Hematologic neoplasms with germline DDX41 variants: Experience from nine spanish centers. Free

Introduction: Neoplasms with germline variants in DDX41 constitute the most frequent hematologic neoplasm (HN) with a germline predisposition. Their clinical peculiarity and the region-specific distribution of variants necessitate a systematic description within distinct geographic contexts.

Methods: Patients diagnosed with HN carrying DDX41 variants were retrospectively collected from 9 centers between 2017 and 2025, including available carrier relatives. Descriptive analysis was performed using IBM SPSS Statistics 26.

Results: A total of 42 patients from 40 different families were identified with HN and a pathogenic or likely pathogenic germline variant in DDX41: 26 myelodysplastic syndromes (MDS), 14 acute myeloid leukemias (AML), 1 primary myelofibrosis, and 1 Burkitt lymphoma (BL). Additionally, 44 healthy carrier relatives were identified.

The median age of patients was 69 years (range 45–81, excluding one 4-year-old BL patient). Seventy-six percent were male. Twelve percent had a history of solid neoplasms, and 21% had a family history of HN. Among MDS cases, 57% presented with increased blasts, and all AML cases were classified as myelodysplasia-related or NOS. Bone marrow studies revealed hypocellularity in 29%, normocellularity in 59%, and hypercellularity in 12%. Circulating blasts were observed in only 10% of cases (median 1%) and median bone marrow blast percentage was 30%.

The median follow-up time was 36 months (IQR 13–53 months). Median survival for AML (42 months) and MDS (152 months) exceeded the median follow-up time. Forty percent (16) of patients underwent allogeneic transplantation, 50% of whom received grafts from related donors (RD); 19% (3) developed donor cell leukemia, all from RD.

Ninety-five percent of cases showed a normal karyotype. The most frequent germline variants were p.R339C (24%), p.G173R (20%), p.R311* (9.5%), and p.D140Gfs*2 (9.5%). Sixty percent were non-synonymous variants, 37% truncating variants, and one splice site variant. Seventy-one percent had an associated somatic DDX41 variant: R525 (44%) or other (27%). While DDX41 somatic variants were the most frequent, 75% of patients harbored other co-occurring somatic variants, ASXL1, DNMT3A, SRSF2 and TET2 being the most frequent.

The median age of healthy carriers was 46 years (range 37–55), with a median follow-up of 10 months. Only 4 carriers presented with mild cytopenia. In 32% (14) of cases, clonal hematopoiesis was evaluated by NGS, present in 21% (3 cases; DNMT3A, TET2, ASXL1). None of the healthy carriers developed a myeloid neoplasm. Among patients, two pairs of related individuals were identified.

Conclusion: Our findings corroborate previously described characteristics of this entity, although the frequency of identified germline variants in our population differs from other European cohorts. A high percentage of donor cell leukemia is reported, albeit in a small number of patients undergoing stem cell transplantation. Although no myeloid neoplasms have been observed in the cohort of healthy carriers, the median follow-up duration remains limited. Extended follow-up is necessary to more accurately assess the risk of myeloid neoplasms in healthy individuals related to a patient with overt disease.