title: 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.
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-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) 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.
authors: Medical School of Ribeirão Preto, Ribeirao Preto, Brazil.
authors: Antonio R
authors: AR
authors: Lucena-Araujo
authors: Haesook T
authors: HT
authors: Kim
authors: Rafael H
authors: RH
authors: Jacomo
authors: Raul A
authors: RA
authors: Melo
authors: Rosane
authors: R
authors: Bittencourt
authors: Ricardo
authors: R
authors: Pasquini
authors: Katia
authors: K
authors: Pagnano
authors: Evandro M
authors: EM
authors: Fagundes
authors: Maria de Lourdes
authors: Mde L
authors: Chauffaille
authors: Carlos S
authors: CS
authors: Chiattone
authors: Ana Silvia
authors: AS
authors: Lima
authors: Guillermo
authors: G
authors: Ruiz-Argüelles
authors: Maria Soledad
authors: MS
authors: Undurraga
authors: Lem
authors: L
authors: Martinez
authors: Hau C
authors: HC
authors: Kwaan
authors: Robert
authors: R
authors: Gallagher
authors: Charlotte M
authors: CM
authors: Niemeyer
authors: Stanley L
authors: SL
authors: Schrier
authors: Martin S
authors: MS
authors: Tallman
authors: David
authors: D
authors: Grimwade
authors: Arnold
authors: A
authors: Ganser
authors: Nancy
authors: N
authors: Berliner
authors: Raul C
authors: RC
authors: Ribeiro
authors: Francesco
authors: F
authors: Lo-Coco
authors: Bob
authors: B
authors: Löwenberg
authors: Miguel A
authors: MA
authors: Sanz
authors: Eduardo M
authors: EM
authors: Rego
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D004273:DNA, Neoplasm / Q000235:genetics; D003630:Daunorubicin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D007843:Latin America / Q000453:epidemiology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D004273:DNA, Neoplasm; D006454:Hemoglobins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D015255:Idarubicin; D003630:Daunorubicin