Viswanatha, David S.

Objective To evaluate the efficacy of cytokine‐directed therapies in VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory somatic) syndrome using previously proposed treatment response criteria. Methods All patients with genetically confirmed VEXAS syndrome who received targeted therapies with JAK inhibitors (JAKi), tumor necrosis factor α inhibitors (TNFαi), or interleukin‐1 (IL‐1) or IL‐6 inhibitors were identified. Clinical and biochemical data were recorded for patients at time of targeted therapy initiation, and at 3‐, 6‐, and 12‐month follow‐up time points. Treatment response was labeled as complete response (CR; normalization of C‐reactive protein [CRP], prednisone <10 mg/day, and resolution of disease activity), partial response (PR; >50% improvement in CRP, >50% prednisone dose reduction, improvement or resolution of disease features), treatment failure (TF; worsening CRP, increasing prednisone, worsening of disease features), or no response (not meeting criteria for CR, PR, or TF). Results Overall, 52 patients received an IL‐1i, IL‐6i, or JAKi therapy. At six‐month follow‐up, 3 of 19 IL‐6i patients experienced CR, 4 of 19 experienced PR, and 7 of 19 experienced TF. 2 of 17 patients receiving JAKi experienced CR, 3 of 17 experienced PR, and 6 of 17 experienced TF. No patients receiving IL‐1i or TNFαi experienced CR, and only 1 of 5 IL‐1i patients experienced PR. Among those still receiving biologic therapy at 12 months, only 1 of 11 receiving IL‐6i and 0 of 7 receiving JAKi experienced CR. Conclusion IL‐6i and JAKi therapies demonstrated limited, unsustained efficacy for management of VEXAS syndrome. IL‐1i and TNFαi therapies were not efficacious. Useful application of previously reported treatment response criteria was demonstrated, but future incorporation of hematologic parameters may be beneficial.

ABSTRACT We examined the prognostic value of routine NGS data in newly diagnosed acute myeloid leukemia (AML) treated with intensive (7 + 3 backbone) induction, specified by AML subtype. A contemporary (2015–2025) series of 545 Mayo Clinic patients (median age 56 years, females 44%) was considered. Median follow‐up was 49 months with 341 (63%) allogeneic hematopoietic stem cell transplantations (AHSCT) recorded. AML subtypes included core‐binding factor (CBF; N = 72; 13%), primary non‐CBF ( N = 403; 74%), post‐myelodysplastic syndromes (MDS) or post‐myelodysplastic/myeloproliferative neoplasms (post‐MDS‐MDS/MPN; N = 28; 5%), post‐MPN ( N = 15; 3%), and therapy‐related (t‐AML; N = 27; 5%). Corresponding complete remission rates, with/without count recovery (CR/CRi), were 89%, 76%, 64%, 27%, and 78% ( p < 0.01) and 5‐year transplant‐censored survival rates 68%, 57%, 21%, 0%, and 55% ( p < 0.01). In multivariable analyses, the prognostic value of specific mutations was mostly limited to primary non‐CBF AML where adverse karyotype (OR 1.9; p = 0.04) predicted inferior and FLT3 ‐ITD (OR 0.4; p < 0.01) or NPM1 MUT / FLT3 WT (OR 0.1; p < 0.01) superior CR/CRi while KRAS MUT (HR 8.8; p < 0.01), TP53 MUT (HR 5.4; p < 0.01), and TET2 MUT (HR 2.3; p = 0.01) predicted inferior and NPM1 MUT / FLT3 WT (HR 0.3; p = 0.01) superior survival. Prognostication in intensively‐treated AML should start with subtype specification and recognition of the limited value of NGS in non‐primary AML. Post‐MPN AML is particularly associated with dismal outcomes and should be prognostically distinguished from post‐MDS‐MDS/MPN AML. In primary non‐CBF AML, in addition to previously established risk factors, the favorable impact of FLT3 ‐ITD on achieving CR/CRi and the unfavorable impact of KRAS MUT and TET2 MUT on transplant‐censored survival were noted and require confirmation from additional studies.

Background: Acute myeloid leukemia (AML) with CBFB::MYH11 fusion and myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) are genetically defined and typically mutually exclusive entities. Case Presentation: We report a unique case of de novo AML harboring two clonal, transcriptionally active class-defining fusions: CBFB::MYH11 and GOLGA4::PDGFRB. A 61-year-old woman presented with leukocytosis with neutrophilia, eosinophilia, and monocytosis; circulating blasts; and a markedly hypercellular marrow. Cytogenetic analysis revealed inv(16)(p13.1q22) and t(3;5)(p21;q32) in all 20 metaphases, and RNA sequencing confirmed expression of both CBFB::MYH11 and GOLGA4::PDGFRB fusions. In addition, an oncogenic WT1 frameshift variant was identified. Hematopathologic findings were largely consistent with AML with CBFB::MYH11 fusion but exhibited features reminiscent of PDGFRB-rearranged MLN-TK. The patient achieved complete remission following the standard 7 + 3 induction chemotherapy regimen for AML with gemtuzumab ozogamicin. Conclusions: This case illustrates the diagnostic challenges posed by concomitant class-defining alterations in hematologic neoplasms and underscores the importance of integrated genomic assessment.

Abstract Background A previous multicenter study of patients with TP53-mutated myeloproliferative neoplasms showed a significantly shorter survival in chronic phase myelofibrosis (MF-CP) that included primary (PMF) and secondary MF and was mostly based on research-based mutation screening and was not systematically controlled for patients without TP53 mutations (AJH 2025;100:552). The objective of the current study was to examine the prognostic impact of TP53 mutations (VAF ≥2%) that were discovered during clinical NGS testing among consecutive patients with PMF-CP. Impact on overall (OS) and leukemia-free (LFS) survival was analyzed in the context of other genetic risk factors and calculated from the time of mutation detection. Methods The current retrospective study includes consecutive patients with PMF-CP who underwent clinical NGS testing at the Mayo Clinic between 2015 and 2025. Diagnoses of PMF-CP and leukemic transformation (LT) were retrospectively fitted to be in accordance with the International Consensus Classification criteria (Blood 2022;140:1200). Mutation and cytogenetic analyses were performed according to institutional protocols for clinical use and reported in conformity with international guidelines. OS and LFS analyses were censored for treatment with allogeneic stem cell transplantation (ASCT) and calculated from the date of NGS. Conventional statistical methods were utilized (JMP Pro 17.1.0, SAS Institute, Cary, NC, USA). Results A total of 633 patients with PMF-CP underwent clinical NGS testing prior to LT and prior to ASCT (median age 65 years; males 59%). Median interval from initial diagnosis/referral to NGS testing was 2 months; 357 (56%), 392 (62%), and 429 (68%) patients had NGS performed within 3, 6 and 12 months of diagnosis, respectively. Risk distribution according to the dynamic International Prognostic Scoring System (DIPSS; Blood 2010;115:1703) were low (19%), intermediate-1 (44%), intermediate-2 (31%), or high (6%). TP53 mutations (TP53MUT) with variant allele frequency (VAF) of ≥2% were detected in 28 (4.4%) patients with a median VAF of 25.3% (range 2.4-85; ICC-defined multihit 43%). Patients with TP53MUT were more likely to harbor IDH2MUT (14% vs. 3%; p&lt;0.01), EZH2MUT (14% vs. 4%; p=0.03), and unfavorable karyotype (36% vs. 19%; p=0.047) and less likely to harbor CALR type 1/like (4% vs. 18%; p=0.02) and SF3B1MUT (0% vs. 6%; p=0.07). The association with unfavorable karyotype was mainly driven by multihit configuration. No significant associations with clinical features were apparent. At a median follow-up of 40 months for surviving patients, 157 (25%) deaths, 48 (8%) LTs and 135 (21%) ASCTs were documented. A near-two-fold lower, albeit not statistically significant OS was observed in the presence of TP53MUT (median 123 vs. 228 months; HR 1.9, 95% CI 0.94-3.7; p=0.074); the difference reached significance for multihit TP53MUT (median 81 months; HR 3.6, 1.7-7.7; p&lt;0.01) but not for non-multihit TP53MUT (median not reached; HR 0.7, 0.2-2.8; p=0.6), both compared to TP53WT (median 228 months). The significant impact of multihit TP53MUT on OS was confirmed in multivariable analysis (MVA) that included other high molecular risk (HMR) mutations and unfavorable karyotype: multihit TP53MUT (HR 2.5, 1.1-5.5; p=0.02), SRSF2MUT (2.4, 1.5-3.8; p&lt;0.01), ASXL1MUT (1.8, 1.2-2.6; p&lt;0.01), U2AF1MUT-Q157 (4.8, 2.6-8.6; p&lt;0.01), and absence of CALR type 1/like (4.0, 2.0-7.8; p&lt;0.01); additional prognostic contribution was not evident for unfavorable karyotype (p=0.17), EZH2MUT (p=0.3), IDH1MUT (p=0.6), IDH2MUT (p=0.7), or any other HMR mutation. Multihit TP53MUT was also associated with inferior LFS (10-year risk 62% vs. 32% for non-multihit TP53MUT vs. 15% for TP53WT; p=0.03) but significance was lost during MVA that included SRSF2MUT, which was the only HMR mutation showing a significant effect on LFS (HR 5.0, 2.5-9.8; p&lt;0.01). Post-ASCT survival among 135 transplanted patients was significantly shorter for patients with multihit TP53MUT (N=4; median 5 months) vs. those with non-multihit TP53MUT (N=7; median not reached) vs. patients with TP53WT (N=124; median not reached) [p=0.02]. Conclusion The current study implicates multihit TP53MUT as an HMR mutation-independent prognostic factor for OS in PMF-CP. By contrast, prognosis in PMF-CP patients with non-multihit TP53MUT was more likely to be influenced by other HMR mutations, as was the case for those with TP53WT.

Abstract Background In our first exploration of mutations in essential thrombocythemia (ET; N=183), we described somatic variants other than JAK2/CALR/MPL in 53% (N=96) of patients with the most frequent being TET2 (16%), ASXL1 (11%), DNMT3A (6%), and SF3B1 (5%) [Blood Adv 2016;1:21]. In a subsequent report (N=270; BJH 2020;189:291), we highlighted the prognostic relevance of SF3B1, SRSF2, and EZH2 mutations for overall survival (OS), SRSF2, EZH2, and TP53 for leukemia-free survival (LFS), and SF3B1 and U2AF1 for myelofibrosis-free survival (MFFS). We have now expanded our NGS-informative patient cohort to 500 and examined the distribution and frequencies of specific mutations at different stages of the disease and corresponding prognostic correlates. Methods Molecularly-annotated ET patients diagnosed at the Mayo Clinic between January 1980 and May 2025 were considered. Diagnoses of chronic phase ET (ET-CP), post-ET MF, and post-ET acute myeloid leukemia (AML) were retrospectively fitted to be in accordance with the International Consensus Classification criteria (Blood 2022;140:1200). Mutation and cytogenetic analyses were performed according to institutional protocols for clinical use that included multi-gene next-generation sequencing (NGS); in a subset of patients, historically archived samples were accessed for analysis in a research setting. Patients were monitored until death or time of last follow-up, determined through electronic medical records or direct communication with patients or healthcare providers. Conventional statistical methods were utilized (JMP Pro 17.1.0, SAS Institute, Cary, NC, USA). Results A total of 500 ET patients (median 57 years; Females 61%) were informative for NGS-derived mutations that were obtained in the chronic (N=401; 80.2%; group A), post-ET MF (N=88; 17.6%; group B), or post-ET AML (N=11; 2.2%; group C) phase of the disease; group C included 9 (1.8%) patients who transformed directly to AML without transitioning through the MF phase. The most frequent mutations with at least 1% (N=5) mutational frequency were (approximately) TET2 (10%), ASXL1 (10%), DNMT3A (7%), SF3B1 (4%), TP53 (5%), SRSF2 (3%), EZH2 (2%), U2AF1 (2%), CBL (1%), IDH1 (1%), IDH2 (1%), RUNX1 (1%), ZRSR2 (1%), and PPM1D (1%). Comparison of distribution of mutations and their frequencies based on timing of NGS (AML phase vs. MF phase vs. ET-CP) revealed significant differences for TP53MUT (72.7% vs. 11.4% vs. 1%; p&lt;0.01), ASXL1MUT (18.2% vs. 25% vs. 7.2%; p&lt;0.01), and EZH2MUT (18.2% vs. 6.8% vs. 0.3%; p&lt;0.01), respectively; borderline significance was also apparent for RUNX1MUT (9.1% vs. 0% vs. 1.3%; p=0.10) and ZRSR2MUT (9.1% vs. 2.3% vs. 0.5%; p=0.08). Notably, among 9 patients in whom NGS was performed at the time of direct transition from ET to AML, without an intermediary MF phase, 8 (88.9%) displayed TP53MUT and only one (11.1%) EZH2MUT and none (0%) ASXL1MUT. At a median follow-up of 66 months, 93 (18.6%) deaths, 26 (5.2%) leukemic transformations (LT), and 108 (21.6%) MF transformations were reported. In group A patients, age-adjusted multivariable analysis (MVA) of mutations identified ASXL1MUT (N=29; HR 3.8, 1.9-7.7; p&lt;0.01) and SF3B1MUT (N=12; HR 3.9, 1.4-11.0; p=0.01) to be associated with inferior OS, ASXL1MUT (HR 4.9, 1.01-24.2; p=0.048) and SRSF2MUT (N=11; HR 11.9, 1.3-104.8; p=0.03) with inferior LFS, and ASXL1MUT (HR 9.0, 2.8-29.5; p&lt;0.01) and SF3B1MUT (HR 15.5, 3.1-77.5; p&lt;0.01) with inferior MFFS, all calculated from time of NGS. A similar analysis in group B patients identified ASXL1MUT (N=22; HR 3.7, 1.2-11.7; p=0.03) to be associated with inferior OS and TP53MUT (N=10; HR 13.4, 1.7-108.6; p=0.02) with inferior LFS. Age-adjusted MVA combining groups A and B (N=489) confirmed the association between inferior OS and ASXL1MUT (N=51; p&lt;0.01) and SF3B1MUT (N=18; p&lt;0.01) while inferior LFS was associated with TP53MUT (N=14; p&lt;0.01) and ASXL1MUT (p=0.03). Conclusions The majority (⁓73%) of patients with post-ET AML harbor TP53MUT, at the time of LT. By contrast, TP53MUT are infrequent in ET-CP (⁓1%) and did not appear to predict LT, as was the case with post-ET MF. ASXL1MUT was shown to be an independent risk factor for OS, MFFS, and LFS in ET-CP and for OS in post-ET MF. SF3B1MUT was associated with inferior OS and MFFS in ET-CP and SRSF2 with inferior LFS in ET-CP. Identifying ET patients with adverse mutations allows for closer surveillance and potentially more tailored therapeutic interventions.

Abstract Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset autoinflammatory disorder defined by somatic UBA1 mutations in hematopoietic stem cells (HSCs). Given the higher median age at onset and prevalent inflammation, approximately 60% of patients have concurrent clonal hematopoiesis (CH) involving epigenetic regulators, DNMT3A and TET2. We have previously demonstrated (Gutierrez-Rodrigues, Blood 2023) that DNMT3A and TET2 mutations in VEXAS are independently associated with increased mortality, without an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). To define the role of CH in VEXAS, we investigated the impact of CH on mortality and related epigenetic dysregulation in primary VEXAS patient samples and validated these findings using an adenine base-editing (ABE) strategy to model cooccurring UBA1 and DNMT3A mutations in CD34+ HSCs. Methods: After IRB approval, 114 VEXAS patients from the Mayo Clinic and the NIH were retrospectively assessed, including 104 screened for CH by error-corrected DNA sequencing (ECS). DNA methylation changes were identified using the Illumina Infinium MethylationEPIC BeadChip and genome-wide using Biomodal 6-base sequencing on peripheral blood samples (PB). Cellular indexing of transcriptomes and epitopes (CITE)-seq was performed using the 10x Chromium 3' GEX platform; 21,114 pooled cells were subjected to UMAP dimensionality reduction, followed by Azimuth based cell identification. HSCs from different donors were base edited for UBA1 M41T mutation with and without cooccurring DNMT3A splice-site mutations. Levels of cytokines in cell culture supernatants were measured using Olink technology, transcriptomic changes were assessed using bulk RNA-seq. Statistical analyses were carried out using R. Results: Patients' median age was 68 (62-74) years; 95% were white and 99% were males. 39% had a pathogenic CH variant, with DNMT3A (18%; median VAF: 42%; range 6-46%) and TET2 (11.5%; median VAF: 11%; range: 2-37%) being most common (2% had both). While the presence of any CH mutation did not impact survival (7.7 vs 11.5yrs, p =0.69), DNMT3Amt CH had an age-independent negative impact on mortality (9.2 vs 5.6yrs, p=0.02), without an increased risk of MDS/AML (p=0.31). Changes in DNA methylation were profiled using the methylation array in 19 VEXAS patients without CH (Median Age: 68 years) and in 9 with DNMT3Amt CH (Median Age: 74 years), respectively. VEXAS samples with DNMT3Amt CH displayed a hypomethylation phenotype compared to VEXAS samples with no CH, with 4,096 unique hypomethylated CpGs, occurring mainly at gene enhancers (Enh) and transcriptional states (Tx, TxWk). This loss of DNA methylation was enriched in inflammatory pathways with extensive hypomethylation observed in the promoters and gene bodies of IL-1 family genes. CITE-seq performed on 7 VEXAS samples (4 DNMT3Amt CH vs 3 no CH) demonstrated an upregulation of gene expression predominantly in T-cell subsets. This increased expression was enriched in inflammatory genes, largely centered around IL-1 and IL-18 family signaling. Pathway analysis revealed an enrichment in respiratory electron transport and oxidative phosphorylation (oxphos), with the VEXAS samples with DNMT3Amt CH demonstrating significantly increased oxphos gene signatures. Base editing of CD34+ cells was done using an adenine base-editing (ABE) strategy to model dual UBA1 and DNMT3A splice-site mutations. We observed that the HSCs base edited for the UBA1 M41T recapitulated the cellular hallmarks of VEXAS demonstrating reduced ubiquitination, unfolded protein response (UPR) activation, and increased inflammation. The addition of cooccurring DNMT3A mutations resulted in decreased DNMT3A expression, further increasing inflammatory markers, confirming altered inflammatory and metabolic pathways. Conclusion Our study validates the age-independent, negative prognostic impact of DNMT3Amt CH on survival in VEXAS syndrome. DNMT3A mutations mediate epigenetic and transcriptional priming associated with upregulation of inflammatory and mitochondrial function pathways. These findings have been validated in a base edited cell model with UBA1 and DNMT3A co-mutations.

Abstract Introduction: DDX41 (DEAD-box helicase 41) mutations (mt) represent the most prevalent germline predisposition syndrome (GPS) in adult patients (pts) with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). This molecular subtype is typically associated with late-onset disease, runs an indolent clinical course, with a relative absence of high-risk co-mutations. While several retrospective studies have reported favorable responses to venetoclax (VEN)-based therapies, anecdotal observations suggest variable outcomes. We aimed to evaluate the clinical characteristics and treatment outcomes of patients with DDX41-mt MDS/AML treated at the Mayo Clinic. Methods: We conducted a retrospective study of pts diagnosed with DDX41-mt germline predisposition syndrome with concurrent myeloid neoplasms at our institution. Germline testing was conducted under an IRB approved protocol (Mayo Clinic IRB# 16-004173; clinical-trials gov. Identifier: NCT02958462). Of 198 pts with DDX41-mt myeloid neoplasms, 77 had high-risk disease—43 with MDS with increased blasts (MDS-IB1, n = 11; IB2, n = 32) and 34 with AML (WHO 2022). We assessed how clinical, and disease features influenced outcomes in this subgroup. Among these pts, 69 (90%) pts had likely pathogenic/pathogenic variant (DDX41path) variants and 8 (10%) pts had variant of undetermined significance (DDX41VUS) according to variant classification criteria from the American College of Medical Genetics/ the Association of Medical Genetics/ the Association for Molecular Pathology (ACMG/AMP) guidelines. Results: The median age was 68 years (yrs) (range [R],34-92), 70% were male and the median bone marrow blast % was 15 (R,5-60). The most common DDX41 germlinevariants (&gt; 5% cases) included p.D140fs (26%), p.M1I (22%), and p.P258L (6.5%). 74% had DDX41 truncating variants. Thirty-one (40%) acquired a somatic DDX41-mt (R525H [81%]) and 43 (56%) had other somatic mutations. Among these, the most frequent were ASXL1 (n= 9, 21%), TP53 (n= 8, 10%), splicing factor (n= 7, 9%), and DNMT3A (n= 5, 6%). Twenty-six, (34%), 26 (34%), 15 (19%) and 9 (12%) pts were treated with hypomethylating agents (HMA), HMA+VEN, intensive chemotherapy (IC) and active surveillance/supportive care, respectively. Overall, the composite complete remission rate (cCR) in high-risk MDS and AML was 56%. The cCR rates (41%, 59% and 68.7%, p= 0.10) and median duration of response (DOR; 43.7, 44.9 and 28.9 months [mo], p= 0.46) were not significantly different with HMA, HMA+VEN, and IC induction. Thirty-one (40%) pts received allogeneic stem cell transplantation (allo-HCT); 4 (36%), 15 (47%) and 12 (35%) in MDS-IB1, MDS-IB2 and AML groups, respectively (p= 0.56). With a median follow up of 34.7 mo (R, 0.7-136.7), the median overall survival (OS) from the time of diagnosis was 56.9 mo (95% CI, 50.7-63.0) and was not significantly (NS) different between MDS-IB1 (not reached, 70% at 3 yrs), MDS-IB2 (56.9 mo, 86% at 3 yrs) and AML (55.7 mo, 60% at 3 yrs) groups, p= 0.16). The median OS was NS different between DDX41path and DDX41VUS (58.6 vs 55.7 mo, p= 0.50), respectively. We conducted a multivariable analysis for OS using variables that showed significance or trend towards significance in univariable analysis. Concurrent splicing factor mutations (HR; 5.29, 95% CI: 1.29-21.6, p= 0.02) remained negatively prognostic, while there was a trend towards better survival outcomes with allo-HCT (HR; 0.48, 95% CI: 0.21-1.07, p= 0.07). Bone marrow blast ≥ 20% (HR; 1.87, p= 0.12) and TP53-mt (HR; 2.14, p= 0.12) did not retain significance. Conclusion: In our cohort of patients with germline DDX41-mt high-risk MDS and AML, VEN-based regimens were not superior to HMA alone or IC, in terms of response rates and outcomes. On multivariable analysis, the presence of concurrent splicing factor mutations independently and negatively impacted survival with a trend towards better outcomes with allo-HCT. These findings highlight the heterogeneity within DDX41-mt myeloid neoplasms and underscore the need for future studies in larger cohorts to better define predictors of response and survival.

Abstract Introduction: The DEAD-box helicase 41 (DDX41) gene, located on chromosome 5q35, is a tumor suppressor gene involved in RNA processing. Germline mutations in this gene can predispose patients to myeloid malignancies. Studies have suggested a more favorable prognosis in those with germline mutations in DDX41, with progression of disease being a frequently encountered cause of death. In this retrospective study, we explored the causes of death in a cohort of patients with pathogenic DDX41 mutations. Methods: This was a retrospective study of patients diagnosed with myeloid neoplasms between 2009-2024 and found to have DDX41 mutation (DDX41m) via next generation sequencing (NGS) at our institution. Myeloid NGS was obtained at or after the diagnosis of myeloid disease. Germline testing (when available) was performed through buccal/skin samples. Carriers of DDX41m without a myeloid neoplasm diagnosis and patients with only DDX41m VUS were excluded. Baseline characteristics at the time of myeloid neoplasm diagnosis included age at diagnosis, DDX41m variant allele frequency (VAF), blood counts (hemoglobin, white blood cell count, platelets), cytogenetics, bone marrow blast percentage, number of co-mutations, and treatment received. Unadjusted comparisons were made using continuous or categorical variables. Median overall survival (OS) was calculated from the time of diagnosis with myeloid neoplasm to the time of death, using BlueSky Statistics V.10.3.4. Results: Of the 112 patients identified to have pathogenic DDX41m, 29 (26%) patients were deceased at the time of data analysis. In this cohort of 29 patients (median age at diagnosis 72 years, 17 (59%) males), disease groups at initial diagnosis included 17 (59%) patients with MDS, 9 (31%) AML, and 3 (10%) MPN. Fourteen of the 17 (82%) of the patients with MDS were classified as MDS-EB1 or MDS-EB2. Seven of the 17 (41%) patients with MDS progressed to AML at the time of death, with 57% of the patients having more than 30% bone marrow blasts at time of progression. Blood counts at diagnosis in the cohort included a median hemoglobin of 9.8 g/dL, platelets of 83 x 109/L, and white blood cell count of 2.1 x 109/L. Twenty-one (72%) of patients had normal cytogenetics. Nine (31%) patients had both a pathogenic mutation and a variant of uncertain significance (VUS) in DDX41, with the remaining 20 patients harboring only a pathogenic DDX41 mutation. Eight (27%) patients underwent germline testing, with 7 confirmed to harbor a germline DDX41m. In the deceased cohort, 9 (31%) patients underwent HSCT. Three of the patients with AML and 1 patient with MDS were observed and did not undergo treatment. Median overall survival of the deceased cohort was 29 months. The median time to AML progression in the group with MDS was 14 months. Causes of death included infection in 11 (38%) patients, 9 (31%) with disease progression/relapse, 3 (10%) with acute gastrointestinal graft versus host disease (GVHD), and 1 (3%) from cerebral bleed. The cause of death was unknown in the remaining 5 (17.2%) patients. Infections included pneumonia, bacteremia, neutropenic enterocolitis, fungal, and unknown etiology. Of the 4 patients who were observed, 2 died from unknown cause and 2 died from disease progression. Of the 16 patients with AML at time of death, 9 (56%) died from disease progression or relapse, 3 (19%) from infection, 2 (13%) from GVHD, and 2 (13%) from unknown causes. Of the 10 deaths in the MDS group, 7 (70%) were from infection, 1 (10%) from GVHD, 1 (10%) from cerebral bleed, and 1 (10%) from an unknown cause. Three cases of infection in the MDS group occurred during remission. Infection was a more common cause of death in the MDS group compared to the AML group, where disease progression prevailed as a cause of death (70% vs 19%, p=0.01). Eight (80%) of the patients with MDS who died from infection were neutropenic prior to death, and 4 (50%) of those patients were on neutropenic antimicrobial prophylaxis. Conclusions: In this cohort of 29 deceased patients with a DDX41-mutated myeloid neoplasm, we characterized causes of death. Disease progression/relapse was a significantly more common cause of death in those with AML, compared to infection in patients with MDS. Our work underscores the need for additional studies looking into non-leukemic causes of death in patients with DDX41m myeloid diseases and potential strategies to mitigate infection-related mortality in this population.