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Clonal Cytopenia of Unknown Significance: To Treat or Not To Treat?

June 24, 2022

July 2022

Kimberly Retzlaff

Kimberly Retzlaff is the managing editor of ASH Clinical News.

David Steensma, MDDavid Steensma, MD
Novartis Institutes for BioMedical Research




Mrinal Patnaik, MBBSMrinal Patnaik, MBBS
Department of Internal Medicine at Mayo Clinic




Clonal cytopenia of unknown significance (CCUS) is characterized by a low blood count without an apparent cause, as well as a portion of blood cells that carry an acquired genetic mutation. Individuals with these genetic mutations have a 75% chance of developing myelodysplastic syndromes (MDS) or a related condition within four to five years, and low blood counts alone can have negative conseqeunces.1 Given this, a clinician may be inclined to initiate treatment. However, there is a lack of data on effective treatments for CCUS2 and a high level of variability in disease progression.3 Additionally, because some therapies have toxic effects, a watch-and-wait strategy may be preferred to maintain better quality of life for the patient while it becomes clearer whether a malignant disease progression is likely.

In this edition of Drawing First Blood, ASH Clinical News invited David Steensma, MD, global hematology head at Novartis Institutes for BioMedical Research (NIBR) and former director of the Center for the Prevention of Progression at Dana-Farber Cancer Institute where patients with CCUS are evaluated, and Mrinal Patnaik, MBBS, a hematologist and oncologist in the Department of Internal Medicine at Mayo Clinic, to discuss CCUS and its diagnosis and progression, and to debate about whether to treat.

Dr. Steensma: For a long time, we’ve known that there are patients with cytopenias who undergo diagnostic evaluation using typical tests, such as measuring B12 levels and doing a bone marrow aspirate and biopsy to look for evidence of a condition like MDS, but at the end of that testing, there’s no apparent diagnosis. These cases have historically been called “idiopathic cytopenia of undetermined significance” (ICUS). In ICUS, one or more blood counts are persistently low and we still don’t know why after evaluation, so the patients are monitored. Some patients with ICUS will eventually declare themselves as having MDS or another disorder, a few will resolve without intervention, and some will have persistent cytopenias over many years that remain unexplained but don’t change.

Now that we routinely do next generation sequencing (NGS) to evaluate patients with unexplained cytopenias, a portion of those ICUS patients are found to have clonal mutations, and that group of cases now is called CCUS. We know the risk of progression to a neoplasm like MDS is a lot higher for CCUS than it is for ICUS without mutations.

I will say also that a detected mutation is probably not related to the cytopenia in all cases. There may be patients who have cytopenias for some immunologic reason and just happen to also have a small hematopoietic clone, and the two are both true but unrelated. In many patients, though, the clonal process does lead to ineffective blood cell production.

Dr. Patnaik: I completely agree. I would add that there are two pressing issues that have not been resolved. First, how directly connected are these somatic mutations to the extent and degree of cytopenias in the patient? Are they merely passenger events, bystanders, or do they contribute toward ineffective hematopoiesis? Second, there is no clear consensus on the somatic mutation variant allele fraction size that should be present, defining the clonal burden as being causative for the cytopenia(s). These variant allele fraction cut offs have ranged from 2-20%, and I don’t think we have enough prospective data to agree on this point.

In addition, the true prevalence of CCUS is really unknown, and all the data we are seeing are biased by the fact that these are patients who sought out health care or were referred because they had abnormal counts while seeking health care, and may represent a more severe subset in the spectrum. The true community-based prevalence rates of CCUS remain to be defined.

Dr. Steensma: When you consider treating any condition, there must be an expected benefit that on balance outweighs the risk of therapy. We don’t yet know that this is the case for CCUS. For CCUS, the hoped-for advantage would be to prevent a complication. There are three groups of complications that we worry about.

One consequence of CCUS is acquisition of subsequent mutations and evolution to, for instance, a myeloid neoplasm. The second would be a non-hematologic consequence like a thrombotic event, which is a risk for certain clonal states; the cardiovascular mortality seen with clonal hematopoiesis of indeterminate potential (CHIP) is a good example.

Finally, sometimes patients with CCUS have quite severe cytopenias and might have a problem or symptoms related to that. We knew from population studies before we knew anything about somatic mutations that patients with anemia, even if it’s mild, have worse health outcomes than those who have hemoglobin in the middle of the normal range. It’s unlikely that somebody with a mild thrombocytopenia would run into a complication from that, but some patients with CCUS have more severe neutropenia or thrombocytopenia and could have a bleeding event or an infection, respectively.

I suspect in most cases, CCUS doesn’t have any consequences, but it could. It could lead to an event like MDS, or the cytopenia itself could cause problems for some patients.

Dr. Patnaik: The biggest disadvantage to treating CCUS is that there is no standard of care for these patients. If you are going to treat them, this will largely be extrapolated from data obtained on patients with MDS, and while MDS arises as an evolution of CCUS, it’s not CCUS. To say that chemotherapeutic agents are going to work in the CCUS space is pure assumption, potentially backed by sporadic case series or reports. While anecdotal responses to hypomethylating agents have been documented, until we confirm these in a rigorous, prospective, evidence-based manner, there exists no standard of care for the management of CCUS.

Our current understanding of CCUS is largely based on associations rather than causalities. Do the somatic mutations really cause ineffective hematopoiesis and marrow failure? Is targeting these mutations going to improve this process, especially since hypomethylating agents do not impact mutational allele burdens, and their responses in MDS are linked to epigenetic restoration of normal hematopoiesis, with eventual clonal evolution being a near certainty.

In addition, let’s not forget that these drugs have side effects. So now you’re taking people who have low blood counts and detectable somatic mutations and giving them drugs that can make their blood counts lower and can be associated with nausea, vomiting, diarrhea, fatigue, and quality of life issues. Not to mention, these treatments are not approved by the U.S. Food and Drug Administration or the European Medicines Agency, and so with this diagnosis, there are many insurance payers that won’t even cover the drugs for a CCUS indication.

I’m a strong proponent that there are subsets of these patients who will need treatment, but this needs to be done in the setting of clinical trials. We need to rationally design these clinical trials and set the right parameters for inclusion, exclusion, and response. We need to understand who benefits and if there are potential biomarkers for response and resistance. As of today, however, we do not have any effective therapies that have been validated or any evidence base to recommend them routinely for this population.

Dr. Steensma: I completely agree. There’s no free lunch with respect to medicine, so in each case we must have a careful assessment of risk versus benefit. If we were confident that by treating we could prevent complications, that would be a much more compelling argument for treating than we have now. Right now, we worry a lot, we know cytopenias are problematic and clonal hematopoiesis confers risks, but we don’t know that we can successfully intervene, so it is a major research priority.

Something that Dr. Patnaik said earlier is very important: this is a spectrum of patients, and there are going to be some who have very low risk, some where the mutation isn’t even related to the cytopenia, and those patients likely aren’t going to benefit therapy directed at the mutation. However, other patients have a higher risk; their risk of developing overt MDS or a related disorder within four or five years is more than 70% based on some of the data sets that we’ve seen, like the one from Luca Malcovati, MD, of the University of Pavia in Lombardy, Italy, and colleagues. If you have someone who has multiple mutations, high-risk mutations, quite large clones – well, that’s somebody who really is likely to be a patient in whom we’ll be able to show that there is benefit from treatment. There’s a large area in between, and just where that cutoff is, that’s going to take quite a bit of work to sort out.

Dr. Patnaik: What really is the distinguishing feature between CCUS and MDS? It’s largely got to do with morphology. Hematopathologists look at the bone marrow under a microscope and look for consensus criteria for calling dysplasia. For example, you need dysplasia in more than 10% of erythroids, granulocytes, or megakaryocytes and their precursor cells before labeling the marrow as showing features of lineage dysplasia (single or multilineage). In the absence of these features, patients are often labeled as having idiopathic cytopenias and when NGS studies come back, this diagnosis is upgraded to CCUS if somatic mutations in myeloid neoplasms-associated genes are identified.

What Dr. Steensma referred to very importantly is that CCUS is not a binary variable. It’s not like you have CCUS or you don’t. CCUS depends on the type of mutation, the size of mutation (variant allele fraction), cooperating mutations, and the context in which it came about (therapy-related, germline predisposition syndromes, or age-related). It also depends on the clonal selection pressures and clonal dynamics, and so the more the community is aware of these nuances, the better served our patients are. In CCUS, there is nothing truer than the old adage, “One size doesn’t fit all.” CCUS is going to be the poster child of individualized medicine, where you’re going to have to approach diagnosis, risk stratification, and management on a case-by-case basis.

We have a CHIP/CCUS clinic at Mayo Clinic that was established in 2017, and my role there is to educate and empower patients to understand their hematologic condition. I am very transparent with them that this is a new entity, so the current data on associations are largely retrospective and hospital referral-biased and the treatments that are currently FDA-approved are approved for MDS and not for CCUS. This is precisely the reason why we are investing in clinical trials for CCUS. My dream is that we have a series of trials individualized to a spectrum of mutations, taking into consideration the clinical presentation, extent, and severity of cytopenias.

Dr. Steensma: This is really an opportunity for clinical trial enrollment because we don’t know which therapies might benefit patients, if any, and as Dr. Patnaik suggests, there are subgroupings within this larger umbrella of CCUS that may benefit from specific approaches. There are very limited targeted therapies here, but there are some common pathways, like inflammasome activation, that may turn out to be more important in one group than another. Perhaps TET2 mutations are more potent inflammasome activators than, say, a DNMT3A mutation. These are things that we need to learn through clinical trials and continued preclinical research.

I’ve been very impressed by the way in which the hematology community that’s interested in clonal hematopoiesis has come together and collaborated. There’s a network forming around clonal hematopoiesis called the SEARCH Network that a number of academic centers are going to be participating in, which would allow for various types of collaborations including trials. There are also informal groupings that have come together to study specific therapies, like vitamin C for TET2-mutant CCUS or isocitrate dehydrogenase (IDH) inhibitors for IDH-mutant CCUS, and this is a vibrant and very active community. Everybody has a sense that these patients are out there with CCUS. They’re often not recognized because many patients with cytopenias, especially if they’re mild, are incompletely evaluated.

The magnitude of the problem is quite large. We know from the National Health and Nutrition Examination Survey data and other datasets that cytopenias, especially anemia, are very common in older people, more than 25% by age 85, and this anemia is often unexplained. There are also really a lot of people who acquire somatic mutations in blood cells from aging. In fact, if you look with DNA sequencing techniques that are very sensitive, clonal hematopoiesis is almost universal by the time people get to middle age. The clones may be very tiny and may not confer the same risks. We also know that cytopenias, especially mild anemia, become quite common with aging, so sorting out who’s really at risk and who we can leave alone is an important question.

Dr. Patnaik: The first statement that I always read in my office when I come to work is, “Do not make the cure of disease more grievous than the endurance of the same.” That’s a tenement that I highly respect, and that’s the point. Are we prolonging survival, are we reducing the rate of progression to AML, are we reducing the cardiovascular side effect profile, or are we just giving them an additional comorbidity from side effects? And let’s not forget the financial toxicity of these drugs.

Dr. Steensma: Yes. “First, do no harm.” The only reason to put patients at risk with a treatment is if ultimately, on balance, there’s an expected net benefit. And we don’t know that that’s the case for CCUS yet.


  1. Dana-Farber Cancer Institute. What is clonal cytopenia of undetermined significance (CCUS)? April 30, 2019. Accessed April 4, 2022.
  2. Xie Z, Nanaa A, Saliba AN, et al. Treatment outcome of clonal cytopenias of undetermined significance: a single-institution retrospective study. Blood Can J. 2021;11:43.
  3. Galli A, Todisco G, Catamo E, et al. Relationship between clone metrics and clinical outcome in clonal cytopenia. Blood. 2021;138(11):965-976.

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