Friday, June 9, 2023
| Variable | Healthy subjects | Anemia of the elderly | Cytopenia of undetermined significance | Myeloid neoplasm with myelodysplasia |
|---|---|---|---|---|
| Patients, n | 355 | 177 | 311 | 592 |
| Sex, male/female | 154/201 | 87/90 | 144/167 | 365/227 |
| Age, y, median (range) | 70 (60-94) | 72 (60-102) | 58 (19-89) | 67 (18-93) |
| Hb, g/dL, median (range) | 14.4 (12.1-18.4) | 12.0 (6.8-17.6) | 12.7 (5.9-16.4) | 10.2 (3.33-17.4) |
| MCV, fL, median (range) | 90.6 (74.0-99.6) | 94.0 (60.3-114.3) | 91.9 (61.7-121.0) | 98.0 (56.1-134.6) |
| WBC, ×109/L, median (range) | 5.94 (2.79-12.44) | 6.07 (3.53-12.9) | 3.48 (0.87-16.0) | 4.66 (0.7-164.0) |
| ANC, ×109/L, median (range) | 3.36 (1.42-7.88) | 3.66 (1.54-6.3) | 1.63 (0.05-10.9) | 2.16 (0.04-109.62) |
| PLT, ×109/L, median (range) | 224 (101-421) | 230.5 (113-481) | 152 (10-917) | 148 (6-1383) |
| BM blasts, %, median (range) | — | — | 2 (1-3) | 2 (1-98) |
| WHO category | ||||
| MDS | — | — | — | 405 |
| MDS/MPN | — | — | — | 152 |
| AML-MRC | — | — | — | 35 |
Table 1. Clinical and hematological features of individuals included in the study
ANC, absolute neutrophil count; BM, bone marrow; Hb, hemoglobin; MCV, mean corpuscular volume; PLT, platelet; WBC, white blood cell; WHO, World Health Organization.
| Variable | Total | Unmutated (ICUS) | Mutated (CCUS) |
|---|---|---|---|
| Patients, n | 311 | 219 | 92 |
| Sex. male/female | 144/167 | 94/125 | 50/42 |
| Age. y, median (range) | 58 (19-89) | 53 (19-89) | 68 (32-87) |
| Hb, g/dL, median (range) | 12.7 (5.9-16.4) | 12.5 (5.9-16.4) | 12.9 (8.9-16.1) |
| MCV, fL, median (range) | 91.9 (61.7-121.0) | 91.9 (61.7-121.0) | 91.2 (76.9-113.0) |
| WBC, ×109/L, median (range) | 3.48 (0.87-16.0) | 3.5 (0.87-10.6) | 3.4 (1.2-16.0) |
| ANC, ×109/L, median (range) | 1.63 (0.05-10.9) | 1.61 (0.05-7.42) | 1.70 (0.36-10.9) |
| PLT, ×109/L, median (range) | 152 (10-917) | 152 (26-559) | 150.5 (10-917) |
| Number of cytopenic lineages, 1/2/3 (%) | 54/33/13 | 56/31/13 | 53/35/12 |
| BM blasts (%), median (range) | 2 (0-3) | 2 (0-3) | 2 (0-3) |
Table 2. Clinical and hematological features of patients with cytopenia of undetermined significance according to mutation status
ANC, absolute neutrophil count; BM, bone marrow; Hb, hemoglobin; MCV, mean corpuscular volume; PLT, platelet; WBC, white blood cell.
This activity is intended for hematologists, oncologists, and other clinicians caring for patients with idiopathic cytopenia of undetermined significance (ICUS) or clonal cytopenia of undetermined significance (CCUS).
The goal of this activity is to describe associations among molecular profiles, hematologic phenotypes, and clinical outcomes in a prospective cohort of patients with CCUS who were sequentially investigated at the time of diagnosis and during follow-up, either in a phase of stable disease or at the time of progression to a myeloid neoplasm with myelodysplasia (MN), and in cohorts of community-dwelling individuals and of patients with MN.
Upon completion of this activity, participants will:
As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.
Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.
Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability
and acceptance of continuing education credit for this activity, please consult your professional licensing board.
This activity is designed to be completed within the time designated on the title page; physicians should claim only those
credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the
activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test.
Follow these steps to earn CME/CE credit*:
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate, but you cannot alter it.
Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period, you can print
out the tally as well as the certificates from the CME/CE Tracker.
*The credit that you receive is based on your user profile.
CME / ABIM MOC Released: 9/16/2021
Valid for credit through: 9/16/2022
processing....
Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.
In the past decade, massive parallel DNA sequencing studies have unveiled the genomic landscape of myelodysplastic syndromes (MDSs) and related myeloid neoplasms with myelodysplasia (MNs). By using targeted gene sequencing in large patient cohorts, independent studies detected somatic mutations in several genes belonging to different biological pathways, and showed that most patients have combinatorial mutation patterns.[1-3] At the same time, population-based studies searched for somatic mutations of these genes in individuals not known to have any hematologic abnormalities.[4,5] These investigations have shown that selected somatic mutations, mainly those in genes of DNA methylation and histone modification, are commonly acquired during aging, resulting in clonal hematopoiesis of indeterminate potential (CHIP), a condition with normal peripheral blood cell counts but increased risk of developing hematologic malignancies.[4-6] Somatic mutations in myeloid malignancy–related genes have also been detected in patients with aplastic anemia and have been found to be associated with worse outcomes, including progression to MDS.[7,8] Moreover, a recent population-based study showed higher prevalence of clonal hematopoiesis (CH) in elderly individuals with unexplained anemia.[9]
From a clinical standpoint, demonstrating the clonal nature of hematopoiesis is particularly important in those disorders that do not fulfill the current diagnostic criteria for myeloid malignancy,[1,10] such as clonal cytopenia of undetermined significance (CCUS) or clonal monocytosis.[10-14] However, how to use molecular profiling in these patients is still unclear.[15-17] In particular, several issues related to CCUS remain to be clarified, including mutation signatures truly causative of cytopenia and factors contributing to the clinical expressivity of clones, as well as mechanisms of progression to overt malignancy.
In this study, we examined a prospective cohort of patients with CCUS who were sequentially investigated at the time of diagnosis and during follow-up, either in a phase of stable disease or at the time of progression to an MN. In addition, we studied cohorts of community-dwelling individuals and of patients with MN, to better define the associations between molecular profiles and hematologic phenotypes with clinical outcomes.
