title: Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features.
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 (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.
authors.affiliation: MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.|Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Palomo
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Garcia
authors.affiliation: Hematology Service, ICO-Hospital Duran i Reynals, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Arnan
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Blanca
authors.initials: B
authors.lastname: Xicoy
authors.affiliation: MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Fuster
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Cabezón
authors.affiliation: Hematology Service, ICO-Hospital Josep Trueta, Girona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Coll
authors.affiliation: MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Vera
authors.initials: V
authors.lastname: Ademà
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Grau
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Maria-José
authors.initials: MJ
authors.lastname: Jiménez
authors.affiliation: Hematology Service, ICO-Hospital Duran i Reynals, Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Pomares
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Marcé
authors.affiliation: MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Mallo
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Fuensanta
authors.initials: F
authors.lastname: Millá
authors.affiliation: Hematology Service, ICO-Hospital Duran i Reynals, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Alonso
authors.affiliation: Hematology Service, ICO-Hospital Duran i Reynals, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Sureda
authors.affiliation: Hematology Service, ICO-Hospital Josep Trueta, Girona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Gallardo
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Evarist
authors.initials: E
authors.lastname: Feliu
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Josep-Maria
authors.initials: JM
authors.lastname: Ribera
authors.affiliation: MDS Research Group, Josep Carreras Leukaemia Research Institute, ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Solé
authors.affiliation: Hematology Service, ICO-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.
authors.forename: Lurdes
authors.initials: L
authors.lastname: Zamora
mesh_terms: D000368:Aged; D002471:Cell Transformation, Neoplastic; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics; D015477:Leukemia, Myelomonocytic, Chronic / Q000175:diagnosis / Q000235:genetics*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis; D016896:Treatment Outcome
keywords: chronic myelomonocytic leukemia; gene mutations; normal karyotype; prognostic factors; targeted deep sequencing