Illuminating Idiopathic Cytopenias

Genetic testing could shed light on unexplained low blood counts

Diagnosing the cause of cytopenia is often challenging. Even after bone marrow biopsy to identify a cytopenia of unknown etiology, the root of the issue may remain elusive. Many cytopenias that can’t be easily characterized are eventually attributed to myelodysplastic syndromes – a mixed bag of malignant hematopoietic stem cell disorders that feature over- or underproduction of blood cells, morphological abnormalities in the cells, changes to the overall blood cell count, and sometimes a risk of transformation into a more aggressive leukemia. But diagnosing myelodysplastic syndrome (MDS) requires the identification of dysplastic features and blast cells, which are notoriously hard to quantify accurately, even for experienced hematopathologists. Patients who don’t meet the diagnostic criteria for MDS and whose cytopenia remains unexplained are usually given the designation of “idiopathic cytopenia of undetermined significance (ICUS)”. As ICUS can progress to more serious conditions, including MDS or acute myeloid leukemia (AML), this uncertainty is far from ideal – so researchers from the University of California set out to discover whether genetic testing might give patients with ICUS a more useful diagnosis.

“We know that some ICUS patients will go on to develop overt malignancies like MDS or AML, disorders characterized by the presence of genetic mutations,” says study author Rafael Bejar. “We wanted to understand the incidence and pattern of acquired mutations in patients with ICUS.” The researchers found that 35 percent of ICUS patients have somatic mutations or chromosomal abnormalities associated with MDS, and they propose that this subset of patients should be described as having “clonal cytopenias of undetermined significance (CCUS)” – potentially leading to new diagnostic criteria (1). “Our working hypothesis is that cytopenic patients with somatic mutations are more likely to develop blood cancers like MDS and AML,” explains Bejar. “Having a diagnosis of CCUS not only gives a name to a patient’s condition, it may prompt their physician to be more vigilant in case their disease does progress.” He also believes that a formal definition of CCUS will help standardize the way investigators classify patients with those cytopenias. That would allow independent studies conducted by different groups to be more easily compared or combined, thanks to a clearer definition of the target populations.

However, Bejar cautions that the study did not track the long-term progression of the patients, and more research will be needed before new diagnostic criteria can be considered. “We do not have a clear understanding of what happens to CCUS patients over time. The presence of an MDS-like gene mutation in a patient who does not otherwise meet the standard diagnostic criteria cannot be used as presumptive evidence of the disease and should not be used to justify treatment with MDS-specific drugs,” he says. Bejar suggests extending the current prospective research to assess how CCUS patients progress over time. “This will allow us to learn which mutations can foretell what is likely to happen to patients in the future. We will also start to learn how the stepwise evolution of CCUS into more overt blood cancers occurs at the molecular level, potentially identifying opportunities for intervention.”

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