TY - JOUR
T1 - 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
T2 - an International Consortium on Acute Promyelocytic Leukemia study
AU - Lucena-Araujo, Antonio R.
AU - Kim, Haesook T.
AU - Jacomo, Rafael H.
AU - Melo, Raul A.
AU - Bittencourt, Rosane
AU - Pasquini, Ricardo
AU - Pagnano, Katia
AU - Fagundes, Evandro M.
AU - Chauffaille, Maria de Lourdes
AU - Chiattone, Carlos S.
AU - Lima, Ana Silvia
AU - Ruiz-Argüelles, Guillermo
AU - Undurraga, Maria Soledad
AU - Martinez, Lem
AU - Kwaan, Hau C.
AU - Gallagher, Robert
AU - Niemeyer, Charlotte M.
AU - Schrier, Stanley L.
AU - Tallman, Martin S.
AU - Grimwade, David
AU - Ganser, Arnold
AU - Berliner, Nancy
AU - Ribeiro, Raul C.
AU - Lo-Coco, Francesco
AU - Löwenberg, Bob
AU - Sanz, Miguel A.
AU - Rego, Eduardo M.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Acute promyelocytic leukemia
KW - ATRA
KW - Developing countries
KW - FLT3-ITD mutations
KW - IC-APL
UR - http://www.scopus.com/inward/record.url?scp=84922245042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922245042&partnerID=8YFLogxK
U2 - 10.1007/s00277-014-2142-9
DO - 10.1007/s00277-014-2142-9
M3 - Article
C2 - 24981688
AN - SCOPUS:84922245042
VL - 93
SP - 2001
EP - 2010
JO - Annals of Hematology
JF - Annals of Hematology
SN - 0939-5555
IS - 12
ER -