Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse

Costa Bachas, Gerrit Jan Schuurhuis, Dirk Reinhardt, Ursula Creutzig, Zinia J. Kwidama, C. Michel Zwaan, Marry M. van den Heuvel-Eibrink, Evelina S. J. M. De Bont, Sarah Elitzur, Carmelo Rizzari, Valerie de Haas, Martin Zimmermann, Jacqueline Cloos, Gertjan J. L. Kaspers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)

Abstract

Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46.5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10.2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2.74, P = 0.013). In patients who achieved second complete remission (70.2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2.32, P = 0.038 and HR = 1.89, P = 0.045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment.

Original languageEnglish
Pages (from-to)902-910
Number of pages9
JournalBritish Journal of Haematology
Volume166
Issue number6
DOIs
Publication statusPublished - Sep-2014

Keywords

  • acute myeloid leukaemia
  • relapse
  • mutation analysis
  • overall survival
  • event free survival
  • INTERNAL TANDEM DUPLICATION
  • ACUTE MYELOGENOUS LEUKEMIA
  • GENE-MUTATIONS
  • AML 10
  • FLT3
  • CHILDREN
  • THERAPY
  • MANAGEMENT
  • PROGNOSIS
  • KARYOTYPE

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