the MRC trials, the difference (70% vs. 60%) did not reach statistical significance but the numbers of patients enrolled did not give the study the power to demonstrate this difference. Several large cooperative group clinical trials for children with AML have found no benefit for autologous HSCT over intensive chemotherapy.[9,10,11,13]
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Because of the improved outcome in patients with favorable prognostic features receiving contemporary regimens, it is now recommended that this group of patients receive an MFD HSCT only after first relapse and the achievement of a second complete remission (CR). The Berlin-Frankfurt-Munster Group uses a combination of day-15 marrow response (<5% blasts) and French-American-British (FAB) subtypes M1 and M2 with Auer rods, M3, or M4Eo to define a good-risk group. The MRC has identified a group of good-risk patients with a 7-year survival from CR of 78% and a disease-free survival (DFS) of 59%. The patients in this group primarily include those with t(8;21), t(15;17), FAB M3, and inv(16). A retrospective analysis of 1,464 children with AML treated on Children's Cancer Group trials suggests that allogeneic HSCT improves overall survival and DFS for patients with low or high white blood cell counts with all subtypes except those with inv(16); however, the ability of patients with t(8;21) treated with chemotherapy to be successfully cured following achievement of a second CR and MFD HSCT has led the Children's Oncology Group (COG) to not recommend transplantation in first CR for patients with t(8;21) and inv(16).