Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents

Koichi Takahashi, Keyur Patel, Carlos Bueso-Ramos, Jianhua Zhang, Curtis Gumbs, Elias Jabbour, Tapan Kadia, Michael Andreff, Marina Konopleva, Courtney Di Nardo, Naval Daver, Jorge Cortes, Zeev Estrov, Andrew Futreal, Hagop Kantarjian, Guillermo Garcia-Manero

Research output: Contribution to journalArticle

Abstract

We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53-mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53-mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53-mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P <0.001). Further, TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53-mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53-mutated MDS are urgently needed.

Original languageEnglish (US)
Pages (from-to)14172-14187
Number of pages16
JournalOncotarget
Volume7
Issue number12
DOIs
StatePublished - Mar 22 2016
Externally publishedYes

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Myelodysplastic Syndromes
Mutation
Survival
Karyotype
Disease Progression
Multivariate Analysis

Keywords

  • Hypomethylating agents
  • Myelodysplastic syndromes
  • TP53

ASJC Scopus subject areas

  • Oncology

Cite this

Takahashi, K., Patel, K., Bueso-Ramos, C., Zhang, J., Gumbs, C., Jabbour, E., ... Garcia-Manero, G. (2016). Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. Oncotarget, 7(12), 14172-14187. https://doi.org/10.18632/oncotarget.7290

Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. / Takahashi, Koichi; Patel, Keyur; Bueso-Ramos, Carlos; Zhang, Jianhua; Gumbs, Curtis; Jabbour, Elias; Kadia, Tapan; Andreff, Michael; Konopleva, Marina; Di Nardo, Courtney; Daver, Naval; Cortes, Jorge; Estrov, Zeev; Futreal, Andrew; Kantarjian, Hagop; Garcia-Manero, Guillermo.

In: Oncotarget, Vol. 7, No. 12, 22.03.2016, p. 14172-14187.

Research output: Contribution to journalArticle

Takahashi, K, Patel, K, Bueso-Ramos, C, Zhang, J, Gumbs, C, Jabbour, E, Kadia, T, Andreff, M, Konopleva, M, Di Nardo, C, Daver, N, Cortes, J, Estrov, Z, Futreal, A, Kantarjian, H & Garcia-Manero, G 2016, 'Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents', Oncotarget, vol. 7, no. 12, pp. 14172-14187. https://doi.org/10.18632/oncotarget.7290
Takahashi K, Patel K, Bueso-Ramos C, Zhang J, Gumbs C, Jabbour E et al. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. Oncotarget. 2016 Mar 22;7(12):14172-14187. https://doi.org/10.18632/oncotarget.7290
Takahashi, Koichi ; Patel, Keyur ; Bueso-Ramos, Carlos ; Zhang, Jianhua ; Gumbs, Curtis ; Jabbour, Elias ; Kadia, Tapan ; Andreff, Michael ; Konopleva, Marina ; Di Nardo, Courtney ; Daver, Naval ; Cortes, Jorge ; Estrov, Zeev ; Futreal, Andrew ; Kantarjian, Hagop ; Garcia-Manero, Guillermo. / Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. In: Oncotarget. 2016 ; Vol. 7, No. 12. pp. 14172-14187.
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