Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features

// Laura Palomo 1, 2 , Olga Garcia 3 , Montse Arnan 4 , Blanca Xicoy 3 , Francisco Fuster 1 , Marta Cabezon 3 , Rosa Coll 5 , Vera Adema 1 , Javier Grau 3 , Maria-Jose Jimenez 3 , Helena Pomares 4 , Silvia Marce 3 , Mar Mallo 1 , Fuensanta Milla 3 , Esther Alonso 4 , Anna Sureda 4 , David Gallardo 5 , Evarist Feliu 3 , Josep-Maria Ribera 3 , Francesc Sole 1 , Lurdes Zamora 3 1 MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autonoma de Barcelona, Badalona, Spain 2 Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Badalona, Spain 3 Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autonoma de Barcelona, Badalona, Spain 4 Hematology Service, ICO-Hospital Duran i Reynals, Barcelona, Spain 5 Hematology Service, ICO-Hospital Josep Trueta, Girona, Spain Correspondence to: Lurdes Zamora, email: lzamora@iconcologia.net 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 ABSTRACT 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 ( TET2 wt) 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.