Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia
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Open Access
- 8 September 2016
- journal article
- Published by American Society of Hematology in Blood
- Vol. 128 (10), 1408-1417
- https://doi.org/10.1182/blood-2016-05-714030
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.Keywords
This publication has 42 references indexed in Scilit:
- OncogenicCSF3RMutations in Chronic Neutrophilic Leukemia and Atypical CMLNew England Journal of Medicine, 2013
- SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic impact in CMMLLeukemia, 2013
- Recurrent SETBP1 mutations in atypical chronic myeloid leukemiaNature Genetics, 2012
- Clinical Effect of Point Mutations in Myelodysplastic SyndromesNew England Journal of Medicine, 2011
- Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System (WPSS)Haematologica, 2011
- A framework for variation discovery and genotyping using next-generation DNA sequencing dataNature Genetics, 2011
- Cytogenetic risk stratification in chronic myelomonocytic leukemiaHaematologica, 2010
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- Morphological evaluation of monocytes and their precursorsPublished by Ferrata Storti Foundation (Haematologica) ,2009
- A Proportional Hazards Model for the Subdistribution of a Competing RiskJournal of the American Statistical Association, 1999