Clinical features ofDDX41mutation-related diseases: a systematic review with individual patient data

Abstract

Background: DDX41 serves as a DNA sensor in innate immunity and mutated DDX41 is pathogenic, mainly for myeloid neoplasms. Methods: In this study, “ DDX41” was searched in PubMed and Web of Science between 1 January 2015 and 29 April 2021 with individual-patient data seeking. A meta-analysis was not valid here due to the absence of a large dataset. Thirty articles were finally included in the qualitative analysis and 277 patients from 20 studies without overlap were involved in the quantitative summary. Results: Pooled incidence was 3.3% (95% confidence interval 2.4–4.2%) of unselected myeloid neoplasms. Patients with hematologic disorders harboring mutated DDX41 were featured as 80% males, median 66 (20–88) years old at diagnosis, 75% acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 64% with normal karyotype. Eighty-five percent of patients had germline variants which were nationally diverse and more of frameshift type, whereas 64% of patients had somatic DDX41 variants where p.R525H and missense dominated. ASXL1 and TP53 were the top frequent concomitant somatic mutations. Therapeutically, 70% overall response rate was obtained of hypomethylating agents in MDS, 96% complete remission of chemotherapy in AML, and 8% of relapse in hematopoietic stem cell transplant. Neither overall survival nor progression-free survival could be summed. Conclusions: Several significant clinical differences were observed in different diagnosis groups, familial and sporadic cases, and p.R525H compared with other somatic variants. In conclusion, myeloid neoplasms carrying DDX41 mutations were mainly older, male, MDS, and AML patients who had promising responses to treatment. Both germline and somatic DDX41 variants possessed unique characteristics and groups of interest presented certain differences worth further research. (CRD42021228886)

Favorable outcomes of DDX41‐mutated myelodysplastic syndrome and low blast count acute myeloid leukemia treated with azacitidine ± lenalidomide

“…Germline DDX41 mutations are found in approximately 5% of patients with MDS and AML, representing the most common myeloid neoplasms associated with germline predisposition [5][6][7]. To date, it is unclear if DDX41-mutated MDS should be treated differently than the standard treatment, such as AZA [8,9]. While DDX41 (5q35.3) is outside the minimal deleted region (q31-q33) of most MDS cases with del(5q), it is variably deleted in 25% of patients [10].…”

“…Sebert et al studied 11 patients with DDX41-mutated MDS/AML who received AZA with 73% ORR and prolonged response duration (median 2.5 years); note seven patients underwent HCT[8]. A pooled analysis of additional patients (total 33 patients) showed similar ORR of 70% to AZA[9]. The small number (n = 5) in our trial cohort prevents any conclusion to be drawn regarding the impact of the addition of lenalidomide (n = 1) on DDX41-mutated MDS in comparison to AZA alone (n = 4).…”

How I Manage Transplant Ineligible Patients with Myelodysplastic Neoplasms

“…While TET2-(with controversial results) and DDX41mutants seem to have a higher rate of HMA response, MDS patients harboring ASXL1 and specific DNMT3A variants (e.g., R882H) tend to have dismal outcomes (Fig. 3) [88][89][90]. Another instance where HMA seems to be promising is the clinical dyad of MDS and VEXAS syndrome, a new hematoinflammatory disorder characterized by the concomitant presence of BM vacuoles, autoinflammatory symptoms, macrocytic anemia, and MDS in up to 60% of cases [91,92].…”

Clinical and mechanistic insights into the roles of DDX41 in haematological malignancies

“…versus Sebert et al cohorts may not be equivalent, a finding that warrants further investigation. In a pooled qualitative analysis looking at 277 patients from 20 studies between 2015 and 2021, the incidence of any kind of DDX41 mutation in myeloid neoplasms was 3.3%, occurring in 80% males, with Additional Sex Combs Like 1 and TP53 being the most frequent concomitant somatic mutations [26]. Based on these studies, understanding the effects of DDX41 mutational status on MDS/AML prognosis and treatment is still an area of exploration.…”

“…TP53 mutations are one of the top co-occurring somatic mutations in DDX41-mutated myeloid neoplasms [12,17,26]. Mechanistically, how do TP53 mutations provide a competitive advantage in the context of DDX41-mutated myeloid neoplasms?…”