DDX41 mutation

Improved survival was observed with transplantation in groups DP2, DP7, and DP9. These findings highlight the role of genomic classifications in guiding personalized treatment strategies, ultimately enhancing the understanding and management of myeloid neoplasms.

While intensive investigations unveiled a strong genotype-phenotype relationship, the optimal therapeutic approach and long-term outcome are undefined. There is an urgent need to scrutinize the patients at single cell and multiomics level and to advance experimental animal and human models to fully elucidate the molecular pathogenesis.

Regarding donor search for allogeneic HSCT for AML with a germline DDX41 mutation, it is essential to ensure that the donor must be negative for this mutation when the donor is a family donor. If the related donor has a positive mutation, which can cause the development of donor-derived leukemia, allogeneic HSCT should performed from an unrelated donor.

These findings are further supported by data from a DDX41 mutated MN patient and human iPSC-derived bone marrow organoids. Our study establishes DDX41 as a G4 dissolver, essential for erythroid genome stability and suppressing the cGAS-STING pathway.

Additionally, this demonstrates that gilteritinib is clinically active as an ALK inhibitor, and could be considered for use in any AML patient presenting with an inv(2(p23q13)) translocation. Finally, it is an example of using a disease-agnostic, precision medicine approach to arrive at a beneficial treatment.

No abstract available

Myelodysplastic syndromes (MDS) patients with DEAD-box helicase 41 (DDX41) mutations have been reported to be treated effectively with lenalidomide; however, there are no randomized studies to prove it. We retrospectively analyzed the genetic features and clinical characteristics of these patients. Our findings suggest that MDS patients with DDX41 mutation may benefit from the therapy, for six subjects received this regimen as initial therapy and five of the six subjects achieved complete remission.

Collectively, we demonstrated that DDX41 plays a key role in the physiological control of R-loops in cooperation with MAC and YTHDC1. These findings provide novel insights into how defects in DDX41 influence MDS pathogenesis and suggest potential therapeutic targets for the treatment of MDS.

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In this review, we will summarize the latest understandings regarding the various roles of DDX41, as well as highlight challenges associated with drug development to target DDX41. Overall, understanding the molecular and cellular mechanisms of DDX41 could help develop novel therapeutic options for DDX41 mutation-related hematologic malignancies.

No abstract available

Treatment with DaunorubicinCytarabine was initiated, and due to the high-risk nature of the patient’s condition, a HSCT from a related donor was considered. However, no suitable donors were found, and the patient underwent a MUD 7/8 transplant. Screening family members for the same mutation when searching for a donor for HSCT can improve the chances of successful transplantation, but raises ethical and counselling considerations.This highlights the importance of reporting mutations that are classified as variants of uncertain significance (VUS) in the literature, as this can aid in identifying new pathogenic mutations in future studies The discovery of germline mutations in genes, including DDX1, that predispose individuals to hereditary hematological malignancies is crucial in allogeneic transplantation management, especially for younger and healthier patients.

Subsequent backwards elimination based on the Akaike information criterion delineated three genetic risk groups: DDX41 mutations (favorable-risk), DDX41/FLT3-ITD/TP53 (intermediate-risk), and FLT3-ITD or TP53 mutations (high-risk). Our data identified distinct trajectories of leukemia development in older AML patients and provide a basis for a clinically meaningful genetic outcome stratification for patients receiving less intensive therapies.

We define the somatic mosaic landscape in DDX41-MT GPS and demonstrate that somatic mutations involving the other allele, especially R525H, are seen in ~20% of pts (>80% of R525H present in MN). The frequency and composition of ARCH and myeloid driver mutations was lower than expected for the age of presentation, in comparison to de novo and secondary MDS/AML and occurred more frequently in DDX41path compared to DDX41VUS. Forty-two % (n=41), including 37% with MN, did not have somatic mosaicism, underscoring the fact that mechanisms of leukemia progression remain to be defined in subsets of affected pts.

36% (n=13) were treated with venetoclax/hypomethylating agent (Ven/HMA) (average age 72 years) with a 69% response rate (Figure 1)... In our cohort of germline DDX41-mutated AML, responses to a 7+3- or Ven/HMA-based regimen were similar. SCT evaluation remains crucial with improved overall survival in pts receiving SCT. Our study highlights the importance of comprehensive genetic testing that includes DDX41 at diagnosis, along with testing of related donors and children of pts with a germline DDX41 mutation due to the impact of positive testing on donor selection and to identify pts at risk of AML.

Response was assessed according to the 2022 ELN criteria Patient characteristics A total of 301 newly-diagnosed AML patients (median age 73 years, 66% male, 62% de novo) received a median of 3 cycles (range 1-48) of azacitidine 75 mg/m2 days 1-7 (n=100) or decitabine 20 mg/m2 days 1-5 (n=201) with Ven. In the current single institutional series of Ven-HMA treated newly-diagnosed AML, response to Ven-HMA was the foremost predictor of survival. Additional risk factors for survival included adverse karyotype, presence of TP53 and absence of IDH2 mutations. These observations allowed for a three-tiered genetics-enhanced survival model with CR/CRi as a backbone, and also confirmed survival advantage from AHSCT, regardless of risk category.

P=N/A, N=910, Recruiting, Institut Claudius Regaud | Not yet recruiting --> Recruiting

Clonal hematopoiesis commonly occurs in healthy individuals, especially in older people. For patients with germline predisposition, clonal hematopoiesis is frequently observed at a younger age and often associated with disease-specific driver mutations, leading to further understating of the pathogenesis of diseases.

No abstract available

However, the efficacy of VEN and HMAs in treating DDX41-mutated (mDDX41) MDS/AML patients remains uncertain. Despite the favourable prognostic nature of mDDX41 MDS/AML patients, there is a lack of clinical experience regarding their response to different treatment regimens, leading to an unknown optimal therapeutic approach.

No abstract available

Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.

P=N/A, N=910, Not yet recruiting, Institut Claudius Regaud

Among previously untreated patients, 89% received treatment, 76% of them with low-intensity therapies (LIT, including low-dose chemotherapy or hypomethylating agents), 22% with low-intensity therapies with venetoclax (LIT-Ven), and 2% with lenalidomide. Most patients with MDS with DDX41 mutations have a germline and a somatic mutation. Normal karyotype is a common finding in these patients, and, in our cohort, ASXL1 and TP53 were the most frequent co-mutations. Response rates were high, and OS was improved in patients receiving venetoclax, although not statistically significative.

Most patients with DDX41 mutations have a combination of a germline and a somatic mutation. Normal karyotype is a common finding in these patients, with TP53, ASXL1 and SRSF2 common co-mutations. Patients treated with low-intensity treatments plus venetoclax have an improved survival and a lower incidence of disease relapse, and outcomes appear favorable with alloSCT.

Finally, we found that higher mean red cell volume and somatic DDX41 mutations in blood DNA identify DDX41-GPV carriers at increased MDS/AML risk. Collectively, our findings give new insights into the prevalence and cognate risks associated with DDX41 variants, as well as the clonal evolution and early detection of DDX41-mutant MDS/AML.

No abstract available

Here, we expand on previous clinicopathologic findings on DDX41 mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterized DDX41 alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.

Like described in most reported adult patients with KMT2A::ARHGEF12 fusion, complete remission could not be achieve by Daunorubicine and Cytarabine , neither with Azacytidine and Venetoclax. The patient is at present included in a clinical trial testing a KMT2A inhibitor, the Ziftomenib... We herein report a first case of AML with rare KMT2A::ARHGEF12 fusion transcript with a rare germline DDX41 variant. We highlight both the importance of multiple methods, including RNA high throughput sequencing, to discover rare KMT2A rearrangements as well as systematic research of DDX41 mutation in myeloid neoplasm. Reporting unusual and rare genetic aberrations is important in order to improve knowledge of their prognosis and treatments modalities including new clinical trials.

We map the landscape of DDX41 germline variants in a cohort of 454792 volunteers and show that carriers are at increased risk of MDS/AML, but not other cancers (including MPN and lymphoma). We estimate variant-specific relative and absolute risks of MDS/AML and show that DDX41 -mutant differs to sporadic MDS/AML evolution, but is not linked to increased mutagenesis. We also report that DDX41 -GPV carriers have normal baseline bloodcounts, but those en route to MDS/AML often had higher MCV or harboured somatic DDX41 mutations.

Targeted sequencing of 263 genes was performed in 604 patients enrolled in the randomized, multi-center phase 3 'ASTRAL-1' trial (NCT02348489) evaluating the second-generation hypomethylating agent guadecitabine (SGI- 110) in treatment-naïve AML pts not eligible for intensive chemotherapy in comparison to a treatment choice of decitabine, azacitidine, or low-dose cytarabine. Using different modelling algorithms, our comprehensive analysis of the so far largest study in older, treatmentnaïve AML patients identified distinct trajectories of leukemia development, provided support for AML with mutated DDX41 as a new clinico-pathologic entity and a basis for the development of a risk stratification that may be applicable for the numerous older patients receiving less intensive therapies. Tumorigenesis, Age, AML, Prognostic groups

DDX41 mut MNs have distinct genetic and clinical/hematological features, representing a unique subset of MNs. IPSS-R/IPSS-M prognostication may not be applied to DDX41 mut MDS.