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Acute myeloid leukemia

Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group

Leukemia volume 31, pages 18–25 (2017)Cite this article

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Abstract

Recurrent molecular markers have been routinely used in acute myeloid leukemia (AML) for risk assessment at diagnosis, whereas their post-induction monitoring still represents a debated issue. We evaluated the prognostic value and biological impact of minimal residual disease (MRD) and of the allelic ratio (AR) of FLT3-internal-tandem duplication (ITD) in childhood AML. We retrospectively screened 494 children with de novo AML for FLT3-ITD mutation, identifying 54 harboring the mutation; 51% of them presented high ITD-AR at diagnosis and had worse event-free survival (EFS, 19.2 versus 63.5% for low ITD-AR, <0.05). Forty-one percent of children with high levels of MRD after the 1st induction course, measured by a patient-specific real-time-PCR, had worse EFS (22.2 versus 59.4% in low-MRD patients, P<0.05). Next, we correlated these parameters with gene expression, showing that patients with high ITD-AR or persistent MRD had characteristic expression profiles with deregulated genes involved in methylation and acetylation. Moreover, patients with high CyclinA1 expression presented an unfavorable EFS (20.3 versus 51.2% in low CyclinA1 group, P<0.01). Our results suggest that ITD-AR levels and molecular MRD should be considered in planning clinical management of FLT3-ITD patients. Different transcriptional activation of epigenetic and oncogenic profiles may explain variability in outcome among these patients, for whom novel therapeutic approaches are desirable.

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Acknowledgements

This work was supported by CARIPARO Istituto di Ricerca Pediatrica-Fondazione Città della Speranza to GB, EM, MZ; Università degli Studi di Padova to CT, VB, BB, MP, and by the special grant 5 × 1.000 of AIRC (Associazione Italiana Ricerca sul Cancro) to FL.

Author contributions

EM, CT, VB, MF, MZ, BB and GC performed experiments; KP, RM, GC, BB, RR, GM, FG, AB, AP, FL, PM and GB collected samples in AIEOP centers; EM, RR and RM performed the statistical analysis; EM, GB, FL, MP designed the research, analyzed and interpreted data, and wrote the manuscript.

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Authors and Affiliations

  1. Istituto di Ricerca Pediatrica - Città della Speranza, Padova, Italy

    E Manara & M Zampini

  2. Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy

    G Basso, B Buldini, C Tregnago, V Bisio, M Frison, K Polato & M Pigazzi

  3. Clinica Pediatrica, Università di Bologna, Ospedale ‘S. Orsola’, Bologna, Italy

    R Rondelli, R Masetti & A Pession

  4. Clinica Pediatrica, Centro Ricerca Tettamanti, Università di Milano-Bicocca, Monza, Italia

    G Cazzaniga & A Biondi

  5. Department of Paediatric Haemato-Oncology, Santobono-Pausilipon Hospital, Napoli, Italy

    G Menna

  6. Stem Cell Transplantation and Cellular Therapy Division, Paediatric Onco-Haematology, Regina Margherita Children's Hospital, Torino, Italy

    F Fagioli

  7. IRCCS Bambino Gesù Children’s Hospital Rome, Università di Pavia, Rome, Italy

    P Merli & F Locatelli

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Correspondence to G Basso.

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Manara, E., Basso, G., Zampini, M. et al. Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group. Leukemia 31, 18–25 (2017). https://doi.org/10.1038/leu.2016.177

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