Results of the prospective EORTC Children Leukemia Group study 58081 in precursor B- and T-cell acute lymphoblastic leukemia

Abstract

Here, we report the results of the prospective cohort study EORTC-CLG 58081 and compare them to the control arm of the randomized phase 3 trial EORTC-CLG 58951, on which treatment recommendations were built. In both studies, patients aged 1-18 years with BCR::ABL1 negative acute lymphoblastic leukemia of the B-lineage (B-ALL) or T-lineage (T-ALL) were treated using a BFM backbone without cranial irradiation. Similarly to the control arm of 58951, prednisolone (PRED) 60 mg/m²/day was used for induction therapy, but a few modifications were made. Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m²/day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients. Between 2011 and 2017, 835 patients were prospectively enrolled in the 58081 study. Overall, the 5-year event-free survival (EFS) was 84.8% versus 83.6% (hazard ratio [HR], 0.96 [95% confidence interval [CI]: 0.76-1.21]) for 58081 versus 58951 considered as a control group, respectively, 84.3% versus 84.9% (HR, 1.06 [99% CI: 0.75-1.49]) in B-ALL but 87.3% versus 76.6% (HR, 0.59 [99% CI: 0.28-1.24]) in T-ALL. The comparison between the two studies regarding EFS differed by risk group (p = 0.012). The HR was 2.15 (99% CI: 0.67-6.85) for very low-risk but 0.34 (99% CI: 0.13-0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification.

Figure 1

General scheme of the EORTC‐CLG 58081 trial. AR, Average risk (group); DEXA, Dexamethasone (DEXA 6: Dexamethasone 6 mg/m²/day−DEXA 10: Dexamethasone 10 mg/m²/day); HDMTX, High Dose Methotrexate (5 g/m²); IA, induction phase starts with 7 days of prephase (Prednisone 60 mg/m²/day and MTX IT therapy); IB, Consolidation phase; IIA/IIB, Late intensification phase (=Re‐induction and re‐consolidation phase); IT, Intra‐thecal; PRED: Prednisone 60 mg/m²/day; TP1 and TP2, Points of MRD evaluation; VHR, Very high risk (group); VLR, Very low risk (group). B‐ALL patients could be stratified into four subgroups: VLR, AR1, AR2, and VHR. −VLR: WBC counts below 10 × 10⁹/L at diagnosis, hyperdiploid karyotype (51–66 chromosomes) or DNA index >1.16 and <1.5, strict CNS1 status, no gonadal involvement, no VHR features. −AR1: WBC <100 × 10⁹/L at diagnosis, no gonadal or CNS involvement. Not VLR and VHR criteria. −AR2: WBC ≥100 × 10⁹/L at diagnosis and/or CNS‐3 or CNS‐2, without VHR criteria. −VHR: blast count in peripheral blood ≥1 × 10⁹/L at completion of the prephase (Day 8), presence of a KMT2A rearrangement, near‐haploidy or hypodiploidy (<43 chromosomes), acute undifferentiated leukemia, MRD ≥ 10⁻² at completion of induction (IA, Day 35, TP1), MRD ≥10⁻³ at completion of consolidation (IB, TP2), failure to achieve complete remission (CR). T‐ALL patients could be stratified into 2 sub‐groups: AR2 and VHR. −AR2: No CNS‐3 involvement and no VHR characteristics. −VHR: CNS3 involvement, blast count in peripheral blood ≥1 × 10⁹/L at completion of the prephase (Day 8), MRD ≥10⁻² at completion of induction (IA, Day 35, TP1), MRD ≥10⁻³ at completion of consolidation (IB, TP2), failure to achieve complete remission (CR).

Figure 2

Event‐free survival (A), overall survival (B), cumulative incidence of relapse (C), and cumulative incidence of death without relapse (D) by protocol (EORTC 58081 vs. EORTC 58951PRED arm). CI, confidence interval; CR, complete remission. The marks indicate censoring and the shaded area, the 95% confidence interval.

Figure 3

Event‐free survival by protocol among very low risk (A), average risk 1 (B), average risk 2 (C), and very high‐risk patients (D). CI, confidence interval; CR, complete remission. The marks indicate censoring, and the shaded area is the 95% confidence interval.

Figure 4

The association between protocol and EFS by risk group and immunophenotype. AR, average risk; CI, confidence interval; HR, hazard ratio; VHR, very high risk; VLR, very low risk. In subgroups, 99% confidence intervals are provided. The estimate among all patients is based on an unadjusted model and is accompanied by a 95% confidence interval.

Figure 5

Event‐free survival by protocol among patients with B‐ALL (A), T‐ALL (B), B‐ALL and average risk group 2 (C), and T‐ALL and average risk group 2 (D). CI, confidence interval; CR, complete remission. The marks indicate censoring, and the shaded area is the 95% confidence interval.

Figure 6

Disease‐free survival by minimal residual disease at the end of induction among all patients from Study 58081 (A), those with B‐ALL (B), and those with T‐ALL (C). CI, confidence interval; CR, complete remission; MRD, minimal residual disease. The marks indicate censoring, and the shaded area is the 95% confidence interval.