Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features
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Laura Palomo1,2, Olga Garcia3, Montse Arnan4, Blanca Xicoy3, Francisco Fuster1, Marta Cabezón3, Rosa Coll5, Vera Ademà1, Javier Grau3, Maria-José Jiménez3, Helena Pomares4, Sílvia Marcé3, Mar Mallo1, Fuensanta Millá3, Esther Alonso4, Anna Sureda4, David Gallardo5, Evarist Feliu3, Josep-Maria Ribera3, Francesc Solé1, Lurdes Zamora3
1MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain
2Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Badalona, Spain
3Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain
4Hematology Service, ICO-Hospital Duran i Reynals, Barcelona, Spain
5Hematology Service, ICO-Hospital Josep Trueta, Girona, Spain
Lurdes Zamora, email: email@example.com
Keywords: chronic myelomonocytic leukemia, normal karyotype, gene mutations, targeted deep sequencing, prognostic factors
Received: May 20, 2016 Accepted: July 01, 2016 Published: July 29, 2016
Clonal cytogenetic abnormalities are found in 20-30% of patients with chronic myelomonocytic leukemia (CMML), while gene mutations are present in >90% of cases. Patients with low risk cytogenetic features account for 80% of CMML cases and often fall into the low risk categories of CMML prognostic scoring systems, but the outcome differs considerably among them. We performed targeted deep sequencing of 83 myeloid-related genes in 56 CMML patients with low risk cytogenetic features or uninformative conventional cytogenetics (CC) at diagnosis, with the aim to identify the genetic characteristics of patients with a more aggressive disease. Targeted sequencing was also performed in a subset of these patients at time of acute myeloid leukemia (AML) transformation. Overall, 98% of patients harbored at least one mutation. Mutations in cell signaling genes were acquired at time of AML progression. Mutations in ASXL1, EZH2 and NRAS correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS). Patients with SRSF2 mutations associated with poorer OS, while absence of TET2 mutations (TET2wt) was predictive of shorter PFS. A decrease in OS and PFS was observed as the number of adverse risk gene mutations (ASXL1, EZH2, NRAS and SRSF2) increased. On multivariate analyses, CMML-specific scoring system (CPSS) and presence of adverse risk gene mutations remained significant for OS, while CPSS and TET2wt were predictive of PFS. These results confirm that mutation analysis can add prognostic value to patients with CMML and low risk cytogenetic features or uninformative CC.
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