Some mutations in patients with aplastic anemia influence the response to therapy and long-term disease outcomes, according to a genomic cohort study by Tetsuichi Yoshizato, MD, from the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Japan, and colleagues, publishedin the July 2 issue of the New England Journal of Medicine.
Investigators performed next-generation sequencing and array-based karyotyping using 668 blood samples from 439 patients with aplastic anemia from the United States and Japan. Eighty-two had serial samples.
Results showed that 36% of the patients had somatic mutations in myeloid cancer candidate genes; the prevalence rose significantly with patient age. In addition, 47% of the patients were found to have clonal hematopoiesis, most frequently resulting from the acquisition of new mutations over time.
The mutations were found in just a handful of genes and were associated, for better or worse, with outcomes. Specifically, patients having mutations in the PIGA and the BCOR and BCORL1 genes had a better response to immunosuppressive therapy and better progression-free and overall survival. In contrast, patients with mutations in a set of genes that included DNMT3A and ASXL1 had poorer outcomes.
"There is a clear clinical implication to the management of patients with this disease, aplastic anemia, in that detecting this very limited number of mutations and cells that contain these mutations should be useful in guiding patients to the best treatment, and also monitoring them over time," said Neal S. Young, MD, one of the study authors and chief of the hematology branch of the National Heart, Lung, and Blood Institute, Bethesda, Maryland.
This new information is already being incorporated into patient care in his clinic and others, he told Medscape Medical News. "We are looking for mutations in patients when they come to us, and for example, in younger patients who have these mutations, we are recommending...if they can go to transplant, that they should, or that we should monitor the size of the clones and for other mutations if they are not willing to go to transplant early on. Conversely, in patients who don't have mutations, we can feel much more comfortable about not performing a bone marrow transplant."
The findings also shed light not only on bone marrow failure and the pathogenesis of leukemia in patients with aplastic anemia, but also on genetic changes seen with normal aging, according to Dr Young.
"Bone marrow failure, which we think is mediated by the immune system in these patients because they respond to therapy that's directed against the immune system, can develop into leukemia or myelodysplasia over time.... So we have an opportunity to look at what happens early before the leukemia actually gets established. And what the paper shows is, even though there are many mutations in leukemia when it's established, there are only a few mutations that occur in these patients who are at risk of leukemia later on. They are really basically in just two genes: DNMT3A and ASXL1."
What's "really new and a big surprise" is that these same two mutated genes are the main ones that have been implicated as risk factors for leukemia in healthy adults older than 65 years, he added.
Dr Young cautioned that despite the association of unfavorable mutations with poorer outcomes in aplastic anemia, their presence does not necessarily mean a worse prognosis for an individual patient. In fact, one older study patient with an unfavorable mutation fared well during a follow-up of more than 10 years, Dr Young noted. "He's essentially supported his hematopoiesis, all his blood cell production, from one big, heavily mutated clone. He's done really quite well, has responded to immunological therapy, is transfusion independent, and [is] going about his life."
One of the authors reports receiving grant support from the Japan Society for the Promotion of Science during the conduct of the study. One of the authors reports receiving grant support from the Aplastic Anemia & MDS International Foundation and the National Institutes of Health, and other reports receiving support from the Robert Duggan Memorial Fund during the conduct of the study. One of the authors reports receiving grant support from the Aplastic Anemia & MDS Foundation during the conduct of the study. One of the authors reports receiving grant support from Daiichi-Sankyo outside the submitted work. One of the authors reports receiving grant support from Japan Society for the Promotion of Science during the conduct of the study.
N Engl J Med. 2015;373:35-47. Abstract
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