From the Journals

Genetic analysis highlights value of germline variants in MDS, AML



Germline DDX41 mutations were found to be relatively prevalent and showed favorable outcomes in a cohort of patients with myelodysplastic syndromes or acute myeloid leukemia, according to a genetic analysis.

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The results demonstrate that systematic genetic testing for DDX41 mutations may aid in clinical decision making for adults with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML).

“We screened a large, unselected cohort of adult patients diagnosed with MDS/AML to analyze the biological and clinical features of DDX41-related myeloid malignancies,” wrote Marie Sébert, MD, PhD, of Hôpital Saint Louis in Paris and colleagues. The results were published in Blood.

The researchers used next-generation sequencing to analyze blood and bone marrow samples from 1,385 patients with MDS or AML to detect DDX41 mutations. A variant allele frequency of greater than 0.4 was regarded as indicative of a germline origin, and only specific variants (minor allele frequency of less than 0.01) were included.

The team analyzed various parameters relevant to DDX41-related myeloid disorders, including patient demographics, karyotyping, and treatment response rates, in addition to the prevalence of DDX41-related malignancies.

A total of 28 distinct germline DDX41 variants were detected among 43 unrelated patients. The researchers classified 21 of the variants as causal, with the rest being of unknown significance.

“We focused on the 33 patients having causal variants, representing 2.4% of our cohort,” they wrote.

The majority of patients with DDX41-related MDS/AML were male, with a median age of 69 years. Few patients (27%) had a family history of blood malignancies, while the majority of patients (85%) had a normal karyotype.

With respect to treatment, most high-risk patients received either azacitidine or intensive chemotherapy, with overall response rates of 73% and 100%, respectively. The median overall survival was 5.2 years.

There are currently no consensus recommendations on genetic counseling and follow-up of asymptomatic carriers and more studies are needed to refine clinical management and genetic counseling, the researchers wrote. “However, in our experience, DDX41-mutated patients frequently presented mild cytopenias years before overt hematological myeloid malignancy, suggesting that watchful surveillance would allow the detection of disease evolution.”

No funding sources were reported, and the authors reported having no conflicts of interest.

SOURCE: Sébert M et al. Blood. 2019 Sep 4. doi: 10.1182/blood.2019000909.

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