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CCUS with dysplasia: A clinically relevant precursor to MDS

May 26, 2021
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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.

Study design

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.
*Data adapted from Jajosky et al.1

Results

Blood cell indices and BM composition

  • More than half the patients with CCUS (25 out of 49) were classified as CCUS-D and the remaining patients (24 out of 49) were classified as CCUS-ND. There were no significant differences in age, gender, or history of smoking or alcohol abuse between the groups (as shown in Table 2).
  • No significant differences were observed in the frequency of red blood cell macrocytosis or the degree of neutropenia, anemia, or thrombocytopenia, indicating no correlation between blood cell indices and low-level BM dysplasia in the CCUS groups. However, BM hypercellularity and erythroid predominance in CCUS was significantly different to the MDS group.

Table 2. Clinical characteristics and BM features of the CCUS-ND, CCUS-D, and MDS groups*

Characteristic
(Data presented as % unless stated otherwise)

CCUS-ND
n = 24

CCUS-D
n = 25

MDS
n = 49

p value

CCUS-ND vs CCUS-D

CCUS-ND vs MDS

CCUS-D
vs MDS

Average age, years (range)

74.4
(53–87)

76.4
(64–93)

72.9
(55–87)

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.
*Data adapted from Jajosky et al.1

†Bold font indicates statistically significant p values.
Hypercellularity was defined as bone marrow cellularity of at least 10% above normal.

Molecular abnormalities

  • The molecular abnormalities were more comparable to MDS in CCUS-D patients compared to CCUS-ND patients. There were increased non-TET2/DNMT3A/ASXL1 variants (p = 0.004) and co-mutations of TET2, DNMT3A, or ASXL along with other genes (p = 0.024) in CCUS-D patients (as seen in Table 3).
  • The mutational burden was also similar in CCUS-D and MDS patients. Larger clone size and >2 pathogenic variants (p = 0.011) occurred more often in CCUS-D patients.  

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
n = 24

CCUS-D
n = 25

MDS
n = 49

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 and molecular alterations

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.

Conclusion

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. 

  1. Jajosky AN, Sadri N, Meyerson HJ, et al. Clonal cytopenia of undetermined significance (CCUS) with dysplasia is enriched for MDS-type molecular findings compared to CCUS without dysplasia. Eur J Haematol. 2021;106:500-507. DOI: 1111/ejh.13574

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