Oncotarget

Research Papers:

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

Guillermo Montalban-Bravo _, Koichi Takahashi, Keyur Patel, Feng Wang, Song Xingzhi, Graciela M. Nogueras, Xuelin Huang, Ana Alfonso Pierola, Elias Jabbour, Simona Colla, Irene Gañan-Gomez, Gautham Borthakur, Naval Daver, Zeev Estrov, Tapan Kadia, Naveen Pemmaraju, Farhad Ravandi, Carlos Bueso-Ramos, Ali Chamseddine, Marina Konopleva, Jianhua Zhang, Hagop Kantarjian, Andrew Futreal and Guillermo Garcia-Manero

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Oncotarget. 2018; 9:9714-9727. https://doi.org/10.18632/oncotarget.23882

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Abstract

Guillermo Montalban-Bravo1,*, Koichi Takahashi1,2,*, Keyur Patel3, Feng Wang2, Song Xingzhi4, Graciela M. Nogueras5, Xuelin Huang5, Ana Alfonso Pierola1, Elias Jabbour1, Simona Colla1, Irene Gañan-Gomez1, Gautham Borthakur1, Naval Daver1, Zeev Estrov1, Tapan Kadia1, Naveen Pemmaraju1, Farhad Ravandi1, Carlos Bueso-Ramos3, Ali Chamseddine1, Marina Konopleva1, Jianhua Zhang4, Hagop Kantarjian1, Andrew Futreal2 and Guillermo Garcia-Manero1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Applied Cancer Science Institute, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

5Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

*These authors contributed equally to this work

Correspondence to:

Guillermo Garcia-Manero, email: [email protected]

Keywords: myelodysplastic syndromes; chronic myelomonocytic leukemia; response; prognosis; mutations

Received: February 24, 2017     Accepted: November 11, 2017     Published: January 03, 2018

ABSTRACT

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.


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