Myeloid Panel Analysis Imperative for Risk Assessment in Patients With CCUS

Mutational analysis is the recommended course of action for patients with clonal cytopenia of undetermined significance (CCUS) who have had a bone marrow examination, according to a study recently published in Lancet Haematology. By determining a patient’s mutation profile, number of mutations, and the presence of high-risk mutations, clinicians can better predict a patient’s disease course and implement earlier intervention methods.¹

Genetic Mutation Concept | image credit: lucadp - stock.adobe.com

CCUS is characterized by low levels of certain types of blood cells that occurs for unknown reasons. Individuals impacted by CCUS can carry various genetic mutations and harbor an increased risk for progression towards myeloid malignancies such as acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Typically, CCUS is diagnosed following a routine blood test and specialized molecular testing when a cause of low blood count cannot be discerned.²

Although somatic mutations are often documented in patients with cytopenia who lack hematological diagnoses, studies on this patient population have been fairly limited in their design, whether due to small cohorts or retrospective analysis. To expand on clinical knowledge in this area, researchers conducted a prospective, long-term investigation into the mutation-related outcomes associated with CCUS and the clinical significance of detecting these mutations.¹

From July 2014 through July 2016, a large cohort of patients submitted bone marrow samples to the Haematological Malignancy Diagnostic Service in Leeds, UK, for investigation of cytopenia. Mononuclear cells from these samples underwent a targeted high-throughput sequencing of 27 genes (referred to as the myeloid panel). Further rounds of genotyping were conducted if the patient was highly suspected of clinical disease (due to progression to a myeloid malignancy or lack of discernable diagnosis). Patients were followed up with for just over 4.5 years on average.

A total of 2083 samples were received during this analysis and patients had an average age of 72 years. Throughout the entire cohort, 856 patients (41.1%) were identified with a somatic mutation.

A morphological diagnosis was confirmed in 28.7% (n = 598) of patients. In this subgroup, 85% (n = 509) of individuals went on to receive a myeloid malignancy. Myelodysplastic syndrome was the most prevalent malignancy, occurring in 373 of those 509 patients (73%). Furthermore, 319 of these 373 patients (85.5%) carried at least one mutation in a gene of the myeloid panel—the most common included mutation in the SF3B1 (n = 93; 24.9%), TET2 (n = 89; 23.9%), and ASXL1 (n = 86; 23.1%) genes.

There were 1485 patients identified as non-diagnostic without any morphological diagnosis. Results from the myeloid panel revealed that 400 of these patients (26.9%) were carriers of at least one mutation. These 400 patients were characterized as having CCUS while the remaining 1085 (73.1%) were characterized as having idiopathic cytopenia of undetermined significance (ICUS).

The authors noted that there were no significant differences observed regarding baseline platelet concentrations, hemoglobin, or white blood cell counts between these groups; however, those with CCUS exhibited significantly increased cell volume and monocyte-basophil-eosinophil count on average, as well as a significantly reduced count of neutrophils (P < .0001) compared with those with ICUS.

For patients with CCUS, the most frequent mutations occurred in TET2, SRSF2, and DNMT3A. Mutations in SF3B1, ASXL1, RUNX1, TP53, STAG2, and EZH2 were more prevalent in patients enduring myelodysplastic syndrome. Additionally, patients with myelodysplastic syndrome had a significantly higher number of mutations on average compared with patients with CCUS (2 vs 1; P < .0001).

Worse survival outcomes were significantly associated with mutations in BCOR (P = .0056), TP53 (P = .0055), and ASXL1 (P = .0009). Notably, the researchers highlighted how the actual number of mutations an individual harbored was the most significant predictor of their vulnerability to myeloid malignancy progression (2 mutations, P = .0024; 3 mutations, P = .0004).

Results from the samples that underwent extended sequencing demonstrated recurring mutations taking place in DDX41, as well as UBA1. This discovery led researchers to believe these genes should be incorporated into clinical testing panels. Considering these findings, they emphasize the importance of early monitoring and detection of these mutations to give patients adequate chances to receive interventions.

References

1. 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. 2024 Jan;11(1):e51-e61. doi: 10.1016/S2352-3026(23)00340-X

2. What is clonal cytopenia of undetermined significance (CCUS)? Dana-Farber Cancer Institute. Accessed January 23, 2024. https://blog.dana-farber.org/insight/2019/04/what-is-clonal-cytopenia-of-undetermined-significance-ccus/