TY - JOUR
T1 - TP53 mutations in newly diagnosed acute myeloid leukemia
T2 - Clinicomolecular characteristics, response to therapy, and outcomes
AU - Kadia, Tapan M.
AU - Jain, Preetesh
AU - Ravandi, Farhad
AU - Garcia-Manero, Guillermo
AU - Andreef, Michael
AU - Takahashi, Koichi
AU - Borthakur, Gautam
AU - Jabbour, Elias
AU - Konopleva, Marina
AU - Daver, Naval G.
AU - Dinardo, Courtney
AU - Pierce, Sherry
AU - Kanagal-Shamanna, Rashmi
AU - Patel, Keyur
AU - Estrov, Zeev
AU - Cortes, Jorge
AU - Kantarjian, Hagop M.
N1 - Publisher Copyright:
© 2016 American Cancer Society
PY - 2016/11/15
Y1 - 2016/11/15
N2 - BACKGROUND: Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML). METHODS: Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis. RESULTS: TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53–mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ≥60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P =.04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P =.001), and overall survival (at 2 years: 9% vs 24%; P ≤.0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy). CONCLUSIONS: The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484–3491.
AB - BACKGROUND: Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML). METHODS: Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis. RESULTS: TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53–mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ≥60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P =.04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P =.001), and overall survival (at 2 years: 9% vs 24%; P ≤.0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy). CONCLUSIONS: The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484–3491.
KW - acute myeloid leukemia (AML)
KW - adverse prognosis
KW - biomarkers of resistance
KW - complex karyotype
KW - tumor protein 53 (TP53)
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U2 - 10.1002/cncr.30203
DO - 10.1002/cncr.30203
M3 - Article
AN - SCOPUS:84994291756
SN - 0008-543X
VL - 122
SP - 3484
EP - 3491
JO - Cancer
JF - Cancer
IS - 22
ER -