Prolonged versus standard native E. coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951

Abstract

Asparaginase is an essential component of combination chemotherapy for childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma. The value of asparaginase was further addressed in a group of non-very high-risk patients by comparing prolonged (long-asparaginase) versus standard (short-asparaginase) native E. coli asparaginase treatment in a randomized part of the phase III 58951 trial of the European Organization for Research and Treatment of Cancer Children's Leukemia Group. The main endpoint was disease-free survival. Overall, 1,552 patients were randomly assigned to long-asparaginase (775 patients) or short-asparaginase (777 patients). Patients with grade ≥2 allergy to native E. coli asparaginase were switched to equivalent doses of Erwinia or pegylated E. coli asparaginase. The 8-year disease-free survival rate (±standard error) was 87.0±1.3% in the long-asparaginase group and 84.4±1.4% in the short-asparaginase group (hazard ratio: 0.87; P=0.33) and the 8-year overall survival rate was 92.6±1.0% and 91.3±1.2% respectively (hazard ratio: 0.89; P=0.53). An exploratory analysis suggested that the impact of long-asparaginase was beneficial in the National Cancer Institute standard-risk group with regards to disease-free survival (hazard ratio: 0.70; P=0.057), but far less so with regards to overall survival (hazard ratio: 0.89). The incidences of grade 3-4 infection during consolidation (25.2% versus 14.4%) and late intensification (22.6% versus 15.9%) and the incidence of grade 2-4 allergy were higher in the long-asparaginase arm (30% versus 21%). Prolonged native E. coli asparaginase therapy in consolidation and late intensification for our non-very high-risk patients did not improve overall outcome but led to an increase in infections and allergy. This trial was registered at www.clinicaltrials.gov as #NCT00003728.

Copyright© 2017 Ferrata Storti Foundation.

Figures

Figure 1.

General scheme of the EORTC-CLG 58951 trial. The EORTC-CLG trial 58951 embedded three main randomized comparisons: [R1] the value of prednisolone (PRED, 60 mg/m2/day) versus dexamethasone (DEX, 6 mg/m2/day) in induction for all patients; [R2] the value of prolonged courses of ASNase throughout consolidation and late intensification for all non-very high risk (non-VHR) patients; and [R3] the value of vincristine (VCR) and corticosteroid pulses introduced in continuation therapy for average risk (AR) patients. IA: induction phase; IB: consolidation phase; II A+B: late intensification phase; VCR: vincristine; VLR: very low risk (group); AR: average risk (group); VHR: very high risk (group).

Figure 2.

CONSORT statement in flow diagram.

Figure 3.

(A) Disease-free survival and (B) overall survival according to the randomized arm.

Figure 4.

Forest plot regarding disease-free survival according to the randomization arm. ALL: acute lymphoblastic leukemia; NHL: non-Hodgkin lymphoma; VL: very low risk; AR1: average risk low; AR2: average risk high; DEX: dexamethasone; PRED: prednisolone; WBC: white blood cell count; NCI: National Cancer Institute; HR: hazard ratio; CI: confidence interval. *NCI Standard Risk: ALL with WBC 9/L and age 1 – <10 years; NCI High Risk: ALL with WBC ≥50×109/L or age <1 or age ≥10 years.

Figure 5.

Forest plot regarding overall survival according to the randomization arm. ALL: acute lymphoblastic leukemia; NHL: non-Hodgkin lymphoma; VLR: very low risk; AR1: average risk low; AR2: average risk high; DEX: dexamethasone; PRED: prednisolone; WBC: white blood cell count; NCI: National Cancer Institute; HR: hazard ratio; CI: confidence interval. *NCI Standard Risk: ALL with WBC 9/L and age 1 – <10 years; NCI High Risk: ALL with WBC ≥50×109/L or age <1 or age ≥10 years.