title: Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia.
abstract: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Chiara
authors.initials: C
authors.lastname: Elena
authors.affiliation: Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Anna
authors.initials: A
authors.lastname: Gallì
authors.affiliation: Department of Hematology, Hospital Universitario y Politecnico La Fe, Valencia, Spain;
authors.forename: Esperanza
authors.initials: E
authors.lastname: Such
authors.affiliation: Munich Leukemia Laboratory GmbH, Munich, Germany;
authors.forename: Manja
authors.initials: M
authors.lastname: Meggendorfer
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany;
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.affiliation: Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy;
authors.forename: Ettore
authors.initials: E
authors.lastname: Rizzo
authors.affiliation: Department of Hematology, Hospital Universitario y Politecnico La Fe, Valencia, Spain;
authors.forename: Jose
authors.initials: J
authors.lastname: Cervera
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy;
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Molteni
authors.affiliation: Munich Leukemia Laboratory GmbH, Munich, Germany;
authors.forename: Annette
authors.initials: A
authors.lastname: Fasan
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany;
authors.forename: Esther
authors.initials: E
authors.lastname: Schuler
authors.affiliation: Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Ilaria
authors.initials: I
authors.lastname: Ambaglio
authors.affiliation: Department of Hematology, Hospital Universitario y Politecnico La Fe, Valencia, Spain;
authors.forename: Maria
authors.initials: M
authors.lastname: Lopez-Pavia
authors.affiliation: Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Zibellini
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany;
authors.forename: Andrea
authors.initials: A
authors.lastname: Kuendgen
authors.affiliation: Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Erica
authors.initials: E
authors.lastname: Travaglino
authors.affiliation: Department of Hematology, Hospital Arnau de Vilanova, Valencia, Spain; and.
authors.forename: Reyes
authors.initials: R
authors.lastname: Sancho-Tello
authors.affiliation: Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Silvia
authors.initials: S
authors.lastname: Catricalà
authors.affiliation: Department of Hematology, Hospital de La Ribera, Alzira, Spain.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Vicente
authors.affiliation: Munich Leukemia Laboratory GmbH, Munich, Germany;
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Munich Leukemia Laboratory GmbH, Munich, Germany;
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: Department of Hematology, Hospital Universitario y Politecnico La Fe, Valencia, Spain;
authors.forename: Guillermo F
authors.initials: GF
authors.lastname: Sanz
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002869:Chromosome Aberrations; D000066491:Clinical Decision-Making; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D010641:Phenotype; D011379:Prognosis; D018570:Risk Assessment / Q000379:methods*; D012307:Risk Factors; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor