Distinct advantages for risk scoring models in patients with clonal cytopenia of undetermined significance.

The impact of cytotoxic therapy on the risk of progression and death in clonal cytopenia(s) of undetermined significance

High-Risk Ccus Is Clinically Indistinguishable from Low-Risk Myelodysplastic Syndromes/Neoplasms

Clonal Compositions Involving Epigenetic Regulator Gene Mutations in Clonal Hematopoiesis, Clonal Cytopenias of Undetermined Significance and Chronic Myelomonocytic Leukemia

Predictors of Survival and Time to Progression to Myeloid Neoplasm in Patients with Clonal Cytopenias

Prevalence and Significance of Clonal Monocytosis of Undetermined Significance (CMUS) Amongst 431,531 United Kingdom Biobank Participants

CCUS and Low-Risk MDS Are Inherently Similar, Sharing Clonal and Clinical Features

Reduced overall survival in TP53-mutated ccus is driven by prior cytotoxic exposure and cytopenia rather than leukemic progression

Reduced Subclone Diversity in Clonal Cytopenia of Undetermined Significance Compared to Myelodysplastic Syndrome

The Transcriptional and Epigenetic Reprogramming of Aged Hematopoietic Stem Cells Drives Myeloid Rewiring in Clonal Hematopoiesis-Associated Cytopenias

Mutant Natural Killer Cell Dysfunction Enables the Immune Escape of Premalignant MDS Cell Clones

The Potential of Molecular Genetic Analysis for Diagnostic and Prognostic Decision Making in Clonal Cytopenia of Undetermined Significance (CCUS) and MDS - a Study on 576 Patients

To examine flow cytometric (FCM) findings in clonal cytopenia of undetermined significance (CCUS) in relation to variant allele fraction (VAF) and mutation risk. Nine FCM parameters, including 5 FCM metrics (Meyerson-Alayed scoring scheme [MASS] parameters) we previously used to identify myelodysplastic syndromes (MDS), were compared among 96 CCUS samples, 100 low-grade MDS samples and 100 samples from patients without somatic alterations (controls). FCM findings did not differ between CCUS samples with less than 20% VAF and controls. CCUS samples with more than 20% VAF (CCUS >20% VAF) demonstrated more than 1 abnormal FCM parameter at a frequency between MDS and controls. Abnormalities in CCUS with high-risk alterations (CCUS(hi)) were similar to MDS, with no statistical difference in the percentage of cases with more than 1 FCM abnormality or a positive MASS score. The positive predictive value (PPV) for clinically significant myeloid processes; MDS, CCUS(hi), and CCUS >20% VAF compared with other CCUS samples and controls was 94.8%, with 96.5% specificity and 61% sensitivity using a modified MASS score. A subset of MDS (43%) was distinguished from CCUS(hi) and CCUS >20% VAF using 3 parameters, with a 93.5% PPV and 83.3% specificity. FCM abnormalities can distinguish high-risk CCUS based on VAF or alteration type from low-risk CCUS and MDS in many cases. The findings are of potential utility in the evaluation of patients with cytopenias.

Treatment-Related and De Novo Ccus Have Similar Molecular Features and Risk of Progression to Myeloid Malignancies

Background:Patients with myelodysplastic syndrome (MDS) often have mutations in epigenetic regulators and altered DNA methylation in their blood cells. Patients with unexplained cytopenia that do not fulfill the criteria for MDS are referred to as having idiopathic cytopenia of undetermined significance (ICUS) or, if they have MDS‐related mutations, clonal cytopenia of undetermined significance (CCUS).A previous study (Zhao et al. BJH 2016) showed that acute myeloid leukemia (AML) patients with preceding MDS (MDS/AML) have hypermethylation of the telomerase reverse transcriptase (TERT) promoter compared to healthy controls. Increased TERT promoter methylation may cause impaired telomerase activity and thereby shortening of telomeres and increased risk of progression to AML.Aims:We aimed to investigate DNA methylation of the TERT promoter to evaluate its potential as a biomarker of disease severity in patients with unexplained cytopenia and MDS.Methods:TERT promoter methylation of two regions (region 1 covering 5 CpG sites 456 to 424 bp upstream of the TSS and region 2 covering 6 CpG sites 384 to 328 bp upstream of the TSS) was analyzed by pyrosequencing in a cohort of 185 patients with ICUS (n = 65), CCUS (n = 49) or MDS (n = 71). Results are presented as DNA methylation percentage of region 1 and 2 (mean ± SD).Results:The 185 included patients (111 men, 74 women) had a median age of 69 years (ICUS: 65 years, CCUS: 70 years, MDS: 72 years) and the 15 healthy controls (6 men, 7 women) had a median age of 57 years.One‐way ANOVA analysis revealed significantly differences in TERT promoter methylation between all groups for both regions (region 1: p = 0.0004, region 2: p = 7.4 × 10–5).TERT promoter methylation in region 1 was significantly higher in all disease groups compared to healthy controls, with increasing methylation and significance levels with increased disease severity (ICUS: 8.3 ± 4.8, p = 0.03; CCUS: 10.2 ± 7.2, p = 0.0007, MDS: 11.3 ± 7.7, p = 1.9 × 10–6; Figure 1A). Furthermore, TERT promoter methylation levels of both CCUS and MDS patients were significantly higher than ICUS patients (p = 0.02 and p = 1.8 × 10–6, respectively.In region 2, MDS patients had significantly higher methylation (MDS: 8.8 ± 8.1, p = 0.001) compared to healthy controls (5.4 ± 3.2). TERT promoter methylation of region 2 in ICUS and CCUS patients was not significantly different from healthy controls or MDS patients (Figure 1B).Figure 1: Box‐and‐whisper plots of TERT promoter methylation percentage in region 1 (A) and region 2 (B) in 185 ICUS, CCUS, MDS patients and 15 age‐matched healthy controls.Summary/Conclusion:Promoter methylation of TERT increases gradually from healthy controls to ICUS, CCUS and MDS patients. Our study suggests that DNA methylation of the TERT promoter reflects disease severity of unexplained cytopenia and MDS patients. We are currently investigating if TERT promoter methylation can be used as a biomarker for survival and progression to MDS and AML.image

A Lower Frequency of Spliceosome Mutations Distinguishes Clonal Cytopenias of Undetermined Significance From Low-Risk Myelodysplastic Syndromes, Despite Inherent Similarities in Genomic, Laboratory, and Clinical Features