Disease Characteristics of AML Patients with Germline DDX41 Variants
Authors: Vagher Jennie , Venkatachalam Shobi , Li Peng , Asch Julie D. , Huber Bryan D. , Tashi Tsewang , Shami Paul J , Kovacsovics Tibor , Maese Luke , Parker Charles J. , Tantravahi Srinivas K. 
Published: November 2021

Abstract
Introduction:
Germline pathogenic variants in DDX41 represent the most common predisposition to myeloid neoplasms accounting for 1-4% of patients (pts). Myeloid neoplasm with germ line DDX41 mutation is included as a separate entity in the revised 2016 World Health Organization classification of myeloid neoplasms and acute leukemia. The risk to develop any myeloid neoplasm in individuals with pathogenic germline DDX41 variants is modest, estimated to be about 20-30%. The recent inclusion of DDX41 on next generation sequencing panel (NGS) for myeloid neoplasms has led to increase in identification of DDX41 variants. Identification of germline DDX41 variants in MDS/AML pts will inform on donor selection and genetic testing of family members who are potential hematopoietic stem cell transplant (HSCT) donors is critical to eliminate the risk for transmission of a donor derived leukemia. Herein, we describe 10 pts with acute myeloid leukemia who were identified to have a DDX41 variantsince January 2020.
Methods
Among the pts diagnosed with acute myeloid leukemia in Utah between January 2020 and April 2021, 10 pts were identified to have a DDX41 variant on myeloid NGS panel (peripheral blood or bone marrow) performed at the time of diagnosis (9 pts) or through genetic testing performed on cultured skin fibroblasts (1 pt). When possible, pts with met a genetic counselor and germline genetic testing was performed utilizing DNA obtained from cultured skin fibroblasts through GeneDX Laboratory and Prevention Genetics. DDX41 variants are classified (Table 1) as per the ACMG criteria.
Results
Of the 10 pts with a DDX41 variant on myeloid NGS panel, 9 (90%) were diagnosed with AML. One pt (10%, Pt 9)) was initially diagnosed as AML and subsequently classified as mixed phenotype T/myeloid leukemia on repeat marrow evaluation after failure of initial induction based on blasts co-expressing cytoplasmic CD3 and MPO. The DDX41 variant was classified as pathogenic and variant of uncertain significance (VUS) in 6 (60%) and 4 (40%) pts, respectively. The variant allele frequency (VAF) of DDX41 variants was above 35% in all pts (Table1). Seven pts had germline testing performed from cultured skin fibroblasts, all were found to have germline DDX41 variants. Three pts did not undergo germline genetic testing, but the VAFs were highly suggestive of germline origin. Baseline demographics and the AML disease characteristics are outlined in Table 1. ELN risk category was unknown in 1 pt (10%), favorable in 1 pt (10%), intermediate in 3 pts (30%) and adverse in 5 pts (50%). Karyotype was normal in6 pts (60%), 20 q deletion in one pt and a complex in 2 pts (20%). Other somatic variants identified on the myeloid NGS panel are outlined in Table 1. First line treatment included intensive chemotherapy in 6 pts (60%) and 4 pts (40%) received hypomethylating agent based (HMA) therapy. Seven pts achieved a complete remission (CR), after first line treatment, of whom 5 received intensive chemo and 2 received HMA based treatment. One pt who received HMA therapy failed to achieve CR or CRi (pt 5), achieved CR after receiving intensive chemo for salvage. One pt failed initial induction with idarubicin and cytarabine (7+3 regimen) and achieved CR after reinduction with cycle 1 A of HyperCVAD. 5 pts relapsed after first line treatment (2 after intensive chemo and 3 after HMA based treatment). At the time of this report, 2 pts received allogeneic stem cell transplant (allo-SCT) both from unrelated donors and 3 pts died.
Conclusion:
In our experience, AML pts with germline DDX41 variant presented after fifth decade similarly to sporadic AML. Most pts had pathogenic variants in DDX41 (per ACMG), though 3 pts were classified as uncertain variants which represent an area of further knowledge. The majority of the pts had a normal karyotype at diagnosis. A second somatic DDX41 variant was observed in 2 pts. ASXL1 mutations were observed in 3 pts. Inclusion of the DDX41 gene in a myeloid NGS panel is necessary to identify this subset of pts and in addition germline testing should also be considered for all MDS/AML pts with age &lt;40. Multicenter registry-based studies are necessary to further characterize and develop a standardized treatment approach for these individuals and the role of allo-SCT.
Figure 1 Figure 1.

Disclosures
Tashi: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Shami: JSK Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bastion Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chimerix: Research Funding; Takeda: Consultancy; Gilead: Consultancy; BMS: Consultancy; Chimerix: Research Funding; Amgen: Research Funding; Aptevo: Research Funding. Kovacsovics: Stemline: Honoraria; Novartis: Research Funding; Amgen Inc.: Research Funding; Janssen Pharmaceuticals: Research Funding; AbbVie: Research Funding; Jazz Pharmaceutials: Honoraria. Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tantravahi: Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Research Funding; Abbvie Inc.: Research Funding; CTI BioPharma: Research Funding; Novartis: Research Funding; BMS: Research Funding.