Treatment-Related and De Novo Ccus Have Similar Molecular Features and Risk of Progression to Myeloid Malignancies
Authors: Santos Jennifer , Abbott Diana , Bosma Grace , Kent Andrew , Schwartz Marc , McMahon Christine M. , Gutman Jonathan , Pollyea Daniel A , Amaya Maria L 
Published: December 2024

Background
Clonal cytopenia of undetermined significance (CCUS) is characterized by cytopenia and a mutation in a gene associated with myeloid neoplasms without overt dysplasia (&lt;10%) in the bone marrow (Valent 2019; Osman 2021; Weeks et al. 2023). This condition is associated with increased risk of development of a myeloid neoplasm (Gallì et al. 2021; Osman et al. 2021). The risk of progression varies widely, with an estimate as high as 90% in certain populations (Malcovati et al. 2017; Weeks et al. 2023). The clonal hematopoetic risk score (CHRS) is a useful tool to differentiate high-risk populations (Weeks et al. 2023). Despite this risk score, it is unclear whether particular cohorts are at an increased risk of progression and thus warrant closer monitoring; additional studies to delineate sub-groups that are high risk of progression are needed. In our study, we analyzed two distinct cohorts. “Therapy-related CCUS” (t-CCUS) was defined as CCUS that occurs after treatment with cytotoxic chemotherapy, immunosuppressive agents or radiation administered for a prior neoplastic or non-neoplastic condition. “De novo CCUS” was defined as CCUS without this antecedent exposure. We sought to understand whether “t-CCUS” patients are at a higher risk of progression to a myeloid malignancy compared to “de novo” CCUS.
Methods
Our study was performed through a retrospective chart review of 36 patients at the University of Colorado and the Rocky Mountain Regional VA Medical Center with a CCUS diagnosis. We analyzed clinical, molecular and risk stratification between patients with de novo CCUS and t-CCUS. We hypothesized t-CCUS carried a higher risk of progression to a myeloid malignancy compared to de novo CCUS. Our null hypothesis was formally tested using an analysis of variance (AOV) test with a Tukey post-hoc test to identify which groups differed significantly. Primary outcomes were baseline counts at diagnosis to include white blood cell count, hemoglobin, and platelets and CHRS risk stratification scores. Secondary outcomes included number of tier 1 or 2 mutations (known as pathogenic myeloid mutations on next-generation sequencing), presence of TP53 mutation and time to progression to myeloid malignancy. The comparison of risk scores between the two groups were performed using Wilcoxon Signed-Rank Tests to compare a difference in medians between groups. A Bonferroni correction was used to adjust for the multiple pairwise comparisons made for these tests.
Results
19 patients with a median age of 73 were in the de novo CCUS group, and 17 patients with a median age of 73 were in the t-CCUS group. 3 patients in the treatment related group had a concomitant history of agent orange (AO) exposure through their military service. Given the unknown clinical significance of AO exposure in the risk of progression to a myeloid malignancy, we also performed our data analysis excluding the 3 patients with prior AO exposure in the t-CCUS group. Our analysis showed there there were no significant differences in the analysis with the inclusion or exclusion of agent orange exposure with the exception of platelet count. The de novo CCUS group had a lower platelet count compared to the treatment-related group at diagnosis (p=0.022), but this difference was no longer present after excluding the 3 agent orange patients from analysis (p=0.069). Baseline data revealed no differences between the white blood cell count, absolute neutrophil count, or hemoglobin. Notably, there were no statistically significant differences between the number of tier 1 or 2 mutations at diagnosis, presence of TP53 mutations or CHRS risk score between the groups. Lastly, the progression free survival and overall survival was similar between the two groups (p=0.98;p=0.95).
Conclusion
The diagnosis and treatment of CCUS is evolving. We sought to understand if there are differences in disease biology and risk of progression between t-CCUS versus de novo CCUS patients. We found no statistically significant differences between the groups based on previously described risk stratification models, progression free survival or overall survival. Larger patient cohorts are required, but this could suggest t-CCUS patients can be monitored in a similar manner to those with de novo CCUS. This information will prove useful to guide informed clinical decisions about risk stratification, treatment and surveillance of this condition.