Outcomes in CCG-2961, a children's oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children's oncology group

Abstract

CCG-2961 incorporated 3 new agents, idarubicin, fludarabine and interleukin-2, into a phase 3 AML trial using intensive-timing 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 x 10(9)/L, -7/7q-, -5/5q-, and/or complex karyotype. No new agent improved outcomes; experience may have contributed to better results time.

Figure 1

Course 1 and Course 2: IdaDCTER is idarubicin 5 mg/m² per day infused more than half an hour daily, cytarabine 200 mg/m² /day and etoposide 100 mg/m² per day both as continuous 96-hour infusions (CI), oral thioguanine 100 mg/m² per day, and dexamethasone 6 mg/m²on days 0 to 3. On days 10 to 13, daunorubicin 20 mg/m² day CI replaces idarubicin. Course 2: FAMP is fludarabine monophosphate, 10.5 mg/m² loading dose, then 30.5 mg/m² per 24 hours for a total of 48 hours, followed by beginning Ara-C 390 mg/m² loading dose and 2400 mg/m² per 24 hours continuous infusion for 72 hours and idarubicin 12 mg/m² per day infused more than half an hour on days 0, 1, and 2 at 12.0 mg/m² per day. G-CSF, 5 μg/kg per day, initiated in patients with less than 5% residual leukemic blasts in day 14 ± 1 marrow and continued until neutrophil recovery. HidAC is cytarabine 3 g/m² as 3-hour infusions at hours 0 to 3, 12 to 15, 24 to 27, and 36 to 39 on days 0 and 7 followed by Escherichia coli L-asparaginase 6000 units/m² intramuscularly at hour 42 given on days 1 and 8. Marrow transplantation cytoreduction consists of 16 doses of busulfan at 40 mg/m² orally every 6 hours on days −9, −8, −7, and −6 and cyclophosphamide 50 mg/kg IV more than one hour on days −5,−4,−3, and −2; interleukin-2 is 9 × 10⁶ IU/m² per day CI day 0 to 3 and 1.6 × 10⁶ IU/m² per day on CI days 8 to 17. Central nervous system prophylaxis was intrathecal cytarabine on days 0 and 10 of course 1 and course 2 regimen A and weekly times 3 following recovering of counts after HidAC.^, In courses 1 and 2, G-CSF, 5 μg/m² per day was started 48 hours after completion of chemotherapy and continued until the neutrophil count was more than 1500 × 10⁹/L.

Figure 2

Event-free survival and overall survival in CCG-2961. Kaplan-Meier plot of survival (OS) and event-free survival (EFS) from time on study.

Figure 3

Outcomes in CCG-2961 according to donor availability. (A) Kaplan-Meier plot of OS and disease-free survival (DFS) from the time of entry to course 3 for those with and without matched related donors for marrow transplantation. (B) OS and DFS for those patients with favorable cytogenetics according to donor status.

Figure 4

Kaplan-Meier plot of OS according to time of study entry.