Prognostic Score Including Gene Mutations in Chronic Myelomonocytic Leukemia
Top Cited Papers
- 1 July 2013
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 31 (19), 2428-2436
- https://doi.org/10.1200/jco.2012.47.3314
Abstract
Several prognostic scoring systems have been proposed for chronic myelomonocytic leukemia (CMML), a disease in which some gene mutations—including ASXL1—have been associated with poor prognosis in univariable analyses. We developed and validated a prognostic score for overall survival (OS) based on mutational status and standard clinical variables. We genotyped ASXL1 and up to 18 other genes including epigenetic (TET2, EZH2, IDH1, IDH2, DNMT3A), splicing (SF3B1, SRSF2, ZRSF2, U2AF1), transcription (RUNX1, NPM1, TP53), and signaling (NRAS, KRAS, CBL, JAK2, FLT3) regulators in 312 patients with CMML. Genotypes and clinical variables were included in a multivariable Cox model of OS validated by bootstrapping. A scoring system was developed using regression coefficients from this model. ASXL1 mutations (P < .0001) and, to a lesser extent, SRSF2 (P = .03), CBL (P = .003), and IDH2 (P = .03) mutations predicted inferior OS in univariable analysis. The retained independent prognostic factors included ASXL1 mutations, age older than 65 years, WBC count greater than 15 ×109/L, platelet count less than 100 ×109/L, and anemia (hemoglobin < 10 g/dL in female patients, < 11g/dL in male patients). The resulting five-parameter prognostic score delineated three groups of patients with median OS not reached, 38.5 months, and 14.4 months, respectively (P < .0001), and was validated in an independent cohort of 165 patients (P < .0001). A new prognostic score including ASXL1 status, age, hemoglobin, WBC, and platelet counts defines three groups of CMML patients with distinct outcomes. Based on concordance analysis, this score appears more discriminative than those based solely on clinical parameters.Keywords
This publication has 65 references indexed in Scilit:
- Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid LeukemiaNew England Journal of Medicine, 2012
- Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in miceProceedings of the National Academy of Sciences of the United States of America, 2011
- New mutations and pathogenesis of myeloproliferative neoplasmsBlood, 2011
- Clinical Effect of Point Mutations in Myelodysplastic SyndromesNew England Journal of Medicine, 2011
- Tet2 Loss Leads to Increased Hematopoietic Stem Cell Self-Renewal and Myeloid TransformationCancer Cell, 2011
- Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignanciesBlood, 2009
- Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasmsBlood, 2009
- High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patientsBlood, 2009
- 250K Single Nucleotide Polymorphism Array Karyotyping Identifies Acquired Uniparental Disomy and Homozygous Mutations, Including Novel Missense Substitutions of c-Cbl, in Myeloid MalignanciesCancer Research, 2008
- FLT3 Mutations Confer Enhanced Proliferation and Survival Properties to Multipotent Progenitors in a Murine Model of Chronic Myelomonocytic LeukemiaCancer Cell, 2007