TY - JOUR
T1 - Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms
AU - Montalban-Bravo, Guillermo
AU - Takahashi, Koichi
AU - Patel, Keyur
AU - Wang, Feng
AU - Xingzhi, Song
AU - Nogueras, Graciela M.
AU - Huang, Xuelin
AU - Pierola, Ana Alfonso
AU - Jabbour, Elias
AU - Colla, Simona
AU - Gañan-Gomez, Irene
AU - Borthakur, Gautham
AU - Daver, Naval
AU - Estrov, Zeev
AU - Kadia, Tapan
AU - Pemmaraju, Naveen
AU - Ravandi, Farhad
AU - Bueso-Ramos, Carlos
AU - Chamseddine, Ali
AU - Konopleva, Marina
AU - Zhang, Jianhua
AU - Kantarjian, Hagop
AU - Futreal, Andrew
AU - Garcia-Manero, Guillermo
N1 - Publisher Copyright:
© Montalban-Bravo et al.
PY - 2018
Y1 - 2018
N2 - 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 independent prognostic factor in MDS and that mutation data can add value to clinical prognostic models.
AB - 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 independent prognostic factor in MDS and that mutation data can add value to clinical prognostic models.
KW - Chronic myelomonocytic leukemia
KW - Mutations
KW - Myelodysplastic syndromes
KW - Prognosis
KW - Response
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U2 - 10.18632/oncotarget.23882
DO - 10.18632/oncotarget.23882
M3 - Article
C2 - 29515765
AN - SCOPUS:85041721713
SN - 1949-2553
VL - 9
SP - 9714
EP - 9727
JO - Oncotarget
JF - Oncotarget
IS - 11
ER -