Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial
Mené sur 6 141 patients pédiatriques atteints d'une leucémie lymphoblastique aiguë récemment diagnostiquée, cet essai de phase III évalue la non-infériorité, du point de vue de la survie sans événement à 5 ans, de la suppression du traitement d'entretien par doses pulsées de vincristine et de dexaméthasone, par rapport à son maintien au-delà d'1 an
Background : Vincristine plus dexamethasone pulses are generally used throughout maintenance treatmentfor childhood acute lymphoblastic leukaemia. However, previous studies remain inconclusive about the benefit of this maintenance therapy and the absence of randomised, controlled trials in patients with low-risk or high-risk acute lymphoblastic leukaemia providesuncertainty. We therefore aimed to determine if this therapy could be safely omitted beyond 1 year of treatment without leading to an inferior outcome in any risk subgroupof childhood acute lymphoblastic leukaemia. Methods : This open-label, multicentre, randomised, phase 3, non-inferiority trial involved 20 major medical centres across China. We enrolled patients who were aged 0–18 yearswith newly diagnosed acute lymphoblastic leukaemia that was subsequently in continuousremission for 1 year after initial treatment. Patients with secondary malignancy orprimary immunodeficiency were excluded. Eligible patients were classified as havinglow-risk, intermediate-risk, or high-risk acute lymphoblastic leukaemia based on minimalresidual disease and immunophenotypic and genetic features of leukaemic cells. Randomisationand analyses were done separately for the low-risk and intermediate-to-high-risk cohorts.Randomisation was generated by the study biostatistician with a block size of six.Stratification factors included participating centre, sex, and age at diagnosis; thelow-risk cohort was additionally stratified for ETV6–RUNX1 status, and the intermediate-to-high-risk cohort for cell lineage. Patients in eachrisk cohort were randomly assigned (1:1) to either receive (ie, the control group)or not receive (ie, the experimental group) seven pulses of intravenous vincristine(1·5 mg/m2) plus oral dexamethasone (6 mg/m2 per day for 7 days) during the second year of treatment. The primary endpoint was difference in 5-year event-free survival between the experimental group and the controlgroup for both the low-risk and intermediate-to-high-risk cohorts, with a non-inferiority margin of 0·05 (5%). The analysis was by intention to treat. This trial is registeredwith the Chinese Clinical Trial Registry, ChiCTR-IPR-14005706. Findings : Between Jan 1, 2015, and Feb 20, 2020, 6141 paediatric patients with newly diagnosed acute lymphoblastic leukaemia were registered to this study. Approximately 1 yearafter diagnosis and treatment, 5054 patients in continuous remission were randomlyassigned, including 2923 (1442 in the control group and 1481 in the experimental group)with low-risk acute lymphoblastic leukaemia and 2131 (1071 control, 1060 experimental)with intermediate-to-high risk acute lymphoblastic leukaemia. Median follow-up forpatients who were alive at the time of analysis was 3·7 years (IQR 2·8–4·7). Amongpatients with low-risk acute lymphoblastic leukaemia, no difference was observed in5-year event-free survival between the control group and the experimental group (90·3%[95% CI 88·4–92·2] vs 90·2% [88·2–92·2]; p=0·90). The one-sided 95% upper confidence bound for the differencein 5-year event-free survival probability was 0·024, establishing non-inferiority.Among patients with intermediate-to-high-risk acute lymphoblastic leukaemia, no differencewas observed in 5-year event-free survival between the control group and the experimentalgroup (82·8% [95% CI 80·0–85·7] vs 80·8% [77·7–84·0]; p=0·90), but the one-sided 95% upper confidence bound for thedifference in 5-year event-free survival probability was 0·055, giving a borderlineinferior result for those in the experimental group. In the low-risk cohort, we foundno differences in the rates of infections, symptomatic osteonecrosis, or other complicationsduring the second year of maintenance treatment between patients in the control andexperimental groups. Patients with intermediate-to-high-risk acute lymphoblastic leukaemiain the control group were more likely to develop grade 3–4 pneumonia (26 [2·4%] of1071 vs ten [0·9%] of 1060) and vincristine-related peripheral neuropathy (17 [1·6%] vs six [0·6%]) compared with the experimental group. Incidence of grade 5 fatal infectionwas similar between the control group and the experimental group in both the low-riskcohort (two [0·1%] of 1442 vs five [0·3%] of 1481) and intermediate-to-high risk cohort (six [0·6%] of 1071 vs five [0·5%] of 1060). Interpretation : Vincristine plus dexamethasone pulses might be omitted beyond 1 year of treatment for children with low-risk acute lymphoblastic leukaemia. Additional studies are neededfor intermediate-to-high-risk acute lymphoblastic leukaemia.
The Lancet Oncology 2021