High-risk patients with clonal cytopenia of undetermined significance have very similar characteristics and outcomes as patients with lower-risk myelodysplastic syndrome (MDS), which can be informative with regard to prognosis, management, and clinical trial eligibility, said Zhuoer (Zoey) Xie, MD, MS, of Moffitt Cancer Center, Tampa, at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.1
Co-investigator of the study, Mikkael Sekeres, MD, MS, Chief of the Division of Hematology at the University of Miami Health System and Sylvester Comprehensive Cancer Center, elaborated. “In this study, we were able to accomplish two objectives: validate prognostic schemes for clonal cytopenia of undetermined significance, a newly recognized premalignant condition, and demonstrate that patients with high-risk clonal cytopenia of undetermined significance have the same prognosis as patients with lower-risk MDS. These data can be used to justify enrolling patients with high-risk clonal cytopenia of undetermined significance into clinical trials alongside patients with lower-risk MDS and ultimately will support active treatment in patients with clonal cytopenia of undetermined significance, to hopefully improve quality of life and delay progression to frank cancer.”
Mikkael Sekeres, MD, MS
Background
Clonal cytopenia of undetermined significance is characterized by unexplained cytopenia and clonal hematopoiesis but does not meet the diagnostic criteria for MDS, primarily by lacking pathologically defined dysplasia in more than 10% of any lineage. Modern risk stratification tools, including the clonal hematopoiesis risk score and the clonal cytopenia risk score, are used to stratify patients with clonal cytopenia of undetermined significance into risk categories based on the likelihood of disease progression, cited at 3% to 13% a year, depending on risk factors. “Of note, neither of these tools is specifically designed for overall survival prediction,” Dr. Xie explained.
Distinguishing clonal cytopenia of undetermined significance from low-risk MDS in real-world clinical settings poses significant challenges. The two conditions share overlapping features such as cytopenias and genetic mutations; thus, they cannot accurately be differentiated based solely on bloodwork and genetic findings. Furthermore, dysplasia can be subtle and subjected to variability among pathologists, and genetic sequencing and expert pathologic review are not universally available, she said.
Finally, even when the genetic profile can be confirmed, Dr. Xie shared these thoughts: “Critical questions remain: When should we intervene for clonal cytopenia of undetermined significance, and how should these patients be managed?” She noted that although almost 2,500 clinical trials for MDS are underway, only 15 are being offered for clonal cytopenia of undetermined significance.
Study Details and Findings
The study compared clonal cytopenia of undetermined significance and lower-risk MDS in terms of clinical features and outcomes using the clonal hematopoiesis risk score and clonal cytopenia risk score risk models. Data were drawn from 409 patients with clonal cytopenia of undetermined significance and 273 patients with MDS from the National MDS Natural History Study and Moffitt data sets. The two disease entities were compared in terms of demographics, presence of cytopenias, progression-free survival, and overall survival. Follow-up for these patients was about 2 years.
Baseline demographics between high-risk clonal cytopenia of undetermined significance and low-risk MDS patients were comparable. The demographics also did not seem to differ significantly when patients with clonal cytopenia of undetermined significance were stratified by clonal hematopoiesis risk score or clonal cytopenia risk score risk score, confirming both scores to be effective tools for predicting risks associated with clonal cytopenia of undetermined significance, Dr. Xie said.
Analysis showed patients with high-risk clonal cytopenia of undetermined significance to be similar to patients with low-risk MDS in terms of the following criteria:
- Median hemoglobin: 10.4 and 10.5 g/dL, respectively
- Median platelets: 138 × 109 and 138 × 109, respectively
- Median absolute neutrophil counts: 2.2 × 109 and 2.0 × 109, respectively
- Degrees of severity of cytopenia
- Progression-free survival and overall survival
- Better progression-free and overall survival for higher-risk clonal cytopenia of undetermined vs low-risk MDS.
Study Limitations
Dr. Xie acknowledged some limitations of the study. “The exact percentage of the dysplasia in each case was not evaluated in this central pathology review; only the presence of more than 10% in any lineage was reported. The IPSS-M [Molecular International Prognostic Scoring System—a prognosis calculator combining genomic profililng with hematologic and cytogenetic parameters] was not used to establish low-risk MDS. We have an ongoing analysis to validate our findings with the IPSS-M. And although the study did not show a statistically significant difference in overall survival between high-risk [clonal cytopenia of undetermined significance] and low-risk MDS, we wondered whether the sample size may not be powered to detect small differences.”
Dr. Xie continued: “Also, both the [clonal hematopoiesis risk score] and [clonal cytopenia risk score] stratification tools are not specifically designed for overall survival, and variables such as hemoglobin are associated with overall survival but are not included in the [clonal cytopenia risk score]. We did additional analysis, however, by adjusting the hemoglobin and found that this further reduces the differences in overall survival…. Patients with a hemoglobin < 10 g/dL, whether they have high-risk [clonal cytopenia of undetermined significance] or low-risk MDS, had inferior overall survival…, suggesting that improving anemia and its associated mortality is a high priority for both entities.”
Expert Point of View
Guillermo Garcia-Manero, MD, Chief of the Section on Myelodysplastic Syndrome at The University of Texas MD Anderson Cancer Center, said he is not ready to accept the study’s findings that high-risk clonal cytopenia of undetermined significance and low-risk myelodysplastic syndrome (MDS) are essentially the same entity. “This is a very important study that asked a very important question. The researchers presented preliminary data, but this analysis was limited by a small sample size, lack of central blinded pathology review, and incorporation of modern molecular risk tools. That said, as the data mature, it is likely that a subset of patients with [clonal cytopenia of undetermined significance] could be treated in the context of lower-risk MDS therapies,” he told The ASCO Post.
Guillermo Garcia-Manero, MD
Session co-moderator Moaath Mustafa Ali, MD, MPH, Assistant Professor at the Cleveland Clinic Taussig Cancer Center, also had suggestions for the study design. “This is an important study, because we physicians often question whether to offer a patient with [clonal cytopenia of undetermined significance] treatment, as we do for MDS. There is no standard approach,” he said.
Dr. Mustafa Ali continued: “I believe the study’s hypothesis, but the study design could be improved. The size could be increased to give it more power, and propensity matching or propensity weighting could be done on the mutations as well as the cytogenetic abnormalities, which would help determine whether dysplasia is really prognostic in this group [clonal cytopenia of undetermined significance],” he noted. “With these improvements in design, the results will be stronger, and the story more convincing.”
DISCLOSURE: Dr. Xie reported no conflicts of interest. Dr. Sekeres has served on the board of directors or advisory committees of Schrödinger, Kurome Therapeutics, and Bristol Myers Squibb. Dr. Garcia-Manero reported financial relationships with Bristol Myers Squibb, Astex Pharmaceuticals, Helsinn, and Genentech. Dr. Mustafa Ali reported no conflicts of interest.
REFERENCE
- Xie Z, Komrokji Z, Otterstatter M, et al: High-risk CCUS is clinically indistinguishable from low-risk myelodysplastic syndromes/neoplasms. 2024 ASH Annual Meeting & Exposition. Abstract 354. Presented December 7, 2024.
