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Clonal Evolution: In Aplastic Anemia, Which Mutations Matter?

December 30, 2021

Mutations in a specific set of genes may predict whether patients with aplastic anemia develop hematologic malignancies, according to research recently published in The New England Journal of Medicine.

"Some mutations appear to have a favorable impact, especially on response to immunosuppressive therapy," Neal S. Young, MD, one of the study's co-authors and chief of the hematology branch of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, told ASH Clinical News. "As only a few genes are involved and this study was very large [for aplastic anemia], determination of the presence of a mutated clone should be helpful in choosing among therapies in [aplastic anemia], especially for younger patients, and reassuring patients, especially older ones."

Approximately 15 percent of patients with acquired aplastic anemia will develop late myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or both through a process historically referred to as "clonal evolution." However, recent research has provided evidence of clonal hematopoiesis in patients who do not develop these malignancies, leading Tetsuichi Yoshizato, MD, and colleagues to question whether specific mutations are associated with malignant transformation in patients with aplastic anemia.

Dr. Yoshizato, of the Graduate School of Medicine at Kyoto University in Japan, and his team performed targeted deep sequencing of genes implicated in MDS, AML, or both, with clonal populations of mutated cells correlated to clinical outcomes.

The researchers obtained blood, bone marrow, and buccal samples from 439 patients with aplastic anemia and analyzed a total of 668 blood samples through next-generation sequencing and single-nucleotide polymorphism (SNP)–based karyotyping. Serial samples were available from 82 patients. The panel of 106 genes for targeted sequencing focused on genes known to be mutated in other bone marrow failure conditions or myeloid cancers, including: PIGA, BCOR and BCORL1, and DNMT3A.

The researchers found 249 somatic mutations among 156 patients (36%); 56 of those patients (36%) demonstrated multiple mutations, ranging from one to seven. The most frequently observed mutations were BCOR and BCORL1 (9.3% of patients), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%) – accounting for 77 percent of all mutation-positive patients.

As the study's authors expected based on previous reports, the most common abnormality in SNP-based karyotyping was uniparental disomy of the 6p arm, occurring in 13 percent of patients. Clonal hematopoiesis was detected in 47 percent of patients, most frequently presenting as acquired mutations.

The researchers established that the prevalence of mutations increased with age, and that mutations had an age-related signature: DNMT3A and ASXL1 mutations tended to increase in size over time, while BCOR, BCORL1, and PIGA mutations declined or remained stable over time (p<0.001).

No relationship between the presence of mutations and response to immunosuppressive therapy was established (p=0.28). However, when the mutated genes were assessed individually, the authors noted that "mutations in PIGA and BCOR and BCORL1 mutations correlated with a better response to immunosuppressive therapy (p=0.013) and a longer and higher rate of overall (p=0.008) and progression-free survival (p=0.03)," compared with mutations in the subgroup of mutations in the DNMT3A, ASXL1, TP53, RUNX1, and CSMD1 genes.

In addition to the "unfavorable" mutations, age >60 years (p<0.001), male sex (p=0.006), and a lower initial reticulocyte count (p=0.014) were associated with poor overall survival.

The mean allelic burden of mutations in aplastic anemia was substantially lower than that in MDS (9.3% vs. 30.4%, respectively). In addition, some patients carried multiple mutations in the same gene. No significant difference in overall survival and progression-free survival was determined among patients with somatic mutations compared with those without mutations.

In a more detailed analysis of clonal evolution in serial samples from 35 patients, clonal hematopoiesis typically originated from a minor clone that was already present at the time of diagnosis. "However, the subsequent temporal course of these clones was highly variable," the authors noted, and, despite the association of particular gene mutations observed early in the course of disease with response to therapy and survival, "the complex dynamics of clonal hematopoiesis are highly variable and not necessarily determinative."

"The pattern over time of mutated clones shows that patients can do well with a large, very genetically abnormal clone for many years, so a mutation is not an absolute determinant of prognosis," Dr. Young added.

In the future, Dr. Yoshizato and colleagues wrote, "close monitoring of clonal hematopoiesis by means of both deep sequencing and SNP array karyotyping will need to be combined with clinical evaluation to estimate prognosis and to guide treatment of patients with aplastic anemia."


Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med. 2015;373:35-47.


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