October 06, 2014
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Somatic mutations linked to malignant transformation of aplastic anemia
Somatic mutations in patients with aplastic anemia were associated with longer disease duration and an increased risk for transformation to myelodysplastic syndrome, according to study results.
Austin G. Kulasekararaj, MD, of the department of hematological medicine at King’s College London School of Medicine, and colleagues evaluated data from 150 patients with aplastic anemia who had no morphological evidence of myelodysplastic syndrome. Patients had a median age of 44 years (range, 17-84) and the median disease duration was 10 months (range, 0-246) from diagnosis.
Fifty-seven patients underwent screening for 835 genes associated with bone marrow failure and myeloid cancer. Researchers screened the other 93 patients for ASXL1, DNMT3A, BCOR, TET2 and MPL mutations.
Twenty-nine patients (19%) harbored somatic mutations.
The most common mutations were ASXL1 (n=12), DNMT3A (n=8) and BCOR (n=6). Researchers also detected one occurrence each of SRSF2, U2AF1, TET2, MPL, IKZF1 and ERBB2 mutations.
Patients who harbored somatic mutations were older (median age, 47 years vs. 43 years; P˂.2) and had a significantly longer aplastic anemia disease duration (37 months vs. 8 months; P˂.04) than patients without somatic mutations.
Patients with somatic mutations also exhibited significantly longer median telomere length (Telomere-to-Single Copy Gene ratio [T/S]=1.1) than patients without somatic mutations (T/S=0.9; P=.0016).
Seventeen patients (11%) progressed to myelodysplastic syndrome during a median disease duration of 86 months (range, 9-260). Eleven of these patients (65%) harbored somatic mutations, and two went on to develop acute myeloid leukemia.
Overall, a greater proportion of patients with somatic mutations had disease which evolved to myelodysplastic syndrome (38% vs. 6%; P˂.001). The risk for myelodysplastic syndrome with somatic mutations intensified among patients with a disease duration longer than 6 months (40% vs. 4.5%; P˂.0002).
“We have identified clonal hemopoiesis in a fifth of aplastic anemia patients and specific gene mutations associated with a transformation to myelodysplastic syndrome,” Kulasekararaj and colleagues concluded. “Large prospective studies with sequential analysis of somatic mutations are now indicated to determine more accurately the impact and dynamics of mutations in predicting the risk of evolution to myelodysplastic syndrome and AML prior to the onset of frank morphological dysplasia.”
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Ramon Tiu, MD
Differentiating aplastic anemia from the hypocellular variant of myelodysplastic syndrome (MDS), and predicting who among the patients diagnosed with aplastic anemia ultimately will transform to MDS, is a big challenge in the management of bone marrow disorders. Our current standards of morphology and cytogenetics cannot always give us the right answer. The ability to predict the right diagnosis and who among the patients will progress complicates therapy and prognosis. The study by Kulasekararaj and colleagues gives us new insights into how somatic molecular mutations may be involved in the pathogenesis of aplastic anemia. Mutations in genes important in epigenetic regulation — particularly
ASXL1, DNMT3A and
TET2 — are common, whereas some cases also have mutations in
BCOR and
MPL genes. They showed that patients with aplastic anemia who have somatic mutations have longer disease duration and are more likely to progress to MDS. It is clearly instructive and definitely warrants further studies. Ultimately, a systematic follow-up of patients with aplastic anemia with larger numbers of patients — with consistent sampling from time of diagnosis and multiple time points during the disease course and careful attention to types of therapies received — will be important to understand the potential short- and long-term impact of these genetic mutations in aplastic anemia.
Ramon Tiu, MD
HemOnc Today Editorial Board member
Cleveland Clinic
Disclosures: Tiu reports no relevant financial disclosures.
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