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Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL

Lina Hamadeh, Amir Enshaei, Claire Schwab, Cristina N. Alonso, Andishe Attarbaschi, Gisela Barbany, Monique L. den Boer, Judith M. Boer, Marcin Braun, Luciano Dalla Pozza, Sarah Elitzur, Mariana Emerenciano, Larisa Fechina, Maria Sara Felice, Eva Fronkova, Irén Haltrich, Mats M. Heyman, Keizo Horibe, Toshihiko Imamura, Marta Jeison, Gábor Kovács, Roland P. Kuiper, Wojciech Mlynarski, Karin Nebral, Ingegerd Ivanov Öfverholm, Agata Pastorczak, Rob Pieters, Henriett Piko, Maria S. Pombo-de-Oliveira, Patricia Rubio, Sabine Strehl, Jan Stary, Rosemary Sutton, Jan Trka, Grigory Tsaur, Nicola Venn, Ajay Vora, Mio Yano, Christine J. Harrison and Anthony V. Moorman on behalf of the International BFM Study Group

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Definition of the cytogenetic, copy number alteration and integrated classifications used in this study. Definition of the classifiers used in the current study: cytogenetic (A), UKALL-CNA (B), and original genetic risk (C). CYTO, cytogenetic; GEN, genetics; GR, good risk; IR, intermediate risk; PR, poor risk.

  • Figure 2.

    Outcome of 3239 patients in the iBFM cohort stratified by the UKALL-CNA classifier. (A-B) Kaplan-Meier survival curves (A) and forest plots depicting the hazard ratio and 95% CI from univariate Cox regression models comparing the EFS for CNA-GR or CNA-PR against CNA-IR (B). Patients in the Israeli National Study were excluded from the forest plot, as no event occurred in the CNA-GR or CNA-IR groups. DCOG, Dutch Childhood Oncology Group.

  • Figure 3.

    Outcome of 3239 patients in the iBFM cohort stratified by the original genetic risk group. (A-B) Kaplan-Meier survival curves (A) and forest plot (B) depicting the hazard ratio and 95% confidence interval from univariate Cox regression models comparing the EFS for GEN-PR vs GEN-GR. Patients in the Israeli National Study were excluded from the forest plot, as no event occurred in the GEN-GR group.

  • Figure 4.

    Integration of cytogenetic and CNA subgroups using the 3239 patients in the iBFM cohort reveals a new genetic risk classification. (A) EFS of the 9 subgroups derived from cross-tabulating the 3 cytogenetic and 3 CNA risk groups. (B) Visualized inspection of these curves reveals 4 overall genetic risk groups. (C) EFS of the revised genetic risk groups, which are significantly different from one another.

  • Figure 5.

    Outcome of 1405 patients in the iBFM cohort with IR cytogenetics classified according to their CNA profile. (A-B) Kaplan-Meier survival curves (A) and forest plot (B) depicting the hazard ratio and 95% confidence interval from univariate Cox regression models comparing the EFS for group B (CYTO-IR/CNA-IR and CYTO-IR/CNA-PR) vs group A (CYTO-IR/CNA-GR). Patients in the Israeli National and Sweden studies were excluded from the forest plot, as no event occurred in group B.

Tables

  • Table 1.

    Cox regression models comparing the risk of an event between different genetic ungroups defined by the UKALL-CNA and revised genetic classifiers

    ClassifierOverallMRD adaptedNon–MRD adapted
    Hazard ratio95% CIPHazard ratio95% CIPHazard ratio95% CIP
    Univariate models
     UKALL-CNA
      CNA-GR vs CNA-IR0.480.40-0.57<.0010.510.39-0.66<.0010.450.35-0.58<.001
      CNA-PR vs CNA-IR1.431.12-1.82.0041.390.96-2.01.081.421.03-1.96.03
     Genetic risk
      GEN-GR vs GEN-VGR1.681.29-2.19<.0011.330.93-1.91.122.191.46-3.29<.001
      GEN-IR vs GEN-GR2.051.65-2.53<.0012.031.46-2.82<.0012.031.53-2.69<.001
      GEN-PR vs GEN-IR1.951.51-2.53<.0011.831.23-2.72.0032.131.51-3.01<.001
    Models stratified by treatment risk group
     UKALL-CNA
      CNA-GR vs CNA-IR0.530.44-0.64<.0010.530.41-0.70<.0010.520.41-0.67<.001
      CNA-PR vs CNA-IR1.311.02-1.66.031.270.87-1.84.221.330.97-1.83.08
     Genetic risk
      GEN-GR vs GEN-VGR1.621.24-2.12<.0011.300.90-1.89.162.061.37-3.09.001
      GEN-IR vs GEN-GR1.861.50-2.31<.0011.891.36-2.65<.0011.821.37-2.42<.001
      GEN-PR vs GEN-IR1.361.02-1.81.041.460.94-2.26.091.360.94-1.99.11
    • CI, confidence interval; VGR, very good risk.