Detalle Publicación

Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms

Autores: Montalbán-Bravo, G. (Autor de correspondencia); Takahashi, K.; Patel, K.; Wang, F.; Xingzhi, S.; Nogueras, G.; Huang, X.; Alfonso Piérola, Ana; Jabbour, E.; Colla, S.; Gañán-Gómez, I.; Borthakur, G.; Daver, N.; Estrov, Z.; Kadia, T.; Pemmaraju, N.; Ravandi, F.; Bueso-Ramos, C.; Chamseddine, A.; Konopleva, M.; Zhang, J.; Kantarjian, H.; Futreal, A.; García-Manero, G.
Título de la revista: ONCOTARGET
ISSN: 1949-2553
Volumen: 9
Número: 11
Páginas: 9714 - 9727
Fecha de publicación: 2018
The prognostic and predictive value of sequencing analysis in myelodysplastic syndromes (MDS) has not been fully integrated into clinical practice. We performed whole exome sequencing (WES) of bone marrow samples from 83 patients with MDS and 31 with MDS/MPN identifying 218 driver mutations in 31 genes in 98 (86%) patients. A total of 65 (57%) patients received therapy with hypomethylating agents. By univariate analysis, mutations in BCOR, STAG2, TP53 and SF3B1 significantly influenced survival. Increased number of mutations (¿ 3), but not clonal heterogeneity, predicted for shorter survival and LFS. Presence of 3 or more mutations also predicted for lower likelihood of response (26 vs 50%, p = 0.055), and shorter response duration (3.6 vs 26.5 months, p = 0.022). By multivariate analysis, TP53 mutations (HR 3.1, CI 1.3-7.5, p = 0.011) and number of mutations (¿ 3) (HR 2.5, CI 1.3-4.8, p = 0.005) predicted for shorter survival. A novel prognostic model integrating this mutation data with IPSS-R separated patients into three categories with median survival of not reached, 29 months and 12 months respectively (p < 0.001) and increased stratification potential, compared to IPSS-R, in patients with high/very-high IPSS-R. This model was validated in a separate cohort of 413 patients with untreated MDS. Although the use of WES did not provide significant more information than that obtained with targeted sequencing, our findings indicate that increased number of mutations is an inde