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Acute Leukemias

Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia

Leukemia volume 25, pages 254–258 (2011)Cite this article

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Abstract

Response to therapy as determined by minimal residual disease (MRD) is currently used for stratification in treatment protocols for pediatric acute lymphoblastic leukemia (ALL). However, the large MRD-based medium risk group (MRD-M; 50–60% of the patients) harbors many relapses. We analyzed MRD in 131 uniformly treated precursor-B-ALL patients and evaluated whether combined MRD and IKZF1 (Ikaros zinc finger-1) alteration status can improve risk stratification. We confirmed the strong prognostic significance of MRD classification, which was independent of IKZF1 alterations. Notably, 8 of the 11 relapsed cases in the large MRD-M group (n=81; 62%) harbored an IKZF1 alteration. Integration of both MRD and IKZF1 status resulted in a favorable outcome group (n=104; 5 relapses) and a poor outcome group (n=27; 19 relapses), and showed a stronger prognostic value than each of the established risk factors alone (hazard ratio (95%CI): 24.98 (8.29–75.31)). Importantly, whereas MRD and IKZF1 status alone identified only 46 and 54% of the relapses, respectively, their integrated use allowed prediction of 79% of all the relapses with 93% specificity. Because of the unprecedented sensitivity in upfront relapse prediction, the combined parameters have high potential for future risk stratification, particularly for patients originally classified as non-high risk, such as the large group of MRD-M patients.

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Acknowledgements

We thank Patricia Hoogeveen, Maaike de Bie, Annemarie Wijkhuijs, Phary Hart, Jane Voerman, Christa Homburg, Erik Bus and Rob Dee for performing the MRD analyses, Edwin Sonneveld for help in collecting the clinical data, Eveline Kamping for technical assistance and Paul Span and Peggy Manders for advice regarding the statistical analyses. This work was supported by grants from the Dutch Cancer Society (KUN2009–4298 to RPK, AGvK and PMH; EMCR2006–3547 to VHJvdV; and SNWLK 97–1567 and SNWLK 2000–2268 to JJMvD and CEvdS), KiKa (to FNvL, PMH and RPK) and the Quality of Life Gala Foundation (to PMH, FNvL, AGvK and RPK).

Author contributionsEW, RPK, AGvK, FNvL, VHJvdV, JJMvD and CEvdS were responsible for the study design, and SVvR, EW, RPK, VHJvdV and CEvdS contributed to generation experimental data. AJV and VdH were responsible for collection of samples and clinical data. EW, VHJvdV and RPK analyzed and interpreted the data, and EW, VHJvdV, PMH and RPK wrote the manuscript, which was critically reviewed and approved by all authors.

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Author notes

  1. E Waanders, V H J van der Velden and C E van der Schoot: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Radboud University Centre of Oncology and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

    E Waanders, S V van Reijmersdal, A Geurts van Kessel & R P Kuiper

  2. Department of Immunology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands

    V H J van der Velden & J J M van Dongen

  3. Department of Experimental Immunohematology, Sanquin Research and Landsteiner Laboratory, Amsterdam Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

    C E van der Schoot

  4. Department of Pediatric Oncology, Radboud University Nijmegen Medical Centre, Radboud University Centre of Oncology and Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands

    F N van Leeuwen & P M Hoogerbrugge

  5. Dutch Childhood Oncology Group, The Hague, The Netherlands

    V de Haas, A J Veerman & P M Hoogerbrugge

  6. Department of Paediatric Oncology, VU University Medical Centre, Amsterdam, The Netherlands

    A J Veerman

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  1. E Waanders
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  7. A J Veerman
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Corresponding author

Correspondence to P M Hoogerbrugge.

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Waanders, E., van der Velden, V., van der Schoot, C. et al. Integrated use of minimal residual disease classification and IKZF1 alteration status accurately predicts 79% of relapses in pediatric acute lymphoblastic leukemia. Leukemia 25, 254–258 (2011). https://doi.org/10.1038/leu.2010.275

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