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Br J Haematol. 2019 Apr;185(2):266-283. doi: 10.1111/bjh.15770. Epub 2019 Feb 3.

Aneuploidy in children with relapsed B-cell precursor acute lymphoblastic leukaemia: clinical importance of detecting a hypodiploid origin of relapse.

Author information

1
Department of Paediatric Oncology/Haematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
2
Department of Haematology/Oncology, Charité Universitätsmedizin Berlin, Berlin, Germany.
3
Institute of Visual Computing & Human-Centered Technology, Vienna University of Technology, Vienna, Austria.
4
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
5
Department of Pathology, University of Gießen, Gießen, Germany.
6
Labor Berlin Charité Vivantes, Berlin, Germany.
7
Institute of Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
8
St. Anna Children's Hospital, Medical University of Vienna, Austria.
9
German Cancer Consortium (DKTK), and German Research Center (DKFZ), Heidelberg, Germany.

Abstract

Aneuploidy is common in paediatric B-cell precursor acute lymphoblastic leukaemia (ALL). Specific subgroups, such as high hyperdiploidy (>50 chromosomes or DNA Index ≥1·16) and hypodiploidy (<45 chromosomes), predict outcome of patients after primary treatment. Whether aneuploidy has a prognostic value for relapsed disease is yet to be determined. Using DNA index and centromere screening by multiplex ligation-dependent probe amplification, we investigated aneuploidy in 413 children treated for first relapse of B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. Ten-year event-free survival of patients with high hyperdiploid relapses approached 70%, whereas it was only 40% in low hyperdiploid relapses. Three patients with apparent hyperdiploid relapse had TP53 mutations. In these cases, array-based allelotyping revealed a hypodiploid origin with absence of the hypodiploid founder clone (masked hypodiploidy). Collectively, patients with evident or masked hypodiploid relapses showed an extremely low event-free survival rate of 9%. Importantly, the current relapse risk stratification did not identify cases with masked hypodiploidy as high-risk patients, due to their favourable clinical presentation. In multivariate analysis, hypodiploidy proved to be an independent prognostic factor. This finding supports stratification of relapses with hypodiploid origin into high-risk arms in future trials or allocation of patients to alternative treatment approaches.

KEYWORDS:

childhood leukaemia; hyperdiploidy; hypodiploidy; outcome; relapse

PMID:
30714092
DOI:
10.1111/bjh.15770

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