Genomic Landscape and Risk Stratification in Chronic Myelomonocytic Leukemia

The advent of next-generation sequencing has allowed for the annotation of a vast array of recurrent somatic mutations across human malignancies, ushering in a new era of precision oncology. Chronic myelomonocytic leukemia is recognized as a myelodysplastic/myeloproliferative neoplasm and displays heterogenous clinical and genetic features. Herein, we review what is currently understood regarding the genomic landscape of this disease and discuss how somatic mutations have impacted current risk stratification methods.

Genomic studies in chronic myelomonocytic leukemia have identified a characteristic spectrum of cytogenetic and molecular abnormalities. Chromosomal abnormalities are detected in ~30% of patients and somatic gene mutations in up to 90% of patients, most commonly in TET2, SRSF2, and ASXL1. While cytogenetic abnormalities have long been known to impact the prognosis of myeloid neoplasms, recent studies have identified that somatic mutations impact prognosis independent of cytogenetic and clinical variables. This is best exemplified by mutations in ASXL1, which have been uniformly associated with inferior survival. These findings have led to the development of three molecularly inspired prognostic models, in an attempt to more accurately prognosticate in the disease. Our understanding of the genomic landscape of chronic myelomonocytic leukemia continues to evolve, with somatic mutations demonstrating an expanding role in diagnosis, risk stratification, and therapeutic decision-making. Given these findings, molecular profiling by next-generation sequencing should be considered standard of care in all patients.