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Cyclophosphamide/etoposide in pediatric B-ALL
rates were estimated using the method of Kaplan-Meier with stan- dard errors of Peto et al.9,10 Interim monitoring for efficacy utilized an at2 spending function and futility monitoring was based on the method of Anderson and High,11 with the first interim analysis scheduled for when 20% of the expected DFS events had been observed. Prospective interim monitoring rules for efficacy and futility were included where futility would be determined for a one-sided P-value ≥0.7664. Cumulative incidence rates were com- puted using the cumulative incidence function for competing risks, and comparisons were made using the K-sample test.12 Proportions between the two arms were compared using a c2 test or Fisher exact test. A P value <0.05 was considered statistically significant for all comparisons. All analyses were performed using SAS soft- ware version 9.4 (SAS Institute, Cary, NC, USA). Graphics were generated with R version 2.13.1 (http://www.r-project.org).
Results
A total of 732 eligible, evaluable patients were enrolled in the VHR part of AALL1131 and randomized to either the control arm (n=242) or experimental arm 1 (n=490) as of the data freeze for this report (December /31, 2017). The Consolidated Standards of Reporting Trials (CONSORT) diagram for the study is shown in Online Supplementary Figure S1. Two patients on the control arm and seven on experimental arm 1 had induction failures and were exclud- ed from analyses, resulting in 240 and 483 patients, respec- tively, on the two arms included in this report. There were no significant differences in patients’ characteristics between the two arms (Table 2), including no difference in the proportion of patients with minimal residual disease <0.01% at the end of consolidation between those in the control arm (87.4%) and those in experimental arm 1 (87.2%). As of the data cutoff date of December 31, 2016, 20% (n=41) of expected DFS events had occurred, trigger- ing a scheduled interim monitoring for efficacy and futility.
Figure 1. Outcomes based on information in the database at December 31, 2017 with additional follow-up, Four-year disease-free survival rates were 85.5±6.8% in the control arm (Contr) versus 72.3±6.3% in experimental arm 1 (Exp 1) (P=0.76).
The 3-year DFS rates were 88.3±6.3% (control arm) versus 81.2±5.6% (experimental arm 1) (P=0.92). The study was stopped for futility as the interim monitoring boundary was crossed, indicating non-superiority of experimental arm 1 [hazard ratio 0.606 (95% confidence interval: 0.297-1.237)]. As a result, the VHR sub-study of AALL1131 was perma- nently closed in February 2017.
As of December 31, 2017, the date of freezing the data, the 4-year DFS rates were 85.5±6.8% (control arm) versus 72.3±6.3% (experimental arm 1) (P=0.76) (Figure 1). Table 3 gives the distribution of DFS events by arm. The 4-year cumulative incidence rates for each type of relapse are sum- marized in Table 4, by regimen. The cumulative incidence of isolated bone marrow relapses was significantly different between the control arm and experimental arm 1 (2.5±1.1% versus 14.5±3.3%, P=0.025). Grade 5 toxicity rates were 5.0% on the control arm (n=12) and 2.9% on experimental arm 1 (n=14). Of the 12 grade 5 toxicities reported among patients on the control arm, six occurred on therapy. These six deaths were attributed to infection
Table 2. Patients’ characteristics. Characteristic
Age
<10 years ≥10 years
Gender Male Female
Race
American Indian or Alaska
Native
Asian
Native Hawaiian or
other Pacific Islander Black or African American White
Multiple races
Unknown
Ethnicity
Hispanic or Latino Not Hispanic or Latino Unknown
White blood cell count < 50x109/L
≥ 50x109/L
National Cancer Institute risk Standard risk
High risk
Central nervous system status CNS 1
CNS 2
CNS 3
Day 29 bone marrow M1
M2
M3 (were excluded in DFS analysis)
End of induction MRD MRD < 0.01%
MRD ≥ 0.01%
VHR CA
N (%), N=242
97 (40.1%) 145 (59.9%)
142 (58.7%)
100 (41.3%)
4 (1.7%)
9 (3.7%) 5 (2.1%)
16 (6.6%) 176 (72.7%) 1 (.04%) 31 (12.8%)
78 (32.2%) 157 (64.9%) 7 (2.9%)
184 (76.0%) 58 (34.0%)
66 (27.3%)
176 (72.7%)
191 (80.3%) 35 (14.7%) 12 (5.0%)
232 (96.3%) 7 (2.9%) 2 (0.8%)
114 (47.1%)
128 (52.9%)
VHR Exp1 N (%) N=490
196 (40.0%) 294 (60.0%)
270 (55.1%)
220 (44.9%)
8 (1.6%)
20 (4.1%) 2 (0.4%)
24 (4.9%) 355 (72.5%) 6 (1.2%) 75 (15.3%)
133 (27.1%) 334 (68.2%) 23 (4.7%)
389 (79.4%) 101 (20.6%)
143 (29.2%)
347 (70.8%)
410 (84.0%) 56 (11.5%) 22 (4.5%)
466 (95.3%) 16 (3.3%) 7 (1.4%)
207 (42.2%)
283 (57.8%)
VHR: very high-risk; CA: control arm; Exp1: experimental arm 1; CNS: central nervous system; MRD: minimal residual disease.
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