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Acute lymphoblastic leukemia

Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study

Leukemia volume 30, pages 32–38 (2016)Cite this article

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Abstract

Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4–7 and exons 1–8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case–control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2–7 (P=0.03), DEL 2–8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4–7 and DEL 1–8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.

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Acknowledgements

This work was supported by the Dutch Cancer Society (KWF, Grant EMCR 2007-3718 to MLdB and RP; Grant KUN 2009-4298 to RPK and PH), the Sophia Foundation for Scientific Research (SSWO, grant 658 to AvdV and MLdB), the Paediatric Oncology Foundation Rotterdam (to MLdB and RP), the European Union’s Seventh Framework Program (FP7/2007-2013) under the project European Network for Cancer research in Children and Adolescents (ENCCA, grant agreement HEALTH-F2-2011-261474 to MLdB and GC), the Center for Translational Molecular Medicine BioChip program (to MLdB), the National Health and Medical Research Council and Tour de Cure Foundation in Australia (to RS), the Polish Ministry of Education and Science (project NN407 137738 and project NN407 254440 to WM), the Polpharma Scientific Foundation (to WM), Anniversary of the Austrian National Bank (ÖNB, Grant 14133 to KN), Italian Association for Cancer Research (AIRC), the Czech Ministry of Health (NT 12397-4 to EF; NT 13170-4 to MZa) and Fondazione Cariplo and MIUR (to GC). AVM, CJS, AE and AV thank Leukaemia & Lymphoma Research (LLR) for financial support and the UK Cancer Cytogenetic Group (UKCCG) laboratories and the LLR Childhood Leukaemia Cell Bank for providing data and samples.

Author contributions

MLdB, AvdV, MZi, AVM and RP designed this study. Patients’ samples and follow-up data were supplied by HAdGK, PH, JT, MH, MdSPdO, WM, AA, RS, AE, MSc, AV, GC, VC, MZi and AVM. Multiplex ligation-dependent probe amplification assays were performed by AvdV, ES, RPK, MZa, EF, ME, TS, KN, AA, NV, CJS, MSt and CP. AvdV, JMB, DR, MF, HAdGK, MZi, AVM and MLdB performed the statistical analysis of data. The manuscript was written and approved by all authors.

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Author notes

  1. J M Boer and A van der Veer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Oncology, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands

    J M Boer, A van der Veer, R Pieters & M L den Boer

  2. Department of Biostatistics, Erasmus MC, Rotterdam, The Netherlands

    D Rizopoulos

  3. DCOG, Dutch Childhood Oncology Group, the Hague, The Netherlands

    M Fiocco, E Sonneveld, H A de Groot-Kruseman, P Hoogerbrugge, R Pieters & M L den Boer

  4. Department of Medical Statistics and Bioinformatics, Leiden University Medical Centre, Leiden, The Netherlands

    M Fiocco

  5. Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands

    R P Kuiper

  6. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    P Hoogerbrugge & R Pieters

  7. COALL Study Group, Research Centre and Clinic for Pediatric Oncology, University Medical Centre Eppendorf, Hamburg, Germany

    M Horstmann

  8. BFM-G, Berlin-Frankfurt-Münster-Germany Study Group, University of Schleswig-Holstein, Kiel, Germany

    M Zaliova & M Schrappe

  9. CLIP, Childhood Leukaemia Investigation Prague, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

    M Zaliova, J Trka & E Fronkova

  10. AIEOP, Associazione Italiana Ematologia Oncologia Pediatrica, University of Milano‐Bicocca, Monza, Italy

    C Palmi, G Cazzaniga & V Conter

  11. Pediatric Haematology and Oncology Program, Research Centre, Instituto Nacional de Câncer, Rio de Janeiro, Brazil

    M Emerenciano & M do Socorro Pombo-de-Oliveira

  12. Department of Pediatrics, PPLLSG, Polish Pediatric Leukaemia Lymphoma Study Group, Oncology, Haematology and Diabetology, Medical University of Lodz, Lodz, Poland

    W Mlynarski

  13. Department of Pediatric Hematology and Oncology, PPLLSG, Polish Pediatric Leukaemia Lymphoma Study Group, Medical University of Silesia, Zabrze, Poland

    T Szczepanski

  14. Children's Cancer Research Institute, St Anna Kinderkrebsforschung, Vienna, Austria

    K Nebral

  15. Department of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, BFM-A, Berlin-Frankfurt-Münster-Austria Study Group, St Anna Children's Hospital, Medical University of Vienna, Vienna, Austria

    A Attarbaschi

  16. ANZCHOG, Australian and New Zealand Children’s Oncology Group, Children’s Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia

    N Venn & R Sutton

  17. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK

    C J Schwab, A Enshaei & A V Moorman

  18. Department of Haematology, Sheffield Children’s Hospital, Sheffield, UK

    A Vora

  19. Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    M Stanulla & M Zimmermann

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  1. J M Boer
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  27. G Cazzaniga
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  32. M L den Boer
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Correspondence to M L den Boer.

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Boer, J., van der Veer, A., Rizopoulos, D. et al. Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study. Leukemia 30, 32–38 (2016). https://doi.org/10.1038/leu.2015.199

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