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Objective Medium‐vessel vasculitis involving the visceral vasculature in adults is rare. Pancreatic ductal adenocarcinoma (PDAC) has been implicated in medium artery vascular thickening secondary to extravascular migratory metastasis with involvement of the celiac and superior mesenteric vessels. Methods Patients presenting to the rheumatology vasculitis subspecialty clinic were retrospectively identified using an electronic health record data exploration tool evaluating for diagnosis of pancreatic cancer, periaortitis, and vasculitis between January 2015 and December 2024. Results We retrospectively identified four patients with PDAC initially presenting with periarterial thickening of the celiac and superior celiac and superior mesenteric vessels (100% White, 50% male, median age 70.5 years). All four patients had abdominal pain with significant unintentional weight loss, with a median weight loss of 25 pounds (range 25–50 pounds). The median time to correct diagnosis was 221 days (range 162–340 days). All four patients had an elevated carbohydrate antigen 19‐9 level (range from 114 to 10,702, with a median of 341.5 U/mL). All four patients were diagnosed with endoscopic ultrasound–guided fine‐needle aspirations. The median number of biopsies required to make the diagnosis was three. Conclusion Isolated celiac and superior mesenteric periarterial thickening or “cuffing” is a vasculitis mimic that should prompt a comprehensive malignancy workup. Expedited referral to a tertiary center is essential given difficulty in tissue sampling with conventional methods and to avoid further delays in diagnosis.

VEXAS (Vacuoles, E1 ubiquitin-activating enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a systemic disorder characterized by an overlap of hematologic and inflammatory features. Most patients require chronic use of moderate-to-high doses of glucocorticoids (GCs) to maintain disease control. Data on GC-sparing therapies is limited, and there have been no prospective pharmacotherapeutic trials in VEXAS syndrome published to date. Pacritinib, an oral inhibitor of IRAK1, JAK2, and ACVR1, has emerged as a promising therapeutic option for VEXAS syndrome. The PAXIS trial is the first prospective, randomized pharmacotherapeutic study conducted in this rare and severe disease. Utilizing a novel study design and disease-specific endpoints, the trial will evaluate the efficacy and safety of two dose levels of pacritinib compared with placebo in patients with VEXAS syndrome (NCT06782373, EUCTR: 2024-516347-41-00).

Erdheim-Chester disease (ECD) is a rare disease characterized by the accumulation of neoplastic histiocytes in various extra-nodal tissues. Tissue biopsies involved by ECD are difficult to distinguish from reactive inflammatory infiltrates given the bland appearance of the neoplastic histiocytes. Confirmation of the ECD diagnosis often relies on molecular studies to confirm BRAF V600E mutation or other activating mutations involving MAPK pathway genes. In this study, we examined the diagnostic utility of cyclin D1 and pERK as immunohistochemical markers of MAPK pathway activation in ECD compared with its histopathologic mimics. The cohort included 41 clinically confirmed ECD patients, most with known genetic alterations in MAPK pathway genes (n=38). In 3 cases no mutation was identified. 37 of 41 (90%) of ECD cases showed cyclin D1 overexpression, with frequent staining in the cytoplasm as well as the nucleus. pERK expression was observed in 32 of 39 (82%) cases. Cyclin D1 staining was negative in histopathologic mimics of ECD, apart from weak patchy staining in fat necrosis and uniform staining in a subset of cases of juvenile/adult xanthogranuloma. While not entirely sensitive or specific, in the proper clinical and radiologic context strong nuclear and cytoplasmic cyclin D1 expression within histiocytic infiltrates helps to support a diagnosis of ECD.

Abstract Introduction: Somatic mutations in UBA1, encoding an E1 ubiquitin activating enzyme, have recently been linked to an adult-onset, severe inflammation syndrome called VEXAS (Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic). VEXAS is characterized by systemic inflammation and hematologic abnormalities. While the majority of identified mutations in UBA1 are located in exonic regions, the role of non-coding and intronic mutations in the pathogenesis of VEXAS remains largely unexplored. In this study, we investigated the potential contribution of intronic mutations to VEXAS pathogenesis. Methods: To investigate mutations affecting UBA1 outside the region typically covered in targeted panels (exon 3), whole exome (WES) and genome sequencing (WGS) was performed on peripheral blood of patients with VEXAS-associated clinical presentation previously negative for UBA1 mutations per clinical testing. 265 patients were profiled by WES (~100X) and 36 patients were profiled by WGS (~55X). Clinical history was reviewed for these patients for VEXAS-associated presentation including a combination of hematologic and rheumatologic disease in adults. Participants with known pathogenic or likely pathogenic (P/LP) variants in UBA1 or other genetic causes of systemic autoinflammatory disease were excluded. UBA1 transcript and protein expression were assessed by PCR and western blot, respectively, in one case where peripheral blood mononuclear cells were available. Results: We identified 7 patients with VEXAS-like presentation with intronic single nucleotide variants or deletions. Five patients had a recurrent point mutation (median VAF: 0.78; range: 0.38-0.97). 5 patients had been diagnosed with MDS, and bone marrow biopsy revealed vacuolated progenitor cells in 3 patients. The most frequent clinical manifestations included skin rash (n=6), joint pain (n=4), vasculitis (n=4), and chondritis (n=2). One patient had been diagnosed with acute myeloid leukemia with myelodysplasia related changes, with co-mutations in IDH1 and SRSF2. Two additional patients had mutations in ASXL1 of which one also had a ZRSR2 mutation. No co-occurring myeloid driver gene mutations were found in the other cases. Noncoding mutations, similar to canonical UBA1 disease causing mutations, were shown to be lineage restricted to myeloid cells. To assess the functional impact of mutations, CD14+ monocytes were isolated from the peripheral blood. Compared to the CD14- fraction, the CD14+ fraction revealed a decrease in the UBA1 transcript as well as UBA1 protein level. One patient demonstrated loss of novel UBA1 mutation after hypomethylating agent treatment, and allogeneic transplant, placing the patient in remission.Conclusions:Our findings of intronic and non-coding UBA1 mutations in patients with VEXAS-associated clinical presentation suggests these variants may affect the regulation of UBA1 transcription, representing a potential new mechanism of pathogenesis. Further functional studies are underway to understand how these variants contribute to impaired UBA1 activity and VEXAS disease pathogenesis. Collectively, our results advocate for a broader approach in genetic testing for UBA1 mutations and pave the way for improved diagnostic and therapeutic strategies for VEXAS syndrome.

Abstract Background: VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a hemato-inflammatory syndrome due to somatic mutations in UBA1 gene. Recently, DNA methyltransferase inhibitors (specifically, 5-azacitidine) and allogeneic hematopoietic stem cell transplantation (alloHSCT) have shown success in eradication of UBA1 clones and clinical remission in some patients. This study aims to provide a comparative efficacy analysis between DNA methyltransferase inhibitors (hypomethylating agents/HMA) versus alloHSCT in VEXAS syndrome patients. Methods: This is a multi-center, retrospective cohort study. UBA1 mutations were detected either through next generation sequencing [NGS, limit of detection (LOD) 2% variant allele fraction (VAF)] or quantitative droplet digital polymerase chain reaction testing (ddPCR, LOD 0.5% VAF). Outcomes of interest included overall survival (OS), glucocorticoid (GC) discontinuation/reduction in dose (prednisone < 10 mg/day), and complete molecular remission (CMR, defined as an undetectable UBA1 mutation). OS was calculated from the time of diagnosis to death or last follow up. Cumulative incidence of reduction in GC dose was calculated using competing risk analysis after accounting for death. Results: Between years 2020-2024, a total of thirty-nine male patients (median age 67, range 45-82 years) with VEXAS syndrome, necessity for therapy (GC-refractory inflammation and/or progressive marrow failure/myeloid neoplasm) and confirmed UBA1 pathogenic mutation were included. Of these, 18 (46%) received HMA therapy (5-azacitidine 72% and Decitabine 28%) with a median of 4 (range 1-36) cycles. and 21 (54%) underwent alloHSCT (MSD=4, MUD=12, MMUD=2, and haploidentical=3), all received reduced intensity conditioning (Flu/Mel =11, Flu/Bu=5, Flu/Cy/TBI=2, and TBF=3) and 91% received post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis (only 2 patients in alloHSCT group received prior HMA without benefit). Baseline characteristics were well-balanced between HMA and alloHSCT groups; age at treatment (median 70 vs 65 years, p=0.2), and UBA1 M41V subtype (25% vs 40%, p=0.3), cytogenetic and non-UBA1 mutation abnormalities (p=0.4), prior lines of therapy (median 4 in both, p=0.5), time from diagnosis to therapy (median 7 vs 13 months, p=0.15), indication for therapy (p=0.12), Charlson CI scores (median 4 in both, p=0.4) and HCI-CI scores (median 4 in both, p=0.7). At a median follow-up of 45 (range 7-57) months, 11 (28%) deaths (alloHSCT=3 and HMA=8) were documented. Causes of death included infections (n=6), cardiac disease (n=2), poor graft function (n=2) and pulmonary GVHD (n=1). Compared to HMA therapy, alloHSCT group demonstrated higher rates of GC discontinuation (52% vs 6%, p<0.01) and CMR (evaluable= 22, 100% vs 50%, p<0.01). In the HMA group, 50% (n=9) discontinued therapy after a median of 4 months due to infectious complications or lack of benefit. In the alloHSCT group, 3 (14%) patients developed grade 2 acute GVHD (1-skin, 2-gut, no grade 3-4 acute GVHD) and 4 (19%) experienced moderate to severe chronic GvHD (2-lung, 2-mucocutaneous). In multivariable analysis (MVA) adjusted for age and HCT-CI, alloHSCT was identified as the strongest favorable predictor for OS (HR 0.18 95% CI 0.04-0.8) with similar results when analysis was restricted to transplant-eligible patients < 75 years of age (HR 0.1, 95% CI 0.03-0.6). In a 6-month post-treatment landmark analysis (n=31 evaluable), patients who underwent alloHSCT (n=17) exhibited numerically superior GC discontiuation rate (29% vs 14%, p=0.049) and subsequent OS compared to HMA (2-years OS: 84% vs. 61%, median not reached vs 25 months, 95% CI: 0.06–1.7). In a post-treatment competing risk [GC dose reduction (death)] analysis alloHSCT was associated with superior 2-, and 3-year rates of 57% (10%), and 76% (10%), compared to HMA 22% (24%), and 31% (42%) [p<0.01 (0.04)]. AlloHSCT was also associated with higher rate of CMR (evaluable= 21, alloHSCT N=16 and HMA N=5, 100% vs 60%, p=0.01). At the last follow up, none of the patients who achieved CMR had re-emergence of the UBA1 clone (despite early mixed chimerism). Conclusions: This study represents the largest comparative analysis of alloHSCT versus HMA therapy in VEXAS syndrome, and confirms superiority of alloHSCT in achieving molecular remission, GC discontinuation/dose reduction, and overall survival. Prospective clinical trial confirmation is warranted.

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 Histiocytic neoplasms (HN) are a rare, heterogeneous group of hematologic disorders derived from myeloid-dendritic cell lineages. The most common forms include Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD). These disorders are driven by recurrent activating mutations in the MAPK pathway, most frequently involving BRAF, MAP2K1, PIK3CA, KRAS, and NRAS. This discovery enabled a major therapeutic advance with the use of BRAF and MEK inhibitors, resulting in durable responses. For patients harboring KRAS mutations, MEK inhibitors (MEKi) remain the primary therapeutic approach. However, the impact of KRAS mutation subtypes on treatment response remains poorly understood. Our study aimed to characterize the spectrum of KRAS mutations in LCH, ECD, and RDD and evaluate the responses to MEKi, providing insights to guide future treatment strategies. Methods We conducted a retrospective review of patients with LCH, ECD, and RDD who were evaluated at Mayo Clinic or University of Alabama at Birmingham. Patients were included if next-generation sequencing identified a KRAS mutation. The response assessment was based on radiographic evaluation under the most recent Histiocyte Society consensus guideline. Results We identified 23 patients with a KRAS mutation: 17 females (73.9%) and 6 males (26.1%), with a median age at diagnosis of 61 years (range, 20–78). RDD accounted for 73.9% (17/23) and ECD for 26.1% (6/23); no KRAS mutations were detected in LCH patients. The most frequent KRAS variants were p.K117N (34.8%), p.G12D (17.4%), p.A146T (13.0%), p.G13C (8.7%), and p.G13D (8.7%), with additional variants including p.T58I, p.A59G, p.A146P, and p.A146V. Mutation distribution differed by disease group: p.G12D was more common in ECD (50%) than RDD (5.9%) (p=0.01), whereas p.K117N occurred in 47.1% of RDD and was absent in ECD. Regarding treatment, 57% (13/23) received MEKi, all initially cobimetinib, with 1 patient switched to trametinib due to progression. Of the 10 patients who did not receive MEKi, 1 was treated with vemurafenib for a concurrent BRAF p.V600E mutation; 3 remained on observation; 2 underwent surgery without recurrence; 3 received other systemic therapies including corticosteroid, methotrexate, rituximab, lenalidomide, or sirolimus; and 1 developed diffuse large B-cell lymphoma, treated with R-CHOP. The overall response rate in the 12 patients on MEKi (excluding 1 patient too early for assessment) was 75%—3 (25%) CR and 6 (50%) PR (including 1 who initially progressed on cobimetinib but responded to trametinib). All 3 non-responders had RDD. Among the 5 patients with p.K117N, 3 had no response to cobimetinib, 1 achieved PR, and 1 achieved CR; notably, 1 non-responder switched to trametinib and achieved PR in 2 months. All 3 patients with codon 146 mutations achieved PR. Of the 2 patients with p.G12D, 1 achieved CR with a co-occurring MAP2K1 mutation, and 1 had no response. No additional genotype–response patterns were observed. Similar heterogeneity has been reported in prior studies. In a phase II cobimetinib trial, an ECD patient with p.R149G achieved PR, whereas another ECD patient with p.G12R and an LCH patient with p.G13C achieved CR in the presence of co-occurring ARAF and NRAS mutations, respectively. A retrospective cohort described an ECD patient with p.K117N achieving PR on dabrafenib and trametinib with a concurrent BRAF mutation and another with p.G12A achieving PR on trametinib. In a multicenter analysis of trametinib, a patient with p.A59T (co-occurring BRAF and NRAS mutations) had no response, whereas another with p.A146P achieved PR. Collectively, these findings, together with our data, underscore that KRAS-mutated histiocytoses exhibit heterogeneous responses to MEKi, likely influenced by variant type and co-mutations. Discussion KRAS mutations represent an important subset of MAPK pathway alterations in HN, although their prevalence varies by disease type and appears extremely rare in LCH, with no cases identified in our cohort. The most common variants include p.K117N and p.G12D, which may be linked to suboptimal response to MEKi in the absence of concurrent MAPK pathway alterations. As MEKi acts downstream, efficacy likely depends on the level of pathway activation conferred by specific KRAS variants. Larger studies are needed to confirm these observations and identify mutation-specific predictors to guide personalized treatment.

Abstract Introduction: Langerhans Cell Histiocytosis (LCH) is a rare histiocytic neoplasm, with approximately 90% of patients exhibiting alterations in the MAPK pathway. BRAF and MEK inhibitors have shown promising results in treating MAPK pathway-altered LCH. However, treatment interruptions due to adverse effects are common, and limited access to targeted therapies complicates care globally. While chemotherapy remains a common treatment for LCH, the outcomes for patients with MAPK pathway-altered LCH specifically receiving chemotherapy are still unclear. Methods: This multi-institutional international retrospective cohort study analyzed adult patients with BRAF or MAP2K (gain-of-function, GOF) altered LCH that were consecutively seen at Mayo Clinic, MN, AZ, and FL, University of Alabama at Birmingham, and Peking Union Medical College Hospital in China between 2007 and 2024. All patients who were included in this study were treated with chemotherapy, and those who have received targeted therapies or other modalities of frontline treatment were excluded. All time-to-event analyses were performed from the frontline therapy initiation, using the Kaplan-Meier method. Progression-free survival (PFS) included death and progression as events and was measured from the time of treatment initiation. The response assessment was based on radiographic evaluation in accordance with the most recent Histiocyte Society consensus guideline. Risk organ involvement was defined as disease involving the liver, spleen, bone marrow or central nervous system. Results: A total of 63 patients with LCH were included. The median age of the population was 34 years (range: 27-43), and males were 59%. Risk organ involvement was seen in 44 (70%) of patients and multisystemic LCH was observed in 48 (76%) patients. Among the 63 patients, BRAF gain-of-function alterations were observed in 79%, MAP2K mutations in 19%, and BRAF fusions in 2%. Of the BRAF gain-of-function alterations, BRAFV600E mutation was seen in 64% patients and [p.N486_P490del] deletion in 36%. There was no significant difference in organ involvement (single-system versus multisystem) or risk organ involvement between patients with BRAF and MAP2K alterations. All 63 patients received systemic therapy with chemotherapy and the regimens included Cytarabine (n=43), Cladribine (n=5), Etoposide (n=1), Methotrexate (n=1), and combined Methotrexate and Cytarabine (n=13). The median follow-up for the entire cohort was 3.8 years (range 3.2–5.0 years), with similar durations observed in patients with single-system vs. multisystem involvement and those with risk-organ involvement vs. no risk-organ involvement. The overall response rate among patients who received chemotherapy was 89%, with complete responses in 15 patients (26%) and partial responses in 40 patients (64.5%). The median progression-free survival (PFS) for the entire cohort was 2.61 years (95% CI: 2.06–NA). The 3-year PFS did not significantly differ based on risk organ involvement: 50.6% (95% CI: 36–71) for patients with risk organ involvement versus 47.4% (95% CI: 28–81) for those without, p=0.52. Patients with single-system disease experienced longer PFS compared to those with multisystem disease; the 3-year PFS was 80.2% (95% CI: 58.7–100) versus 42.2% (95% CI: 29–61.5), respectively, p=0.04. Conclusions: Our results indicate that LCH patients with a GOF alteration in the MAPK pathway derive significant clinical benefit from chemotherapy, achieving deep and durable responses. Therefore, patients should not be excluded from treatment due to the absence of targeted therapies, as they can still attain substantial responses and clinical improvement with chemotherapy, even in the context of MAPK pathway-driven disease.

Abstract Background Erdheim-Chester disease (ECD) is a very rare histiocytic/dendritic cell neoplasm driven by mutations in genes of the MAPK pathway, such as BRAFV600E. Its clinical presentation is highly heterogeneous, and data on its natural history and prognosis in large cohorts are limited. Here, we investigated the clinical features and outcomes of a very large international cohort of patients with ECD. Methods We included patients diagnosed with ECD between 1990 and 2024, followed at 13 referral centers in Europe and the Americas, who had available clinical and follow-up data (with a minimal follow-up duration of 6 months). We analyzed the clinical presentation, treatment, and outcomes, and sought to identify predictors of survival. The study was conceived and conducted within the ECD Global Alliance network. Results A total of 1044 patients with ECD were included. The median age at diagnosis was 57 years (IQR 46-66), and the male-to-female ratio was 2.2. The median age at the first ECD manifestation was 55 years (IQR 43-65). Bone pain (20%), kidney and urinary manifestations (18%), and diabetes insipidus (11%) were the most frequently reported initial features. The median number of involved sites was 4 (IQR 3-6), most frequently including the long bones (n=768, 74%), the retroperitoneum, (n=605, 58%), the periaortic space (n=449, 43%), the CNS (n=368, 35%), the facial/orbit area (n=347, 33%), and the heart (n=334, 32%). Among 955 tested patients, 572 (60%) harbored the BRAFV600E mutation, and 86 (9%) a MAP2K1 mutation. Clinical and/or pathology overlap with Langerhans cell histiocytosis and Rosai-Dorfman-Destombes disease was observed in 115 (11%) and 42 (4%) patients, respectively. Clonal hematopoiesis was identified in 217 of 556 tested patients (39%), and a history of second cancer was reported in 272 patients (26%), including both solid (14%) and hematologic (12%) neoplasms. First-line treatment mostly included interferon-alpha (n=342, 33%) and BRAFi/MEKi (n=314, 30%), while second- and third-line treatments mostly consisted of BRAFi/MEKi (55% and 63%, respectively). After a median follow-up of 51 months (IQR 20-89), 222 (21%) patients died; causes of death were related to ECD in almost half of the patients (n=101). A multivariate Cox regression model identified the following factors as significantly associated with increased mortality: older age (HR 1.058, 95%CI 1.033-1.083; p<0.001), pseudo-neurodegenerative lesions (HR 2.280, 95%CI 1.337-3.891; p=0.022), elevated CRP at diagnosis (HR 2.574, 95%CI 1.024-6.467; p=0.044), and second hematologic cancer (HR 2.639, 95%CI 1.602-4.348; p<0.001). Conclusions Despite advances in treatments over the last decade, ECD remains associated with substantial mortality. Age, neurodegenerative lesions, elevated CRP levels, and the presence of a second hematologic cancer are the main predictors of poor survival.

Abstract Background Adult xanthogranuloma (AXG) is a rare clonal histiocytic neoplasm (HN) with a poorly defined mutational landscape. Clinically and immunophenotypically, AXG can resemble other HNs such as Erdheim-Chester Disease (ECD) which frequently harbor MAPK pathway alterations and carry BRAF V600E mutations in close to 50% of cases. However, due to the rarity of AXG, the prevalence of the BRAF V600E mutation and the broader mutational landscape is not well known. In this study, we characterize the mutational profile of AXG. Methods We conducted a retrospective analysis of patients diagnosed with AXG at our institution between January 1, 2016, and July 15, 2025. The study was approved by the institutional review board. To ensure inclusion of true AXG cases, only patients with a confirmed histopathologic diagnosis and without multisystemic involvement or characteristic imaging findings of ECD, such as symmetric long bone osteosclerosis, were included. BRAF alterations were identified by immunohistochemistry (IHC) and/or next-generation sequencing (NGS). We also performed an extensive literature review of mutational studies in AXG and included cases that underwent comprehensive NGS. Results Seventeen patients with AXG were identified. The median age at diagnosis was 40 years (range: 18–75 years). Out of the 17 patients, 11 (65%) reported the face as the primary site of disease, and 11 (65%) had solitary lesions. Of the 17 patients, 13 (76%) underwent BRAF V600E IHC staining, and none tested positive. Twelve (71%) patients had tissue samples analyzed via NGS, and none exhibited the BRAF V600E mutation. Eight of the 12 (67%) patients with NGS testing harbored other alterations involving the MAPK pathway. These included BRAF fusions (n=3), KRAS mutations (n=2), and individual cases with TRAF7 mutation, ALK1 fusion and FGFR1 fusion. One patient was found to have a mutation in WRN, which is not previously reported in AXG. Three patients had no identifiable pathogenic alterations on NGS. Ten patients were monitored without treatment, 2 underwent surgical resections and 3 received chemotherapy (1 had a complete response [CR], 2 achieved a partial response). One patient with FGFR1 fusion was treated with pemigatinib and achieved a CR for over 3 years. One patient with TRAF mutation obtained a CR after treatment with rituximab. We also identified 51 cases of AXG with adequate mutational testing reported in the literature, which reported findings similar to ours. In a retrospective study from France involving 29 patients, MAPK alterations were observed in 55% of cases: however, only 10% harbored BRAF V600E mutations (1). Another analysis of 270 patients with various HN subtypes included 13 individuals with AXG, none had BRAF mutations. MAP2K1 mutations were seen in 31% of patients (2). Taken together, across a combined cohort of 68 AXG patients, the most common alterations were: KRAS mutations (16%), fusions (14%), MAP2K1 mutations (7%) and BRAF V600E (6%). Among fusions, the most involved gene was BRAF (50%), and GAB2 was the most common fusion partner (n=2). In total, 59% of patients had MAPK alterations. These findings collectively underscore the diverse mutational landscape of AXG and highlight the rarity of BRAF V600E mutations relative to closely related HNs. Conclusion We present a series of AXG cases with mutational profiling, from our institution and the published literature. We demonstrate that MAPK alterations are frequently observed in AXG and are driven by heterogeneous mutations. In contrast to other HNs where BRAF V600E mutations are common, we identified no such mutations in our cohort and found only rare cases in the literature. Our institutional data, along with findings from the existing literature, suggest that AXG may have a distinct molecular profile compared to other HNs. A deeper understanding of its mutational landscape may offer insights into disease biology and identify therapeutic targets. ReferencesAnnabi E, Mahévas T, Chasset et al. Clinical, Histopathologic, and Molecular Features and Treatment of Multiple Xanthogranuloma in Adults. JAMA Dermatol. 2025;161(7):765-768. doi:10.1001/jamadermatol.2025.0886.Durham BH, Lopez Rodrigo E, Picarsic J, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25(12):1839-1842. doi:10.1038/s41591-019-0653-6