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

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.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Med Sch Ribeirao Preto, Ribeirao Preto, BrazilCtr Cell Based Therapy, Ribeirao Preto, BrazilDana Farber Canc Inst, Boston, MA 02115 USAFundacao HEMOPE, Recife, PE, BrazilUniv Fed Rio Grande do Sul, Porto Alegre, RS, BrazilUniv Fed Parana, BR-80060000 Curitiba, Parana, BrazilUniv Estadual Campinas, Campinas, SP, BrazilUniv Fed Minas Gerais, Belo Horizonte, MG, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilSanta Casa Med Sch, São Paulo, BrazilClin Ruiz Puebla, Puebla, MexicoHosp Salvador, Santiago, ChileAsociac Espanola Primera Socorros Mutuos, Montevideo, UruguayNorthwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USAAlbert Einstein Canc Ctr, New York, NY USAUniv Med Ctr, Freiburg, GermanyStanford Univ, Stanford, CA 94305 USAWeill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY USAKings Coll London, Sch Med, London WC2R 2LS, EnglandHannover Med Sch, Hannover, GermanyHarvard Univ, Sch Med, Boston, MA USASt Jude Childrens Res Hosp, Memphis, TN 38105 USAUniv Roma Tor Vergata, Rome, ItalySanta Lucia Fdn, Rome, ItalyErasmus Univ, Med Ctr, Rotterdam, NetherlandsUniv Valencia, Sch Med, Valencia, SpainUniv São Paulo, Med Sch Ribeirao Preto, BR-14048900 Ribeirao Preto, SP, BrazilUniversidade Federal de São Paulo, São Paulo, BrazilFAPESP: 1998/14247-6CNPq: 573754/2008-0FAPESP: 2007/55067-1Web of Scienc