TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes

Tapan M. Kadia, Preetesh Jain, Farhad Ravandi, Guillermo Garcia-Manero, Michael Andreef, Koichi Takahashi, Gautam Borthakur, Elias Jabbour, Marina Konopleva, Naval G. Daver, Courtney Dinardo, Sherry Pierce, Rashmi Kanagal-Shamanna, Keyur Patel, Zeev Estrov, Jorge Cortes, Hagop M. Kantarjian

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3484-3491
Number of pages8
JournalCancer
Volume122
Issue number22
DOIs
StatePublished - Nov 15 2016
Externally publishedYes

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Acute Myeloid Leukemia
Mutation
Neoplasms
Proteins
Therapeutics
fms-Like Tyrosine Kinase 3
Chromosomes, Human, Pair 5
Chromosomes, Human, Pair 17
Chromosomes, Human, Pair 7
Incidence
Missense Mutation
Amino Acid Substitution
Karyotype
Histidine
Codon
Sarcoma
Arginine
Age Groups
Bone Marrow
Drug Therapy

Keywords

  • acute myeloid leukemia (AML)
  • adverse prognosis
  • biomarkers of resistance
  • complex karyotype
  • tumor protein 53 (TP53)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kadia, T. M., Jain, P., Ravandi, F., Garcia-Manero, G., Andreef, M., Takahashi, K., ... Kantarjian, H. M. (2016). TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. Cancer, 122(22), 3484-3491. https://doi.org/10.1002/cncr.30203

TP53 mutations in newly diagnosed acute myeloid leukemia : Clinicomolecular characteristics, response to therapy, and outcomes. / Kadia, Tapan M.; Jain, Preetesh; Ravandi, Farhad; Garcia-Manero, Guillermo; Andreef, Michael; Takahashi, Koichi; Borthakur, Gautam; Jabbour, Elias; Konopleva, Marina; Daver, Naval G.; Dinardo, Courtney; Pierce, Sherry; Kanagal-Shamanna, Rashmi; Patel, Keyur; Estrov, Zeev; Cortes, Jorge; Kantarjian, Hagop M.

In: Cancer, Vol. 122, No. 22, 15.11.2016, p. 3484-3491.

Research output: Contribution to journalArticle

Kadia, TM, Jain, P, Ravandi, F, Garcia-Manero, G, Andreef, M, Takahashi, K, Borthakur, G, Jabbour, E, Konopleva, M, Daver, NG, Dinardo, C, Pierce, S, Kanagal-Shamanna, R, Patel, K, Estrov, Z, Cortes, J & Kantarjian, HM 2016, 'TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes', Cancer, vol. 122, no. 22, pp. 3484-3491. https://doi.org/10.1002/cncr.30203
Kadia TM, Jain P, Ravandi F, Garcia-Manero G, Andreef M, Takahashi K et al. TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. Cancer. 2016 Nov 15;122(22):3484-3491. https://doi.org/10.1002/cncr.30203
Kadia, Tapan M. ; Jain, Preetesh ; Ravandi, Farhad ; Garcia-Manero, Guillermo ; Andreef, Michael ; Takahashi, Koichi ; Borthakur, Gautam ; Jabbour, Elias ; Konopleva, Marina ; Daver, Naval G. ; Dinardo, Courtney ; Pierce, Sherry ; Kanagal-Shamanna, Rashmi ; Patel, Keyur ; Estrov, Zeev ; Cortes, Jorge ; Kantarjian, Hagop M. / TP53 mutations in newly diagnosed acute myeloid leukemia : Clinicomolecular characteristics, response to therapy, and outcomes. In: Cancer. 2016 ; Vol. 122, No. 22. pp. 3484-3491.
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abstract = "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.",
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AU - Kadia, Tapan M.

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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.

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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.

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