TY - JOUR
T1 - Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents
AU - Takahashi, Koichi
AU - Patel, Keyur
AU - Bueso-Ramos, Carlos
AU - Zhang, Jianhua
AU - Gumbs, Curtis
AU - Jabbour, Elias
AU - Kadia, Tapan
AU - Andreff, Michael
AU - Konopleva, Marina
AU - Di Nardo, Courtney
AU - Daver, Naval
AU - Cortes, Jorge
AU - Estrov, Zeev
AU - Futreal, Andrew
AU - Kantarjian, Hagop
AU - Garcia-Manero, Guillermo
PY - 2016/3/22
Y1 - 2016/3/22
N2 - 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.
AB - 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.
KW - Hypomethylating agents
KW - Myelodysplastic syndromes
KW - TP53
UR - http://www.scopus.com/inward/record.url?scp=84971622488&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84971622488&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.7290
DO - 10.18632/oncotarget.7290
M3 - Article
C2 - 26871476
AN - SCOPUS:84971622488
SN - 1949-2553
VL - 7
SP - 14172
EP - 14187
JO - Oncotarget
JF - Oncotarget
IS - 12
ER -