CCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensivetiming remission induction/consolidation and related donor marrow transplantation or high-dose cytarabine intensification. Among 901 patients under age 21 years, 5-year survival was 52%, and event-free survival was 42%. Survival improved from 44% between 1996 and 1998 to 58% between 2000 and 2002 (P ؍ .005), and treatment-related mortality declined from 19% to 12% (P ؍ .025). Partial replacement of daunomycin with idarubicin in the 5-drug induction combination achieved a remission rate of 88%, similar to historical controls. Postremission survival was 56% in patients randomized to either 5-drug reinduction or fludarabine/ cytarabine/idarubicin. For patients with or without a related donor, respective 5-year disease-free survival was 61% and 50% (P ؍ .021); respective survival was 68% and 62% (P ؍ .425). Donor availability conferred no benefit on those with inv(16) or t(8;21) cytogenetics. After cytarabine intensification, patients randomized to interleukin-2 or none experienced similar outcomes. Factors predictive of inferior survival were age more than 16 years, non-white ethnicity, absence of related donor, obesity, white blood cell count more than 100 000 ؋ 10 9 /L, ؊7/7q؊, ؊5/5q؊, and/or complex karyo-
IntroductionIn the past 2 decades, cooperative group trials in pediatric acute myeloid leukemia (AML) have increased overall 5-year survival (OS) from approximately 30% to more than 50%. [1][2][3][4][5][6] Intensification of dose, increased number of days of conventional induction chemotherapy, matched related donor bone marrow transplantation (MRD BMT) in first remission, and risk stratification of treatment have all contributed to this progress. Risk stratification typically classifies as favorable those patients with Down syndrome or with AML characterized by t(8;21), t(15;17), or inv(16) cytogenetic abnormalities and rapid early response to induction therapy. Unfavorable features include high white blood cell count, Ϫ7/7qϪ, Ϫ5/5qϪ, or complex cytogenetics, and slow or no early response. [7][8][9][10][11] The emerging consensus is that patients with favorable AML do not benefit from MRD BMT in first remission. 2,12 Since 1986, the Children's Cancer Group (CCG) explored a strategy to treat newly diagnosed AML using intensively timed 5-drug combination chemotherapy consisting of dexamethasone, cytarabine, thioguanine, etoposide, and rubidomycin (daunomycin) (DCTER) for remission induction followed by BMT for patients with matched related donors or intensively timed high-dose cytarabine/asparaginase (HidAC) after remission therapy for patients without related donors. [13][14][15] Intensive timing involves administration of the second cycle of 5 drugs on day 10 regardless of remission status or blood counts. In the previous phase 3 trial, CCG-2891, intensively timed DCTER achieved an event-free survival (EFS) of 41% and OS of 49% at 5 years.This manuscript describes the successor phase...
