Mutational Status Predicts Survival Outcomes Among Patients With Clonal Cytopenia of Undetermined Significance

Mutational status predicted survival outcomes among patients with clonal cytopenia without a confirmed hematological diagnosis who had undergone bone marrow examination, according to findings from a prospective cohort study published in The Lancet Haematology. 

Patients with clonal cytopenia without a confirmed hematological diagnosis, known as clonal cytopenia of undetermined significance (CCUS), who also possess somatic mutations, have “an increased risk of progression to a myeloid malignancy and worse overall survival than those with no such mutations,” stated Catherine Cargo, MB, PhD, St James's University Hospital, Leeds, United Kingdom, and coauthors. 

The study authors aimed to expand the current research on this patient population in a large cohort. To do so, the bone marrow samples of 2083 patients who were referred for investigation of cytopenia were included in this study. It was noted that patients with a history of myeloid malignancy were ineligible, and therefore, not included. Routine clinical testing and targeted sequencing were conducted on these samples. Then, baseline mutational analysis was assessed, including longitudinal blood counts, disease progression to a myeloid malignancy, and overall survival at the median follow-up. 

Among the total eligible patients whose samples were included, 598 were given a diagnosis based on their biopsy sample, and 1485 samples were deemed non-diagnostic. Of the non-diagnostic samples, clonal cytopenia of undetermined significance was indicated in 400 patients. 

The most common mutated genes among the 400 patients with clonal cytopenia of undetermined significance were TET2, SRSF2, and DNMT3A—80% of these patients (n = 320) presented with 1 or more of these genes. The study authors noted that although age, sex, and mutations in ASXL1, BCOR, and TP53 all were correlated with worsened overall survival, the number of mutations had the strongest predictive value for progression to a myeloid malignancy (2 mutations, p = 0.0024; 3 or more mutations, p = 0.0004). Through extended sequencing of bone marrow samples from a subgroup of patients with sequential samples and no mutations, repeated mutations in DDX41 and UBA1 were present. This finding indicated that these genes must be included in clinical test panels. 

Based on the study findings, Cargo and the study authors concluded, “Mutation analysis is advised in patients who have undergone bone marrow examination and have an otherwise-unexplained cytopenia.”

They added, “High-risk genetic mutations and increased numbers of mutations are predictive of both survival and progression within 5 years of presentation, warranting clinical surveillance and, when necessary, intervention.”

Source: 

Cargo C, Bernard E, Beinortas T, et al. Predicting cytopenias, progression, and survival in patients with clonal cytopenia of undetermined significance: a prospective cohort study. Lancet Haematol. Published online: January 2024. doi: 10.1016/S2352-3026(23)00340-X