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Customizing first-line BTK inhibitors for CLL
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Clonal cytopenia of undetermined significance (CCUS) is a hematologic disorder characterized by persistent cytopenia with genomic aberrations. Despite research demonstrating similarity of CCUS with lower-risk myelodysplastic syndromes (MDS) in the absence of dysplasia and chromosomal aberrations, patients with CCUS do not have access to the same treatment options.
In a recent study published by Eun-Ji Choi and colleagues1 in the British Journal of Haematology, the clinical and molecular characteristics of idiopathic cytopenia of undetermined significance (ICUS), both non-clonal and clonal, were compared in patients with MDS. We summarize key results below.
Patients with lower-risk MDS (LR-MDS) or ICUS diagnosed between May 2009 and December 2019 at the Asan Medical Center, University of Ulsan, Ulsan, KR, were included for analysis. Inclusion criteria are summarized in Figure 1.
Figure 1. Study design*
BM, bone marrow; CCUS, clonal cytopenia of undetermined significance; HR-MDS, higher-risk MDS; ICUS, idiopathic cytopenia of undetermined significance; LR-MDS, lower-risk MDS; MDS, myelodysplastic syndromes.
*Adapted from Choi et al.1
Patient characteristics for all subgroups of patients are shown in Table 1.
Table 1. Patient characteristics*
Characteristic |
ncICUS |
CCUS |
LR-MDS |
HR-MDS |
---|---|---|---|---|
Female, % |
60.7 |
39.7 |
33.3 |
39.4 |
Age, median in years (range) |
52 (19–77) |
65 (19–89) |
59 (19–85) |
61 (18–87) |
WBC, × 103/µL, median (range) |
3.4 |
3.4 |
3.2 |
2.9 |
ANC, × 103/µL, median (range) |
1,493 |
1,395 |
1,456 |
922 |
Hb, g/L, median (range) |
115 |
105 |
90 |
84 |
PLT, × 103/µL, median (range) |
96 |
88.5 |
106 |
73 |
BM cellularity, median (range) |
30 |
30 |
40 |
50 |
BM blast, %, median (range) |
1.0 |
1.2 |
1.4 |
5.2 |
IPSS-R karyotype risk, % |
||||
Very good |
0 |
9.0 |
6.1 |
0.8 |
Good |
96.7 |
79.5 |
80.8 |
33.1 |
Intermediate |
0 |
9.90 |
13.1 |
33.9 |
Poor |
0 |
0 |
0 |
14.2 |
Very poor |
0 |
0 |
0 |
18.1 |
Unknown |
1.6 |
2.6 |
0 |
— |
IPSS-R, % |
||||
Very low |
44.3 |
28.2 |
9.1 |
0 |
Low |
45.9 |
59.0 |
69.7 |
0 |
Intermediate |
8.2 |
9.0 |
21.2 |
46.5 |
High |
0 |
0 |
0 |
29.9 |
Very high |
0 |
0 |
0 |
23.6 |
Unknown |
1.6 |
3.8 |
0 |
— |
ANC, absolute neutrophil count; BM, bone marrow; CCUS, clonal cytopenia of undetermined significance; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; HR-MDS, higher-risk myelodysplastic syndromes; IPSS-R, revised International Prognostic Scoring System; LR-MDS, lower-risk myelodysplastic syndromes; ncICUS, non-clonal idiopathic cytopenia of undetermined significance; PLT, platelets; RBC, red blood cells; WBC, white blood cells. |
Figure 2. 5-year median OS for all subgroups of patients*
CCUS, clonal cytopenia of undetermined significance; HR-MDS, higher-risk myelodysplastic syndromes; LR-MDS, lower-risk myelodysplastic syndromes; ncICUS, non-clonal idiopathic cytopenia of undetermined significance; OS, overall survival.
*Adapted from Choi et al.1
Table 2. Multivariate analysis for survival in CCUS*
Characteristic |
OS |
PFS |
Prognostic score |
||
---|---|---|---|---|---|
HR (95% CI) |
p value |
HR (95% CI) |
p value |
|
|
Hb at diagnosis, g/L |
|||||
≥90 |
1 |
0.011 |
1 |
0.008 |
|
<90 |
7.39 |
|
7.39 |
|
1 |
DDX41 mutation |
|||||
Absent |
1 |
0.004 |
|
0.002 |
|
Present |
12.22 |
|
10.62 |
|
1 (germline and somatic) |
ETV6 mutation |
|||||
Absent |
1 |
0.003 |
— |
— |
|
Present |
30.68 |
|
— |
— |
2 |
RUNX1 mutation |
|||||
Absent |
1 |
|
— |
— |
|
Present |
7.07 |
0.039 |
— |
— |
1 |
CCUS, clonal cytopenia of undetermined significance; CI, confidence interval; Hb, hemoglobin; HR, hazard ratio; IPSS-R, revised International Prognostic Scoring System; OS, overall survival; PFS, progression-free survival. |
Figure 3. 5-year OS based on prognostic risk score in patients with CCUS*
CCUS, clonal cytopenia of undetermined significance; IPSS-R, revised International Prognostic Scoring System; OS, overall survival.
*Adapted from Choi et al.1
The study1 provided evidence for similar survival outcomes and genetic features in patients with CCUS and LR-MDS. This was particularly pronounced in patients with adverse high-risk features, including lower hemoglobin, high mutation numbers and burden, and DDX41 mutations, who achieved similar or slightly worse OS than patients with LR-MDS. As such, CCUS should be treated in a comparable manner with LR-MDS, and patients with high mutation numbers, allele burden, and mutations in genes encoding splicing factors should be closely evaluated.
Study limitations highlighted by the authors, included the small number of patients enrolled which limited evaluation of prognostic factors and mutational patterns. Also, there is a possibility of selection bias due to the data being collected both prospectively and retrospectively.
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