Dexamethasone and High-Dose Methotrexate Improve Outcome for Children and Young Adults With High-Risk B-Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group Study AALL0232

Abstract

Purpose: Survival for children and young adults with high-risk B-acute lymphoblastic leukemia has improved significantly, but 20% to 25% of patients are not cured. Children's Oncology Group study AALL0232 tested two interventions to improve survival.

Patients and methods: Between January 2004 and January 2011, AALL0232 enrolled 3,154 participants 1 to 30 years old with newly diagnosed high-risk B-acute lymphoblastic leukemia. By using a 2 × 2 factorial design, 2,914 participants were randomly assigned to receive dexamethasone (14 days) versus prednisone (28 days) during induction and high-dose methotrexate versus Capizzi escalating-dose methotrexate plus pegaspargase during interim maintenance 1.

Results: Planned interim monitoring showed the superiority of the high-dose methotrexate regimens, which exceeded the predefined boundary and led to cessation of enrollment in January 2011. At that time, participants randomly assigned to high-dose methotrexate during interim maintenance 1 versus those randomly assigned to Capizzi methotrexate had a 5-year event-free survival (EFS) of 82% versus 75.4% (P = .006). Mature final data showed 5-year EFS rates of 79.6% for high-dose methotrexate and 75.2% for Capizzi methotrexate (P = .008). High-dose methotrexate decreased both marrow and CNS recurrences. Patients 1 to 9 years old who received dexamethasone and high-dose methotrexate had a superior outcome compared with those who received the other three regimens (5-year EFS, 91.2% v 83.2%, 80.8%, and 82.1%; P = .015). Older participants derived no benefit from dexamethasone during induction and experienced excess rates of osteonecrosis.

Conclusion: High-dose methotrexate is superior to Capizzi methotrexate for the treatment of high-risk B-acute lymphoblastic leukemia, with no increase in acute toxicity. Dexamethasone given during induction benefited younger children but provided no benefit and was associated with a higher risk of osteonecrosis among participants 10 years and older.

Fig 1.

Consort diagram for Children’s Oncology Group AALL0232. DC, dexamethasone plus Capizzi escalating-dose methotrexate regimen; DH, dexamethasone plus high-dose methotrexate regimen; IF, induction failure; ID, induction death; PC, prednisone plus Capizzi escalating-dose methotrexate regimen; PH, prednisone plus high-dose methotrexate regimen; RER, rapid early responder; SER, slow early responder; Unk, unknown; VHR, very high risk.

Fig 2.

(A) Event-free survival (EFS) and overall survival (OS) for eligible, evaluable enrolled participants. The 5-year EFS and OS rates were 75.3 ± 1.1% and 85.0 ± 0.9%, respectively. (B) EFS and OS for non–Down syndrome, non–very-high-risk randomly assigned participants. The 5-year EFS and OS rates were 77.5 ± 1.2% and 87.5 ± 0.9%, respectively.

Fig 3.

(A) Event-free survival (EFS) comparisons by methotrexate regimen, all randomly assigned participants. The 5-year EFS rates for Capizzi escalating-dose methotrexate (C-MTX) and high-dose methotrexate (HD-MTX) were 75.2 ± 1.7% and 79.6 ± 1.6%, respectively. (B) EFS comparisons by methotrexate regimen, randomly assigned participants with a rapid early response. The 5-year EFS rates for C-MTX and HD-MTX were 82.8 ± 1.7% and 84.9 ± 1.6%, respectively. (C) EFS comparisons by methotrexate regimen; randomly assigned participants with a slow early response. The 5-year EFS rates for C-MTX and HD-MTX were 49.4 ± 4.2% and 57.8 ± 4.6%, respectively.

Fig 4.

(A) Event-free survival (EFS) comparisons by treatment regimen, randomly assigned participants age 1 to 9 years. The 5-year EFS rates by regimen were prednisone plus Capizzi escalating-dose methotrexate regimen (PC), 82.1 ± 3.5%; prednisone plus high-dose methotrexate regimen (PH), 80.8 ± 3.7%; dexamethasone plus Capizzi escalating-dose methotrexate regimen (DC), 83.2 ± 3.4%; and dexamethasone plus high-dose methotrexate regimen (DH), 91.2 ± 2.8%. (B) EFS comparisons by steroid regimen, participants age 10 years or older. The 5-year EFS rates for dexamethasone regimens and prednisone regimens were 73.1 ± 2.1% and 73.9 ± 2.2%, respectively.

Fig A1.

(A) Event-free survival (EFS) comparison of rapid early responders (RERs) and slow early responders (SERs). The 5-year EFS rates for RERs and SERs were 83.9 ± 1.1% and 53.3 ± 3.1%, respectively. (B) Overall survival (OR) RERs and SERs. The 5-year OS rates for RERs and SERs were 91.3 ± 0.9% and 74.3 ± 2.8%, respectively.

Fig A2.

(A) Overall survival (OS) comparisons by methotrexate regimen, all randomly assigned participants. The 5-year OS rates for Capizzi escalating-dose methotrexate (C-MTX) and high-dose methotrexate (HD-MTX) were 86.1 ± 1.4% and 88.9 ± 1.2%, respectively. (B) OS comparisons by methotrexate regimen, randomly assigned rapid early responders. The 5-year OS rates for C-MTX and HD-MTX were 90.7 ± 1.3% and 91.8 ± 1.2%, respectively. (C) OS by methotrexate regimen, randomly assigned slow early responders. The 5-year OS rates for C-MTX and HD-MTX were 71.2 ± 3.9% and 77.9 ± 3.8%, respectively.

Fig A3.

(A) Overall survival (OS) comparisons by treatment regimen, randomly assigned participants age 1 to 9 years. The 5-year OS rates by regimen were prednisone plus Capizzi escalating-dose methotrexate regimen (PC), 92.4 ± 2.5%; prednisone plus high-dose methotrexate regimen (PH), 92.7 ± 2.4%; dexamethasone plus Capizzi escalating-dose methotrexate regimen (DC), 92.3 ± 2.4%, and dexamethasone plus high-dose methotrexate regimen (DH), 96.3 ± 1.9%. (B) OS comparisons by steroid regimen, participants age 10 years or older. The 5-year OS rates for dexamethasone regimens and prednisone regimens were 83.8 ± 1.8% and 83.7 ± 1.8%, respectively.

Fig A4.

Event-free survival (EFS) comparison by methotrexate regimen, randomly assigned participants age 10 years and older assigned to prednisone (enrolled after April 2008). The 4-year EFS rates Capizzi escalating-dose methotrexate (C-MTX) and high-dose methotrexate (HD-MTX) were 77.0 ± 4.8% and 79.1 ± 4.3%, respectively. Note that there was insufficient follow-up to report 5-year EFS.