Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation.

J Clin Oncol 2016 Oct;34(30):3627-3637

Matteo G. Della Porta, Anna Gallì, Silvia Zibellini, Ettore Rizzo, Marianna Rossi, Marta Ubezio, Virginia V. Ferretti, Silvia Catricalà, Chiara Milanesi, Emilio P. Alessandrino, and Mario Cazzola, Fondazione IRCCS Policlinico, San Matteo; Matteo G. Della Porta, Alberto Malovini, Ivan Limongelli, Riccardo Bellazzi, and Mario Cazzola, University of Pavia, Pavia; Andrea Bacigalupo, Maria Teresa van Lint, Sarah Pozzi, and Silvia Luchetti, San Martino Hospital, Genova; Massimo Bernardi, Cristina Tresoldi, and Fabio Ciceri, San Raffaele Scientific Institute; Paola Marenco and Laura Pezzetti, Ospedale Niguarda Ca' Granda, Milan; Bernardino Allione and Benedetto Bruno, University of Torino, Torino; Pietro Pioltelli, Ospedale San Gerardo, Monza; Alberto Bosi, Azienda Ospedaliera Universitaria Careggi, Florence; Maria Teresa Voso and Simona Sica, Catholic University of the Sacred Heart, Rome; Mariella Cuzzola, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria; Emanuele Angelucci, Ospedale Oncologico di Riferimento Regionale A. Businco, Cagliari; Orietta Spinelli and Alessandro Rambaldi, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo; Francesca Bonifazi, University of Bologna, Bologna; Armando Santoro, Humanitas University, Rozzano, Italy; Alberto Riva, University of Florida, Gainesville, FL; and Elli Papaemmanuil, Memorial Sloan-Kettering Cancer Center, New York, NY.

Purpose: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear.

Patients And Methods: We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT.

Results: Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%.

Conclusion: Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

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Source
http://dx.doi.org/10.1200/JCO.2016.67.3616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366344PMC
October 2016
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