Allogeneic hematopoietic stem cell transplantation in germline DDX41 mutated patients with myeloid malignancies Open Access

• HSCT in patients with DDX41-related myeloid malignancies is safe, not associated with an increased risk of GVHD but with later relapse.

• Using DDX41mut donor is associated with a risk of donor cell leukemia after HSCT in patients with DDX41-related myeloid malignancies

Germline DDX41 mutations (DDX41mut) are identified in approximately 5% of myeloid malignancies with excess of blasts, representing a distinct MDS/AML entity. The disease is associated with better outcomes compared to DDX41 wild-type (DDX41WT), but patients who do not undergo allogeneic hematopoietic stem cell transplantation (HSCT) may experience late relapse. Due to the recent identification of DDX41mut, data on post-HSCT outcomes remain limited. Here, we first report the HSCT outcomes of 83 DDX41mut MDS/AML patients. With a median follow-up (FU) of 4.4 years, the 2-year leukemia-free survival (LFS) was 68.6% (95% CI, 57.1 - 77.6), with a 2-year non-relapse mortality (NRM) of 21.1% (95% CI, 12.9 - 30.6). We then assessed the impact of DDX41mut using a pair match analysis performed on patients who underwent transplantation in AML clinical trials. No significant differences were observed between DDX41mut and DDX41WT patients in terms of LFS at 2 years (HR: 1.06, 95% CI, 0.59-1.90, p=0.84), overall survival (OS), NRM, relapse, or graft-versus-host disease (GVHD) incidence. The CIR for DDX41mut showed a trend toward a lower relapse rate during the first year and a higher relapse rate after 1 year. Given the familial nature of the disease, we specifically examined patients who relapsed after HSCT with a related donor, identifying 7 cases of DDX41mut donor cell leukemia (DCL). In our study, HSCT in DDX41mut AML patients was not associated with an increased risk of toxicity. However, we observed a potential for later relapse, which could potentially be mitigated by selecting related donors based on DDX41 status.