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Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study

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Abstract

Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITDpositive patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITDnegative patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17–4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.

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Acknowledgements

We gratefully acknowledge all members of the International Consortium on Acute Promyelocytic Leukemia of the American Society of Hematology. This investigation was supported by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP–Grant #1998/14247-6) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNpQ - #573754/2008-0). In addition, ARLA received a fellowship from FAPESP (#2007/55067-1).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Medical School of Ribeirão Preto, Ribeirao Preto, Brazil

    Antonio R. Lucena-Araujo, Rafael H. Jacomo, Ana Silvia Lima & Eduardo M. Rego

  2. Center for Cell Based Therapy, Ribeirao Preto, Brazil

    Antonio R. Lucena-Araujo, Rafael H. Jacomo, Ana Silvia Lima & Eduardo M. Rego

  3. Dana-Farber Cancer Institute, Boston, MA, USA

    Haesook T. Kim

  4. Fundação HEMOPE, Recife, Brazil

    Raul A. Melo

  5. Federal University of Rio Grande do Sul, Porto Alegre, Brazil

    Rosane Bittencourt

  6. Federal University of Paraná, Curitiba, Brazil

    Ricardo Pasquini

  7. University of Campinas, Campinas, Brazil

    Katia Pagnano

  8. Federal University of Minas Gerais, Belo Horizonte, Brazil

    Evandro M. Fagundes

  9. Federal University of Sao Paulo, Sao Paulo, Brazil

    Maria de Lourdes Chauffaille

  10. Santa Casa Medical School, Sao Paulo, Brazil

    Carlos S. Chiattone

  11. Clínica Ruiz de Puebla, Puebla, Mexico

    Guillermo Ruiz-Argüelles

  12. Hospital del Salvador, Santiago, Chile

    Maria Soledad Undurraga

  13. Asociación Española Primera de Socorros Mutuos, Montevideo, Uruguay

    Lem Martinez

  14. Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Hau C. Kwaan

  15. Albert Einstein Cancer Center, New York, NY, USA

    Robert Gallagher

  16. University Medical Center, Freiburg, Germany

    Charlotte M. Niemeyer

  17. Stanford University, Stanford, CA, USA

    Stanley L. Schrier

  18. Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College, New York, NY, USA

    Martin S. Tallman

  19. King’s College London School of Medicine, London, UK

    David Grimwade

  20. Hannover Medical School, Hannover, Germany

    Arnold Ganser

  21. Harvard Medical School, Boston, MA, USA

    Nancy Berliner

  22. St. Jude Children’s Research Hospital, Memphis, TN, USA

    Raul C. Ribeiro

  23. University Tor Vergata, Rome, Italy

    Francesco Lo-Coco

  24. Santa Lucia Foundation, Rome, Italy

    Francesco Lo-Coco

  25. Erasmus University Medical Center, Rotterdam, The Netherlands

    Bob Löwenberg

  26. Valencia University Medical School, Valencia, Spain

    Miguel A. Sanz

  27. Medical School of Ribeirao Preto and Center for Cell Based Therapy, University of São Paulo, Av. Bandeirantes, 3900, Ribeirao Preto, SP, 14048-900, Brazil

    Eduardo M. Rego

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  1. Antonio R. Lucena-Araujo
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Correspondence to Eduardo M. Rego.

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Lucena-Araujo, A.R., Kim, H.T., Jacomo, R.H. et al. Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline-based chemotherapy: an International Consortium on Acute Promyelocytic Leukemia study. Ann Hematol 93, 2001–2010 (2014). https://doi.org/10.1007/s00277-014-2142-9

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