ASH 2025 | Decoding DDX41: clinical impact of germline and somatic mutations in high-risk myeloid neoplasms

DDX4-1, related myeloid neoplasm. DDX4-1 is the most prevalent regulatory bone marrow failure syndrome among patients with MDS, AML, which have superseded other bone marrow failure syndromes. Our knowledge suggests that these patients tend to have an indolent course. They’re more commonly seen in elderly AML population, their bone marrow hypoplasia doesn’t present with a proliferative phenotype, and they have a long time from disease progression to more advanced stage disease. Earlier studies suggest that when we utilize either cytarabine or decitabine plus venetoclax among these patients, they tend to have an overall response rate close to 100%. Having led to inclusion among the favorable category in AML 2024, low-intensity eligible treated patients with acute myeloid leukemia. That means patients with AML, elderly who receive low-intensity chemotherapy, hypomethylating agent plus mild venetoclax, tends to respond better with DDX4 mutation and tends to be in a favorable category. Anecdotally, what we observed in our clinic, that not all patients tend to respond to venetoclax-based therapy. There are certain hotspots, certain missing variants, where we see that they have primary refractory disease. So we utilize our DDX4-1 database, one of the largest databases in the country, among 200 patients from our bone marrow failure syndrome clinic, and we identified 77 patients with high-risk MDS and AML with DDX4 bona fide mutation. We look at their baseline characteristics and outcome to venetoclax-based therapies or other intensive chemotherapy or hypomethylating agent-based therapy, what we observed that these are predominantly male. They most likely have a truncating variant. Among these germline, the most common somatic variant that triggers the leukemogenesis among these patients were R525H, around 40%, and less commonly was splicing factor and AXL mutation. When we look at the response rate, contrary to what had been reported, we saw an overall response rate around 60% or so. We didn’t see that patients who received venetoclax plus HMA had a better outcome compared to those who received intensive chemotherapy or hypomethylating signaling therapy. Having said that, the data is heterogeneous among patients who had MDS-EB-1, MDS-EB-2, and AML, but there are still some patients who are primarily refractory to venetoclax therapy. In multivariate analysis, what we observe, that patients with concurrent splicing function mutations tend to have an inferior outcome, and allogeneic stem cell transplant has a trend towards improved long-term survival outcome. Among these groups of patients, the overall response rate, the three-year overall survival rate, around 60 to 70%, having said that these patients tend to do better than traditionally acute myeloid leukemia patients with similar journey.

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