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

Antonio R. Lucena-Araujo, Haesook T. Kim, Rafael H. Jacomo, Raul A. Melo, Rosane Bittencourt, Ricardo Pasquini, Katia Pagnano, Evandro M. Fagundes, Maria de Lourdes Chauffaille, Carlos S. Chiattone, Ana Silvia Lima, Guillermo Ruiz-Argüelles, Maria Soledad Undurraga, Lem Martinez, Hau C. Kwaan, Robert Gallagher, Charlotte M. Niemeyer, Stanley L. Schrier, Martin S. Tallman, David GrimwadeArnold Ganser, Nancy Berliner, Raul C. Ribeiro, Francesco Lo-Coco, Bob Löwenberg, Miguel A. Sanz, Eduardo M. Rego

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2001-2010
Number of pages10
JournalAnnals of Hematology
Volume93
Issue number12
DOIs
Publication statusPublished - 2014

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Keywords

  • Acute promyelocytic leukemia
  • ATRA
  • Developing countries
  • FLT3-ITD mutations
  • IC-APL

ASJC Scopus subject areas

  • Hematology
  • Medicine(all)

Cite this

Lucena-Araujo, A. R., Kim, H. T., Jacomo, R. H., Melo, R. A., Bittencourt, R., Pasquini, R., Pagnano, K., Fagundes, E. M., Chauffaille, M. D. L., Chiattone, C. S., Lima, A. S., Ruiz-Argüelles, G., Undurraga, M. S., Martinez, L., Kwaan, H. C., Gallagher, R., Niemeyer, C. M., Schrier, S. L., Tallman, M. S., ... Rego, E. M. (2014). 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. Annals of Hematology, 93(12), 2001-2010. https://doi.org/10.1007/s00277-014-2142-9