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Clonal hematopoiesis of indeterminate potential (CHIP) evolves into hematologic cancers at a much slower rate compared to clonal cytopenia of undetermined significance (CCUS). CCUS therefore appears to be a more immediate precursor to myelodysplastic syndromes (MDS) than CHIP. However, there is limited evidence on the indication of CCUS progression and its molecular mechanism. The MDS Hub has previously published two articles on this theme: Immune dysregulation and genetic mutations associated with MDS pathogenesis and Genetic pathogenesis of MDS: Translating molecular advances into better diagnosis and prognosis of CCUS and MDS, both of which focused on gene mutations and their association with CCUS.
Jojosky and colleagues recently published a study in the European Journal of Haematology, examining the clinical, histologic, and molecular features of patients with CCUS to provide an improved understanding of the factors that influence CCUS progression.1 Here, the MDS Hub summarizes the key findings.
An observational cohort study was conducted, including patients who underwent bone marrow (BM) biopsies for unexplained cytopenias who were categorized into CCUS–sub-diagnostic dysplasia (CCUS‑D; n = 25), CCUS-no dysplasia (CCUS-ND; n = 24), and MDS groups (n = 49). Patients were classified as CCUS-D and CCUS-ND based on the criteria shown in Table 1. Myeloid next-generation sequencing and flow cytometry on either blood samples and/or BM aspirates were used.
Table 1. Classification criteria*
CCUS-D |
CCUS-ND |
---|---|
2–10% erythroid precursors |
≤2% atypical erythroid cells |
>50% erythroid cells with megalo-blastoid changes and/or basophilic stippling |
≤5% atypical granulocyte cells |
5–10% hypogranular and/or hypolobated granulocytes |
≤10% atypical megakaryocytic cells |
≥10% megakaryocytes (small, hypolobated, or other nuclear abnormalities) |
|
CCUS-D, clonal cytopenia of undetermined significance sub-diagnostic dysplasia; CCUS-ND clonal cytopenia of undetermined significance with no dysplasia. |
Table 2. Clinical characteristics and BM features of the CCUS-ND, CCUS-D, and MDS groups*
Characteristic |
CCUS-ND |
CCUS-D |
MDS |
p value† |
||
---|---|---|---|---|---|---|
CCUS-ND vs CCUS-D |
CCUS-ND vs MDS |
CCUS-D |
||||
Average age, years (range) |
74.4 |
76.4 |
72.9 |
0.43 |
0.54 |
0.11 |
Sex, males |
54 |
72 |
74 |
0.20 |
0.12 |
0.90 |
History of smoking |
63 |
60 |
60 |
0.86 |
0.87 |
0.97 |
History of alcohol abuse |
8 |
8 |
13 |
0.97 |
0.58 |
0.54 |
ANC <1.8 × 109/L |
13 |
32 |
43 |
0.10 |
0.003 |
0.37 |
Platelets <100,000 µL |
46 |
40 |
51 |
0.69 |
0.68 |
0.38 |
Hemoglobin <10 g/dL |
42 |
44 |
71 |
0.87 |
0.019 |
0.028 |
Hypercellular BM‡ |
46 |
64 |
92 |
0.21 |
<0.001 |
0.013 |
BM M:E ratio ≤1 |
13 |
12 |
35 |
0.96 |
0.023 |
0.020 |
Flow cytometry abnormalities |
33 |
60 |
86 |
0.06 |
<0.0001 |
0.027 |
ANC, absolute neutrophil count; BM, bone marrow; CCUS-D, clonal cytopenia of undetermined significance sub-diagnostic dysplasia; CCUS-ND, clonal cytopenia of undetermined significance with no dysplasia; MDS, myelodysplastic syndromes; M:E, myeloid:erythroid. †Bold font indicates statistically significant p values. |
Table 3. Comparison of molecular features of the CCUS-D, CCUD-ND, and MDS groups*
Molecular feature (Data presented as % unless stated otherwise) |
CCUS-ND |
CCUS-D |
MDS |
p value |
||
---|---|---|---|---|---|---|
CCUS-ND vs CCUS-D |
CCUS-ND vs MDS |
CCUS-D vs MDS |
||||
Non-TET2/DNMT3A/ASXL1 variants |
21 |
60 |
86 |
0.004 |
<0.0001 |
0.027 |
Co-mutation of TET2/DNMT3A/ASXL1 with ≥1 other gene(s) |
4 |
28 |
33 |
0.024 |
<0.001 |
0.69 |
Spliceosome (SF3B1, SRSF2, ZRSR2, or U2AF1) variants |
13 |
48 |
51 |
0.006 |
<0.001 |
0.81 |
IDH1, IDH2, RUNX1, or CBL variants |
0 |
24 |
16 |
0.011 |
0.004 |
0.46 |
TP53 variant |
8 |
4 |
27 |
0.54 |
0.038 |
0.004 |
>2 variants |
0 |
24 |
29 |
0.011 |
<0.0001 |
0.68 |
≥1 variant with VAF |
33 |
68 |
78 |
0.015 |
<0.001 |
0.40 |
Average number variants per patient, n (range) |
1.3 (1–2) |
1.8 (1–4) |
1.9 (0–5) |
0.08 |
0.007 |
0.70 |
Average VAF per variant (range) |
14 (2–47) |
31 (2–57) |
37 (2–97) |
<0.0001 |
<0.0001 |
0.06 |
CCUS-D, clonal cytopenia of undetermined significance sub-diagnostic dysplasia; CCUS-ND, clonal cytopenia of undetermined significance with no dysplasia; MDS, myelodysplastic syndromes; VAF, variant allele frequency. *Data adapted from Jajosky et al.1 †Bold font indicates statistically significant p values. |
Smoking was associated with non-TET2/DNMT3A/ASXL1 variants (p = 0.020), RUNX1 variant (p = 0.043), and co-mutation of TET2/DNMT3A/ASXL1 along with other genes (p = 0.013) compared to non-smokers within the total CCUS cohort. However, the overall mutational burden did not differ between CCUS smokers versus non-smokers. No associations were noted for smokers versus non-smokers in the MDS patient group.
The study demonstrates that CCUS with dysplasia bears a closer resemblance to MDS than CCUS-ND. Clonal expansion and acquisition of further mutations may result in a linear progression from CHIP to CCUS-ND then to CCUS-D, which may be a precursor to MDS. Therefore, distinguishing between CCUS-ND and CCUS-D maybe a useful measure to monitor disease progression and clinical outcomes. A long-term follow-up in larger cohort of patients is warranted to determine whether patients with CCUS-D are at increased risk of disease progression.
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