Table of Contents
- Key Points
- What Is Clonal Cytopenia of Undetermined Significance?
- Why This Research Matters
- How the Study Was Conducted
- Key Findings: Building the Risk Score
- Validating the Risk Score in a Second Group of Patients
- Treatment Approaches and Outcomes
- What This Means for Patients
- Limitations of the Study
- Recommendations for Patients
- Frequently Asked Questions
- Source Information
Key Points
- In a study of 357 patients with CCUS, three factors predicted progression to a myeloid neoplasm: splicing mutations, platelet count below 100×10⁹/L, and two or more mutations.
- These factors were combined into the Clonal Cytopenia Risk Score (CCRS), which sorted patients into low, intermediate, and high risk groups.
- Over two years, progression occurred in 6.4% of low-risk, 14.1% of intermediate-risk, and 37.2% of high-risk patients in that study.
- The CCRS was validated in a separate group of 104 patients, with a c-index of 0.64, indicating moderate predictive ability.
- Even in the high-risk group, 62.8% of patients did not progress to a myeloid neoplasm within two years.
What Is Clonal Cytopenia of Undetermined Significance?
Clonal cytopenia of undetermined significance (CCUS) is a blood condition that sits in a gray zone between normal aging and blood cancer. Patients with CCUS have low blood cell counts (cytopenia) that doctors cannot explain, along with specific gene mutations in their blood or bone marrow. These mutations are called somatic mutations, meaning they are acquired during a person's lifetime rather than inherited.
The World Health Organization (WHO) formally defined CCUS in its fifth edition of the Classification of Haematolymphoid Tumours. To receive a CCUS diagnosis, a patient must have a myeloid-related somatic mutation with a variant allele fraction (VAF) of at least 2%. The VAF measures what percentage of a patient's blood cells carry the mutation. The patient must also have unexplained low blood cell counts but must not meet the criteria for a myeloid neoplasm (a type of blood cancer).
There are related conditions that doctors also recognize. If a patient has these mutations but normal blood counts, the condition is called clonal hematopoiesis of indeterminate potential (CHIP). A patient may have elevated monocyte counts, a specific type of white blood cell. If the patient does not have the bone marrow features of chronic myelomonocytic leukemia (CMML), the condition is called clonal monocytosis of undetermined significance (CMUS). When both cytopenia and monocytosis are present, it is called clonal cytopenia and monocytosis of undetermined significance (CCMUS).
CHIP is considered an early precursor to blood cancer, but the annual risk of progression is low. Transformation to a myeloid neoplasm occurs in only 0.5% to 1% of CHIP cases each year. However, CHIP is linked to an increased risk of other health problems, especially cardio-cerebrovascular diseases (conditions affecting the heart and blood vessels in the brain).
CCUS is more concerning. Patients with CCUS have a 10-fold higher likelihood of progressing to a myeloid neoplasm compared with patients who have CHIP. Specific mutation patterns play a major role in both diagnosing blood cancer and predicting disease progression. These patterns include splicing mutations, co-mutations involving the genes DNMT3A, TET2, or ASXL1 (often called DTA mutations), the total number of mutations, and the VAF level.
Why This Research Matters
Doctors are now finding more cases of CCUS because next-generation sequencing (NGS) is used more often to evaluate patients with low blood cell counts. NGS is a technology that can read the genetic code of many genes at once. As more patients receive a CCUS diagnosis, understanding who is at highest risk of progression becomes critical.
Currently, there is no established standard of care for treating CCUS. Existing therapies have low response rates. This creates an urgent need to identify high-risk patients who should be enrolled in clinical trials testing new treatments.
Two earlier risk models were developed using data from the UK Biobank, a large population-based study. The first is the Clonal Hematopoiesis Risk Score (CHRS). The CHRS includes whether a patient has CCUS, their mutation patterns, age, red blood cell measurements, and other factors. Patients with a CHRS of 12.5 or higher were classified as high-risk. Their cumulative 5-year risk of progression to a myeloid neoplasm was 24%. Patients with a CHRS between 10 and 12 (intermediate risk) had a 5-year progression rate of 2.7%. Those with a CHRS below 9.5 (low risk) had a progression rate of only 0.23%.
The second model is called MN-predict. It uses genetic data, clinical features, and blood chemistry results to provide year-by-year probabilities of progression to a myeloid neoplasm for up to 15 years.
However, these models were built from population-based data, not from patients seen in real-world clinical practice. The researchers behind this new study wanted to develop a risk score specifically for patients diagnosed with clonal cytopenia in actual medical centers.
How the Study Was Conducted
This study was conducted by the CCUS consortium, a collaborative group of 17 academic medical centers across the United States and Europe. The study began in 2020. All patients provided written informed consent, and the research protocol was approved by the medical ethics committee of the Mayo Clinic. The study followed the ethical principles of the Declaration of Helsinki.
To be included in the study, patients had to meet several criteria:
- Be at least 18 years old
- Have a bone marrow biopsy that did not meet the diagnostic criteria for a myeloid neoplasm
- Have unexplained low blood cell counts
- Have a myeloid-related somatic mutation with a VAF of at least 2%
- Not have received any prior therapy for cytopenia at the time of CCUS diagnosis
Patients who had a cytogenetic abnormality (a chromosome change) were included and classified as having CCUS, unless the chromosome change was one that specifically defines myelodysplastic syndrome (MDS). In that case, the patient was excluded from the study.
The researchers collected real-world data on these patients, including their clinical characteristics, mutation profiles, blood counts, and outcomes over time. They then used statistical methods to identify which factors best predicted progression to a myeloid neoplasm.
The research team performed a multivariate analysis, which is a statistical method that examines multiple factors at the same time to determine which ones independently affect outcomes. They used a Cox proportional hazards model, a common statistical tool for analyzing time-to-event data, to calculate the relative importance of each risk factor.
Key Findings: Building the Risk Score
The study analyzed 357 patients with CCUS. The researchers investigated how clonality (the presence of mutated cells), cytopenia (low blood cell counts), and prognosis (likely outcomes) interacted with each other.
The multivariate analysis identified three key factors that independently predicted a higher risk of progression to a myeloid neoplasm:
- Splicing mutations: Patients whose mutations affected the cellular machinery for splicing RNA (a process that helps build proteins) had a worse prognosis. This factor received a score of 2 points.
- Low platelet count: Patients with a platelet count below 100×10⁹/L (less than 100 billion platelets per liter of blood) had a worse prognosis. This factor received a score of 2.5 points.
- Two or more mutations: Patients who had at least two different mutations had a worse prognosis. This factor received a score of 3 points.
The researchers assigned point values based on the coefficients from the Cox proportional hazards model. This means that factors with a stronger association with progression received higher point values.
These three factors were combined into a single tool called the Clonal Cytopenia Risk Score (CCRS). The CCRS sorted patients into three groups:
- Low risk: Score less than 2.5 points
- Intermediate risk: Score between 2.5 and less than 5 points
- High risk: Score of 5 points or higher
The CCRS effectively predicted the 2-year cumulative incidence of progression to a myeloid neoplasm. Cumulative incidence means the total proportion of patients who experienced the outcome over a given time period. The results were:
- Low-risk group: 6.4% of patients progressed within 2 years
- Intermediate-risk group: 14.1% of patients progressed within 2 years
- High-risk group: 37.2% of patients progressed within 2 years
These differences between the groups were highly statistically significant. The researchers used a statistical test called Gray's test, which produced a P value of less than .0001. This means there is less than a 0.01% chance that these differences occurred by random chance alone.
The high-risk group had nearly six times the rate of progression compared with the low-risk group. The intermediate-risk group had more than double the rate of the low-risk group.
Validating the Risk Score in a Second Group of Patients
The researchers tested the CCRS on an independent cohort of 104 patients with CCUS. This cohort was from the University of Pavia in Italy. The test aimed to confirm that the CCRS works beyond the original group of patients. An independent cohort is a separate group of patients who were not part of the original study. Using a separate group helps confirm that the results are not just specific to the first group of patients.
The CCRS performed well in this validation group. The researchers measured its performance using a c-index of 0.64. The c-index is a statistical measure that indicates how well a model can distinguish between patients who will and will not experience an outcome. A c-index of 0.5 means the model is no better than random chance, while a c-index of 1.0 means perfect prediction. A c-index of 0.64 indicates moderate predictive ability.
The result was statistically significant, with a P value of .005. This means there is only a 0.5% chance that this result occurred by random chance. The validation confirmed that the CCRS can stratify patients by their cumulative incidence of progression to a myeloid neoplasm.
Treatment Approaches and Outcomes
The researchers noted that there is limited data available regarding treatment for CCUS. Because of this gap, they also discussed treatment approaches and outcomes for a subgroup of patients in the study who underwent therapy.
The study acknowledged that there is currently no established standard of care for CCUS. Existing therapies have low response rates. This is one reason why identifying high-risk patients is so important. High-risk patients may be appropriate candidates for clinical trials testing new treatments aimed at preventing or delaying disease progression.
What This Means for Patients
The CCRS is a practical and easily calculable tool that doctors can use to assess a patient's risk of CCUS progressing to a myeloid neoplasm. It uses only three factors: whether the patient has splicing mutations, whether their platelet count is below 100×10⁹/L, and whether they have two or more mutations.
This risk score has several important implications for patient care:
- Personalized risk assessment: Doctors can calculate a patient's CCRS score using information from standard blood tests and genetic testing that is already part of the CCUS diagnostic process.
- Informed monitoring: Patients at higher risk may need more frequent monitoring and follow-up appointments.
- Clinical trial eligibility: The CCRS can help identify high-risk patients who should be considered for clinical trials testing new treatments.
- Treatment planning: Understanding a patient's risk level can help doctors and patients make more informed decisions about when to consider treatment.
The study underscores the importance of integrating clinical data (such as blood counts) with molecular data (such as mutation analysis) to assess the risk of CCUS progression. Neither type of information alone provides as complete a picture as the two combined.
The researchers believe these findings are clinically relevant and will help shape management strategies for CCUS. The CCRS also can inform the design of future clinical trials by helping researchers identify appropriate patients to enroll.
Limitations of the Study
This study has several limitations that patients and doctors should consider.
First, the study was conducted at academic medical centers, which may see patients with more complex or severe conditions than community hospitals. The results might differ in other healthcare settings.
Second, the validation cohort from the University of Pavia included 104 patients, which is smaller than the original group of 357 patients. A larger validation group would provide stronger confirmation of the risk score's accuracy.
Third, the c-index of 0.64 in the validation group indicates moderate predictive ability, not perfect prediction. This means the CCRS is useful but cannot predict with certainty which individual patients will progress.
Fourth, the study followed patients for a limited time. Longer follow-up would provide more information about the long-term outcomes of patients with CCUS.
Fifth, there is limited data on treatment outcomes for CCUS. The researchers discussed treatment approaches for a subgroup of patients, but larger studies are needed to determine the best treatment strategies.
Recommendations for Patients
If you have been diagnosed with CCUS, here are some steps to consider:
- Ask your doctor about your CCRS score. Your doctor can calculate this score using your blood test results and genetic testing results. Understanding your risk level can help guide your care.
- Discuss your mutation profile. Ask whether you have splicing mutations and how many mutations were found. These factors affect your risk level.
- Monitor your platelet count. A platelet count below 100×10⁹/L is one of the three risk factors in the CCRS. Regular blood tests can track this.
- Ask about appropriate monitoring frequency. Patients at higher risk may need more frequent follow-up visits and blood tests.
- Inquire about clinical trials. If you are in the high-risk group, ask your doctor whether any clinical trials are available that might be appropriate for you.
- Seek care at a center experienced with CCUS. Academic medical centers that participate in research consortia like the CCUS consortium may have more experience with this condition.
- Stay informed. Research on CCUS is ongoing. New findings may change how doctors assess and manage this condition over time.
It is important to remember that a CCUS diagnosis does not mean you will definitely develop blood cancer. Even in the high-risk group, 62.8% of patients did not progress to a myeloid neoplasm within 2 years. The CCRS helps doctors identify who needs closer monitoring and who might benefit from early intervention, but it cannot predict any individual patient's outcome with certainty.
Frequently Asked Questions
What is clonal cytopenia of undetermined significance (CCUS)?
CCUS is a blood condition between normal aging and blood cancer. Patients have unexplained low blood cell counts plus a myeloid-related somatic mutation with a variant allele fraction of at least 2%. It does not meet the criteria for a myeloid neoplasm. Related conditions include CHIP, which has normal blood counts, and CMUS, which involves elevated monocytes.
What is the Clonal Cytopenia Risk Score (CCRS) and what does it measure?
The CCRS is a tool that estimates the risk of CCUS progressing to a myeloid neoplasm. It uses three factors: splicing mutations (2 points), platelet count below 100×10⁹/L (2.5 points), and two or more mutations (3 points). Scores sort patients into low, intermediate, and high risk. It was developed from 357 patients and validated in 104.
What do the low, intermediate, and high CCRS risk groups mean for progression?
Over two years, progression to a myeloid neoplasm occurred in 6.4% of low-risk patients, 14.1% of intermediate-risk patients, and 37.2% of high-risk patients. These differences were statistically significant. Even in the high-risk group, 62.8% did not progress within two years. The score estimates risk but cannot predict any individual patient's outcome with certainty.
How is the CCRS calculated and what information is needed?
The CCRS is calculated from information already part of the CCUS diagnostic process: whether you have splicing mutations, whether your platelet count is below 100×10⁹/L, and whether you have two or more mutations. Your doctor can calculate it using standard blood test results and genetic testing results. No additional tests are required beyond those used to diagnose CCUS.
If I have CCUS, what monitoring or follow-up might I need?
Patients at higher risk may need more frequent monitoring and follow-up appointments. Regular blood tests can track your platelet count, since a count below 100×10⁹/L is one of the three risk factors. Ask your doctor about the appropriate monitoring frequency for your risk level. The CCRS can help guide these decisions.
Are there clinical trials for CCUS, and who might be eligible?
There is currently no established standard of care for treating CCUS, and existing therapies have low response rates. High-risk patients may be appropriate candidates for clinical trials testing new treatments aimed at preventing or delaying progression. If you are in the high-risk group, ask your doctor whether any clinical trials are available that might be appropriate for you.
Does a CCUS diagnosis mean I will definitely develop blood cancer?
No. A CCUS diagnosis does not mean you will definitely develop blood cancer. Even in the high-risk group, 62.8% of patients did not progress to a myeloid neoplasm within two years. The CCRS helps doctors identify who needs closer monitoring and who might benefit from early intervention, but it cannot predict any individual patient's outcome with certainty.
I was just diagnosed with clonal cytopenia of undetermined significance (CCUS) — when should I seek a second opinion?
A second opinion can be useful when a CCRS score is calculated, since the score depends on whether splicing mutations are present, whether the platelet count is below 100×10⁹/L, and whether two or more mutations were found. A score of 5 points or higher places a patient in the high-risk group, with a 37.2% two-year progression risk, and may prompt consideration of clinical trials. Reviewing the mutation profile and blood counts with an independent expert can help confirm risk level and monitoring plans. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Risk prediction for clonal cytopenia: multicenter real-world evidence
Authors: Zhuoer Xie, Rami S. Komrokji, Najla Al‐Ali, Alexandra Regelson, Susan Michelle Geyer, Anand Ashwin Patel, et al.
Journal: Blood, Volume 144, Issue 19
Publication date: November 7, 2024
DOI: 10.1182/blood.2024024756
Study funding and disclosures: The authors reported numerous financial relationships with pharmaceutical companies, including honoraria, consulting fees, advisory board memberships, and research funding. These relationships are disclosed in the original article. All other authors reported no relevant conflicts of interest.
This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and should not replace discussion with your healthcare provider. Always consult your doctor about your individual medical situation.
