This article is more than 5 years old. Information may no longer be current.
Clonal hematopoiesis common, variable in patients with aplastic anemia
Click Here to Manage Email Alerts
Clonal hematopoiesis commonly occurs in patients with aplastic anemia, according to study results.
Although detected somatic mutations were associated with clinical outcomes, the pattern of somatic mutation in individuals was highly variable and may not be predictive of treatment outcomes, results also showed.
Patients with aplastic anemia often develop pancytopenia due to the destruction of hematopoietic cells by the immune system, according to study background. Although patients frequently respond to immunosuppressive treatments, approximately 15% develop acute myeloid leukemia or other myelodysplastic syndromes (MDS) months or years later, which is known as “clonal evolution.”
The origin, importance and dynamic changes over time of clonal hematopoiesis in aplastic anemia and its relationship to AML, MDS or both had not been previously defined.
Tetsuichi Yoshizato, MD, a researcher in the department of pathology and tumor biology in the graduate school of medicine at Kyoto University in Japan, and colleagues evaluated 668 blood samples from 439 patients with aplastic anemia from three institutions that specialize in the treatment of patients with bone marrow failure. Researchers conducted targeted deep sequencing of genes implicated in AML, MDS or both. They also conducted serial whole-exome sequencing from samples from 82 patients to characterize their hematopoietic clonal architecture over time.
Overall, 36% of the patients harbored somatic mutations in myeloid cancer candidate genes. Of these patients, 36% had multiple mutations (range, 1-7). The most common mutations were BCOR and BCORL1 (9.3%), PIGA (7.5%), DNMT3A (8.4%) and ASXLI (6.2%).
Researchers detected clonal hematopoiesis in 47% of the patients, most frequently as acquired mutations.
Mutation presence and prevalence positively correlated with age (both P ˂ .001). Specifically, the DNMT3A- and ASXL1-mutated clones mostly increased in size over time, whereas the size remained stable or decreased in the BCOR-, BCORL1- and PIGA-mutated clones.
BCOR, BCORL1 and PIGA mutations also were associated with improved response to immunosuppressive therapy as well as longer and higher rates of OS and PFS. Mutations in a subgroup of genes — which included the DNMT3A- and ASXL1-mutated clones — were associated with worse outcomes.
Results of the serial sampling analyses indicated clonal hematopoiesis tended to originate from a minor clone that was present at the time of diagnosis. However, the subsequent temporal course of these clones was highly variable in patients. Cloning mutations were stable for a median of 5 years (range, 2-10) in some patients, whereas a large hematopoietic stem cell clone gradually dominated the blood compartment in other patients, who then harbored new subclones before the development of MDS, AML or both.
“Specific mutations probably have functional relevance, but the exact mechanism of selection of mutated cells in aplastic anemia is unclear,” Yoshizato and colleagues wrote. “We speculate that clones containing mutated genes that are present in aging bone marrow are selected in bone marrow failure; the lower prevalence of such clones in healthy elderly persons as compared with persons with aplastic anemia may be due to the insensitivity of deep sequencing for detecting very small populations of abnormal cells.”
The researchers also pointed out that despite the association of specific gene mutations with response to therapy or survival early on, the complex dynamics of clonal hematopoiesis are highly variable and not completely prognostic or predictive.
“Close monitoring of clonal hematopoiesis by means of both sequencing and [single-nucleotide polymorphism] array karyotyping will need to be combined with clinical evaluation to estimate prognosis and to guide treatment of patients with aplastic anemia,” the researchers concluded. – by Anthony SanFilippo
Disclosure: Yoshizato reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Click Here to Manage Email Alerts