Establishing a diagnosis in patients with suspected myelodysplastic syndromes (MDS) is often challenging; the bone marrow must demonstrate dysplasia in â‰¥10 percent of a myeloid cell lineage, but quantification of these features is subject to variation among hematopathologists. Patients with otherwise unexplained cytopenias who do not meet the criteria for MDS are often diagnosed as having idiopathic cytopenias of undetermined significance (ICUS).
Although several somatic mutations have been identified in myeloid disorders, none are unique to MDS – further complicating its diagnosis.
To examine the frequency and nature of somatic mutations found in patients with ICUS and in those with clearly defined MDS, Rafael Bejar, MD, PhD, from the division of hematology and oncology at the University of California San Diego Moores Cancer Center in La Jolla, California, and colleagues conducted two studies – one prospective and another retrospective.
"Many patients suspected of having MDS because of unexplained cytopenias will be left without a definitive diagnosis even after a bone marrow biopsy is performed," Dr. Bejar told ASH Clinical News. "In the absence of an alternative explanation for their low blood counts, they are described as having ICUS. We do not have a good understanding of what happens to ICUS patients over time, but we know that they can progress to more overt malignancies such as MDS or AML."
The prospective study included 144 patients suspected of having MDS who were scheduled to undergo a bone marrow biopsy as part of routine evaluation. Participants were excluded from the study if they had any other malignancy and were assigned to one of three study groups following the biopsy:
- Positive: confirmed diagnosis of MDS (n=24)
- Equivocal: MDS cannot be ruled in or out (n=21)
- Negative: no evidence of MDS (n=99)
Next-generation sequencing of DNA isolated from the bone marrow of trial participants revealed one or more somatic mutations in 71 percent of MDS patients (Group A), 62 percent of patients with ICUS and some dysplasia (and only rare dysplastic morphology; Group B), and 20 percent of ICUS patients with no evidence of dysplasia (Group C; p<0.0001).
"Combining Groups B and C, 33 out of 120 of these ICUS patients (28%) carried at least one somatic mutation indicative of clonal hematopoiesis," the authors reported, and another nine ICUS patients without a detected somatic mutation harbored a clonal chromosomal abnormality.
"We also learned that 33 percent of ICUS patients will have an acquired gene mutation or chromosomal abnormality, indicating the presence of clonal hematopoiesis [also referred to as clonal ICUS]," Dr. Bejar said. "Many of the mutated genes we identified in clonal ICUS patients are the same genes mutated in patients with MDS and other myeloid malignancies and are particularly common in patients with some evidence of dysplasia."
The retrospective study analyzed bone marrow samples that had been submitted to a commercial laboratory between January and June 2014 for the evaluation of persistent unexplained cytopenias. The analysis identified 249 patients with ICUS and 91 patients with lower-risk MDS. Patients were required to have a comprehensive bone marrow evaluation with a morphology review, flow cytometry, karyotype analysis, fluorescence in situ hybridization, and myeloid gene sequencing, then classified into one of three cohorts:
- ICUS with mild dysplasia
- ICUS with no dysplasia
In this cohort, the researchers identified mutations in 79 percent of patients with MDS, 45 percent of patients with ICUS with mild dysplasia, and 17 percent of patients with ICUS with no dysplasia. The spectrum of mutated genes was similar, with the exception of SF3B1, which was rarely mutated in patients without dysplasia.
It should be noted, however, that identifying a genomic abnormality in a patient with cytopenias does not necessarily produce an MDS diagnosis. "We do not have a clear understanding of what happens to clonal ICUS patients over time," Dr. Bejar cautioned. "The presence of an MDS-like gene mutation in a patient who does not meet the standard diagnostic criteria for MDS cannot be used as presumptive evidence of the disease."
He added: "These mutations should not be used to justify treatment with MDS-specific drugs like the hypomethylating agents. Clonal ICUS patients will have to be followed over time to determine their risk of clinical progression, and eventually, teach us how to interpret mutations in cytopenic patients."
Due to the limited patient follow-up, additional clinical trials are needed to determine the significance of somatic mutations in ICUS patients, the authors concluded.
Kwok B, Hall JM, Witte JS, et al. MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance. Blood. 2015 October 1. [Epub ahead of print]