Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932

Abstract

Purpose: AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL).

Methods: AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 × 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of weekly oral methotrexate of 20 mg/m2 (MTX20) or 40 mg/m2 (MTX40).

Results: Five-year event-free survival and overall survival (OS) from enrollment (with 95% CIs), for all eligible and evaluable SR B-ALL patients (n = 9,226), were 92.0% (91.1% and 92.8%) and 96.8% (96.2% and 97.3%), respectively. The 5-year DFS and OS from the start of maintenance for randomly assigned AR patients were 94.6% (93.3% and 95.9%) and 98.5% (97.7% and 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n = 1,186) versus VCR/DEX12 (n = 1,178) were 94.1% (92.2% and 96.0%) and 98.3% (97.2% and 99.4%) v 95.1% (93.3% and 96.9%) and 98.6% (97.7% and 99.6%), respectively (P = .86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (93.3% and 96.8%) and 98.8% (97.9% and 99.7%) v 94.2% (92.2% and 96.1%) and 98.1% (97.0% and 99.2%), respectively (P = .92 and .89).

Conclusions: The 0NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m2/week did not improve outcomes when compared with 20 mg/m2/week. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families.

Trial registration: ClinicalTrials.gov NCT01190930.

Conflict of interest statement

Anne L. AngiolilloHonoraria: Servier PharmaceuticalsTravel, Accommodations, Expenses: Servier Pharmaceuticals Reuven J. SchoreResearch Funding: Janssen Research & Development, Amgen John A. KairallaStock and Other Ownership Interests: Johnson & Johnson Meenakshi DevidasHonoraria: PSI, Novartis Patrick Zweidler-McKayStock and Other Ownership Interests: Immunogen Michael J. BorowitzConsulting or Advisory Role: AmgenResearch Funding: Becton DickinsonTravel, Accommodations, Expenses: Beckman Coulter Brent WoodHonoraria: Amgen, Seattle Genetics, Abbvie, Janssen, Astellas PharmaConsulting or Advisory Role: SysmexResearch Funding: Amgen, Seattle Genetics, Pfizer, Juno Therapeutics, BiolineRx, Biosight, Stemline Therapeutics, Janssen Oncology, NovartisTravel, Accommodations, Expenses: Amgen Mary V. RellingResearch Funding: Servier Pharmaceutical Elizabeth A. RaetzResearch Funding: PfizerOther Relationship: Celgene Mignon L. LohConsulting or Advisory Role: MediSix Therapeutics Stephen P. HungerStock and Other Ownership Interests: Amgen, MerckHonoraria: AmgenConsulting or Advisory Role: NovartisNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram for Children's Oncology Group AALL0932. AR, average risk; B-ALL, B-acute lymphoblastic leukemia; DS, Down syndrome; HR, hazard ratio; LR, low risk; Ph, Philadelphia chromosome; SR, standard risk; VHR, very high risk.

FIG 2.

(A) Event-free survival (EFS) and overall survival (OS) from enrollment for all eligible B-ALL patients; (B) disease-free survival (DFS) and OS from start of maintenance for the randomly assigned average-risk patients. B-ALL, B-acute lymphoblastic leukemia.

FIG 3.

(A) Disease-free survival (DFS) for the average-risk (AR) subset of patients randomly assigned to receive VCR/DEX12 v VCR/DEX4; (B) overall survival (OS) for AR patients randomly assigned to receive VCR/DEX12 v VCR/DEX4; (C) DFS for the AR subset of patients randomly assigned to receive MTX20 v MTX40; (D) OS for the AR subset of patients randomly assigned to receive MTX20 v MTX40. MTX20, methotrexate of 20 mg/m2; MTX40; methotrexate of 40 mg/m2; VCR/DEX12, vincristine/dexamethasone pulses every 12 weeks; VCR/DEX4, vincristine/dexamethasone pulses every 4 weeks.

FIG 4.

(A) Disease-free survival and (B) overall survival by average risk maintenance arm.

FIGURE A1.

(A) EFS and (B) OS from enrollment for eligible B-ALL patients by sex. (B) OS from enrollment for the eligible B-ALL patients by sex. B-ALL, B-acute lymphoblastic leukemia; EFS, event-free survival; OS, overall survival.

FIGURE A2.

(A) DFS from the start of maintenance for the randomly assigned AR patients by sex. (B) OS from the start of maintenance for the randomly assigned AR patients by sex. AR, average risk; DFS, disease-free survival; OS, overall survival.

FIGURE A3.

(A) Cumulative incidence of all relapses as first events by pulse frequency randomization. (B) Cumulative incidence of all relapses as first events by oral methotrexate dose random assignment. (C) Cumulative incidence of all relapses as first events by AR maintenance arm. AR, average risk.