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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Lucena-Araujo, Antonio R. ^{[1, 2]} ; Kim, Haesook T. ^[3] ; Jacomo, Rafael H. ^{[1, 2]} ; Melo, Raul A. ^[4] ; Bittencourt, Rosane ^[5] ; Pasquini, Ricardo ^[6] ; Pagnano, Katia ^[7] ; Fagundes, Evandro M. ^[8] ; Chauffaille, Maria de Lourdes ^[9] ; Chiattone, Carlos S. ^[10] ; Lima, Ana Silvia ^{[1, 2]} ; Ruiz-Argueelles, Guillermo ^[11] ; Soledad Undurraga, Maria ^[12] ; Martinez, Lem ^[13] ; Kwaan, Hau C. ^[14] ; Gallagher, Robert ^[15] ; Niemeyer, Charlotte M. ^[16] ; Schrier, Stanley L. ^[17] ; Tallman, Martin S. ^[18] ; Grimwade, David ^[19] ; Ganser, Arnold ^[20] ; Berliner, Nancy ^[21] ; Ribeiro, Raul C. ^[22] ; Lo-Coco, Francesco ^{[23, 24]} ; Lowenberg, Bob ^[25] ; Sanz, Miguel A. ^[26] ; Rego, Eduardo M. ^{[27, 1, 2]}

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^[1] Med Sch Ribeirao Preto, Ribeirao Preto - Brazil

^[2] Ctr Cell Based Therapy, Ribeirao Preto - Brazil

^[3] Dana Farber Canc Inst, Boston, MA 02115 - USA

^[4] Fundacao HEMOPE, Recife, PE - Brazil

^[5] Univ Fed Rio Grande do Sul, Porto Alegre, RS - Brazil

^[6] Univ Fed Parana, BR-80060000 Curitiba, Parana - Brazil

^[7] Univ Estadual Campinas, Campinas, SP - Brazil

^[8] Univ Fed Minas Gerais, Belo Horizonte, MG - Brazil

^[9] Univ Fed Sao Paulo, Sao Paulo - Brazil

^[10] Santa Casa Med Sch, Sao Paulo - Brazil

^[11] Clin Ruiz Puebla, Puebla - Mexico

^[12] Hosp Salvador, Santiago - Chile

^[13] Asociac Espanola Primera Socorros Mutuos, Montevideo - Uruguay

^[14] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 - USA

^[15] Albert Einstein Canc Ctr, New York, NY - USA

^[16] Univ Med Ctr, Freiburg - Germany

^[17] Stanford Univ, Stanford, CA 94305 - USA

^[18] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY - USA

^[19] Kings Coll London, Sch Med, London WC2R 2LS - England

^[20] Hannover Med Sch, Hannover - Germany

^[21] Harvard Univ, Sch Med, Boston, MA - USA

^[22] St Jude Childrens Res Hosp, Memphis, TN 38105 - USA

^[23] Santa Lucia Fdn, Rome - Italy

^[24] Univ Roma Tor Vergata, Rome - Italy

^[25] Erasmus Univ, Med Ctr, Rotterdam - Netherlands

^[26] Univ Valencia, Sch Med, Valencia - Spain

^[27] Univ Sao Paulo, Med Sch Ribeirao Preto, BR-14048900 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ANNALS OF HEMATOLOGY; v. 93, n. 12, p. 2001-2010, DEC 2014.
• Citações Web of Science: 14

Resumo

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. (AU)

• Processo FAPESP: 07/55067-1 - Analise in vivo e in vitro da acao oncogenica da forma delta n do gene p73 na leucemia promielocitica aguda.
• Beneficiário: Antonio Roberto Lucena de Araújo
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 98/14247-6 - Center for Research on Cell-Based Therapy
• Beneficiário: Marco Antonio Zago
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs