Ruan, Gordon

Abstract Purpose. Malignant histiocytoses (MHs) including Langerhans cell sarcoma (LCS), interdigitating dendritic cell sarcoma (IDCS), and histiocytic sarcoma (HS) are rare, aggressive neoplasms of the macrophage-dendritic cell lineage. Prognosis is generally poor, particularly in disseminated disease. While mutation-specific therapies are increasingly used in indolent histiocytic neoplasms, their role in MH remains unclear due to the frequent presence of complex mutational profiles. Our understanding of the genomic landscape of MH is limited. This study aimed to comprehensively characterize the molecular alterations in MH.Methods. We conducted a retrospective chart review of MH patients seen at Mayo Clinic and the University of Alabama at Birmingham who underwent comprehensive next-generation sequencing (NGS), including DNA ± RNA analysis. A systematic literature review using PubMed identified additional MH cases with available molecular data.Results. We identified 17 institutional MH cases (3 IDCS, 3 LCS, 11 HS) and 72 cases from the literature (6 IDCS, 11 LCS, 55 HS) with NGS data. Among the 89 total patients, 26 (29%) had DNA-only sequencing and 63 (71%) had combined DNA/RNA sequencing. Twelve patients (n=12; 13%) had a single mutation; the majority had multiple alterations. The most frequently mutated genes were: RAS (n=26; 29%), CDKN1/2 (n=26; 29%), MAP2K1 (n=15; 17%), PTEN (n=11; 12%), BRAF non-V600E (n=8; 9%), PTPN11 (n=8; 9%), CREBBP (n=8; 9%), TET2 (n=8; 9%), DNMT3A (n=7; 8%), fusions (n=7; 8%), BRAFV600E (n=6; 7%), and NF1 (n=4; 4%). Fusions included BRAF::NRF11, BRAF::CLIP2, BRAF::MBP, EGFR::CYTOR, CDKN2A::ADGRG6, IGH::BCL6, and CLIP2-BRAF. Two patients had no alteration detected. Non-V600E BRAF mutations included D594G (n=3), G596R (n=1), G466A (n=1), N581T (n=1), N581I (n=1), and N581S (n=1). Common co-mutations with BRAF included CDKN2A/B (n=9), TP53 (n=6), KRAS/NRAS (n=5), and PDGFR (n=1). Only 2 of 15 MAP2K1-mutated patients (13%) had isolated mutations; the rest had co-mutations, most frequently TP53 (n=3) and BCL2 (n=3). MAP2K1 mutations included F53I (n=2), C121S (n=2), I103N (n=1), Q56P(n=3), E203K (n=1), F53-K57del (n=1), and F53-Q58del (n=1).NRAS mutations (n=6) included Q16K (n=2), G12C (n=1), Q61R (n=1), and 2 unspecified. KRAS mutations (n=20) included G13D (n=3), Q61H (n=3), G12V (n=2), K117N (n=1), V14I (n=1), and 10 unspecified. The most frequent co-mutational pattern (24%) was RAS plus another gene: BRAF (n=3), TP53 (n=6), MAP2K1 (n=2), PTEN (n=4), and CDKN2A/B (n=6).Twelve patients (12/26; 46%) were treated with targeted therapies. Responses included 6 partial and 5 complete responses. Median duration of response was 27.5 months (range 7–54). The sole non-responder had co-occurring NRASand TP53 mutations and received trametinib. Responders received a range of agents matched to their mutations: trametinib (BRAFV600E, MAP2K1F53I, KRASQ16H/PTEND24G/EPHB1R327C, MAP2K1F53I/BCL2/CDKN1B/KIT, and CALR), dabrafenib + trametinib(BRAFG596R/KRASQ61H), imatinib (MAP2K1C121S/METG28881T/DUSP2G137D/HIST1H3BC97Y/GRIN2AS1216C and PTPN11/STK11/GNA11/JAK2), chidamide + sintilimab(IDH2G515A/RHOAG50T/TET23344delC), sirolimus(PTEN/FGFR3/SETD2) and sorafenib (BRAFD594G/KRASK117N/TP53). Most responders (8/11) had multiple mutations; only 3 had single alterations, suggesting multi-mutant MH may still be targetable. Common complex patterns included BRAF+CDKN2A + CDKN2B (n=4), BRAF + CDKN2A + TP53 (n=2), and BRAF + CDKN2A + KRAS (n=2).Conclusion. The MAPK pathway (BRAF, MAP2K1, RAS) is the most altered signaling axis in MH, often accompanied by mutations in tumor suppressors and cell cycle regulators such as TP53, CDKN2A/B, and PTEN. Most MH patients exhibit multiple genomic alterations. Despite this complexity, durable clinical responses to targeted agents are achievable, even in heavily mutated cases. These findings support the use of comprehensive genomic profiling in MH to identify therapeutic targets and guide precision treatment strategies.

Abstract Introduction: The landscape of classical hematology has undergone substantial evolution over the last decade, marked by new diagnostic tools, nuanced therapeutic strategies, and an expanding understanding of underlying pathophysiology. This increasing complexity often presents unique diagnostic and therapeutic challenges. These challenges are further compounded by workforce shortages in classical hematology marked by educational gaps, geographic limitations, and difficulty accessing prompt specialty care. Unlike the well-established “Tumor Boards” in oncology, a comparable dedicated, widely accessible forum for classical hematology has largely been absent. This gap contributes to potential practice heterogeneity and isolation, especially across dissimilar care settings and geographic regions, impacting the consistent application of evidence-based practices and access to specialized expertise. To address this critical need, the “Blood Board” initiative was created to serve as an informal, virtual resource for discussing classical hematology topics and cases, fostering diverse perspectives, and collaborative problem-solving. Methods: The Blood Board was formally launched in April 2025, operating as a bi-monthly, hour-long virtual meeting conducted via non-recorded videoconferencing. The forum was designed with broad inclusivity in mind, welcoming all healthcare professionals involved in the care of adult patients with classical hematologic disorders, including trainees such as hematology/oncology fellows, academic and community-based hematologists, and any other interested providers. To date, dissemination of this initiative has been by word of mouth and e-mails containing a calendar invitation have been sent to anyone interested in participating (https://forms.gle/doyHNSx1SVFBJZmy8). To facilitate participation from various practice models and geographical locations, the virtual format was prioritized, eliminating barriers of travel and time commitment often associated with traditional in-person conferences. Participation is voluntary, encouraging an open and informal environment for de-identified case presentations, didactic discussions, and expert opinion sharing. Self-reported data on participant demographics (e.g., role, practice setting) and geographical representation have been collected to assess the initiative's reach and impact. Results: To date, sessions have consistently garnered engagement with a median of five participants in attendance at each session. There have been over 20 unique participants representing a broad spectrum of roles including both trainees and practicing hematologists/hematologist-oncologists and drawing from private practice, community-based hospitals, and academic medical centers. Over half of all participants were either in fellowship or within five years of completion of training. The virtual format has successfully overcome geographical limitations, attracting attendees from numerous states including Alabama, Florida, Georgia, Maryland, Minnesota, Missouri, Pennsylvania, South Dakota, and Wisconsin highlighting its broad appeal and potential for knowledge dissemination across a wide professional network. Conclusions: The Blood Board has demonstrated utility and met a previously unaddressed need. Sustained intellectual interest in Blood Board, coupled with a wide geographical and professional reach underscores a critical role for accessible, free, and multidisciplinary collaborative platforms in the evolving field of classical hematology. Similar to Tumor Boards, Blood Board promotes knowledge exchange and evidence-based care, garners expert support for challenging cases, and harmonizes clinical approaches, which we hope may ultimately improve patient care outcomes across diverse settings. Furthermore, this platform facilitates a national classical hematology community to support workforce development. Future goals include expanding dissemination efforts, measuring specific educational benefits, analyzing impacts on patient care, and increasing participant diversity, including recruitment of advanced practice providers and pharmacists.

Abstract Erdheim-Chester disease (ECD) is a rare systemic histiocytic neoplasm, with cardiac morbidities, including cardiovascular (CV) risk factors and cardiac conditions, playing a significant yet poorly understood role in the disease burden. This study evaluated the prevalence, characteristics, and prognosis of ECD in patients with (ECD-C) and without cardiac involvement (ECD-noC) and compared the burden of cardiac morbidities with matched controls. Patients diagnosed with ECD between 1990 and 2021 at a tertiary center were included, with cardiac involvement centrally assessed using radiographic studies. Cardiac morbidities were compared with a control group without ECD, matched for age, sex, body mass index, and smoking history. Among 104 patients with ECD, 39 (37%) had cardiac involvement. Patients with ECD-C had higher rates of hypertension (67% vs 46%), hyperlipidemia (67% vs 40%), heart failure (36% vs 8%), and pericardial effusion (28% vs 2%) than those with ECD-noC. Compared with the matched non-ECD cohort, patients with ECD had higher prevalence of coronary artery disease (20% vs 7%), heart failure (18% vs 4%), and antihypertensive drug use (55% vs 40%). Notably, patients with ECD-C had inferior progression-free survival (PFS) from frontline therapy compared with patients with ECD-noC (5-year PFS, 28.3% vs 70.5%). These findings highlight the burden of CV risk factors and cardiac conditions in ECD, even without a clinical diagnosis of ECD-C. Importantly, this cardiac morbidity burden is substantial for patients with ECD-C compared with ECD-noC. Our findings highlight the need for comprehensive cardiac risk assessment and management strategies to improve patient outcomes.

Introduction Malignant histiocytoses (MH), encompassing histiocytic sarcoma (HS), interdigitating dendritic cell sarcoma (IDCS), and Langerhans cell sarcoma (LCS), are a group of rare, hematologic neoplasms with diverse clinical presentations and poor outcomes. There are no established or effective treatments for patients with MH. The discovery of MAPK/ERK pathway mutations in non-malignant histiocytoses have revolutionized the treatment paradigm, but it is unknown whether novel treatments are efficacious for MH. This study aimed to assess the efficacy of targeted agents (TA) and immune checkpoint inhibitors (ICI) in MH. Methods We conducted a retrospective chart review of MH patients seen at our two institutions. Only patients treated with TA and/or ICI were included. We captured the mutational status by next generation sequencing and PD-L1 expression level by immunohistochemistry, where available. We also conducted a systematic literature review using PubMed to identify additional cases of MH patients treated with TA and/or ICI. Responses were reported as complete (CR), partial (PR), or none (NR) using previously published criteria for histiocytic disorders. Results From our institutions, we identified 12 MH patients (7 HS; 4 LCS; 1 IDCS) who received 14 instances of these treatments including TA (n=9) and/or ICI (n=5). The median age at diagnosis was 55 years (range, 33-70) and 50% were males. TAs included BRAF inhibitor (vemurafenib [1]), MEK inhibitors (binimetinib [1], cobimetinib [2], trametinib [2]) and others (dasatinib [1], pazopanib [1], pexidartinib [1]), while ICIs were exclusively pembrolizumab (5). The median number of prior treatments for those who received TAs and ICIs were 4 and 2, respectively. Responses were observed in 44.4% (1 CR, 3 PRs, 5 NR) and 40% (2 CRs, 3 NRs) of patients who received TA and ICI, respectively. Only 1 patient (20%) treated with MEK inhibitor responded [DOCK8-BRAF; PR 5+ mos]. Other responders received dasatinib [PDFGRA-V608I; PR 2 mos], pexidartinib [PTPN11-A72T; PR 5 mos], and vemurafenib [BRAF-V600E; CR 10+ mos]. Two patients (40%) who received pembrolizumab responded (both CRs 12+ [10% PD-L1] and 44+ mos [40% PD-L1]). We identified 29 MH patients in the literature (27 HS; 2 LCS) treated with TAs (22) and/or ICIs (10). TAs included BRAF inhibitor only (vemurafenib [3], dabrafenib [3]), MEK inhibitor only (trametinib [5]), BRAF + MEK inhibitors (2), and others (apatinib, anlotimib, bevacizumab, daratumumab, dasatinib, imatinib, pazopanib, sorafenib, or combinations [9]), while ICIs included pembrolizumab (4), nivolumab (4), tislelizumab (1), and sintilimab (1). Responses were observed in 77% (7 CRs, 10 PRs, 5 NRs) and 100% (2 CRs, 8 PRs) of patients who received targeted agents and ICI, respectively. Most patients carrying BRAF (7/8; V600E, G596R, D594G, TRIM::BRAF) or MAP2K1 (3/3; C121S, F53I) mutations responded to treatments, irrespective of the number of mutations present. The median durations of response for ICI and targeted agents were 10.5 months (range: 1-36+) and 12+ months (range: 3-44+), respectively. After combining the datasets from our institutions and literature review, we analyzed the association between the extent of PD-L1 expression and response to ICI. Those who responded to ICI had higher PDL-1 expression (median 75% [range, 10-75] vs 25% [range, 1-30]; P=0.0097). Conclusion TAs and ICIs can be considered in the management of MH. The responses to ICI therapy may be associated with the degree of PDL1 expression

Introduction. Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD) belong to a group of histiocytic neoplasms often driven by mutations in the mitogen activated protein kinase (MAPK) pathway, most commonly in BRAF, MAP2K1 and K/NRAS. Currently, there are 2 drugs approved by the US Food and Drug Administration for the treatment of histiocytic neoplasms, cobimetinib and vemurafenib, both small molecule kinase inhibitors (SMKI) targeting mitogen-activated extracellular signal-regulated kinase (MEK) and BRAF, respectively. BRAF mutations are functionally classified as RAS-independent - either monomers (class I) or dimers (class II) - and RAS-dependent (class III). MAP2K1 mutations are functionally classified as RAF-independent, RAF-regulated, or RAF-dependent. Preclinical studies suggest class I, but not classes II-III, BRAF mutations are sensitive to RAF monomer inhibitors (dabrafenib, encorafenib, vemurafenib) while classes I-II, but not class III, BRAF mutations are sensitive to MEK inhibitors (Yaeger R, Cancer Discovery 2019). In contrast, RAF-regulated MAP2K1 mutants have variable sensitivities to allosteric MEK inhibitors (binimetinib, cobimetinib, selumetinib, trametinib) while RAF-dependent and RAF-independent MAP2K1 mutations are resistant. KRAS mutations are generally resistant to MEK inhibitors (Johnson C, Cancer Discovery 2022). Our study described the clinical efficacy of commercially available SMKIs in patients with histiocytic neoplasms harboring non-BRAFV600E mutations and compared the findings with preclinical data. Methods. We conducted a retrospective chart review of patients with histiocytic neoplasms who were treated with SMKI at Mayo Clinic. Only those who had adequate genomic testing and non-BRAFV600E mutations were included. Responses were categorized as complete (CR), partial (PR), or none (NR) based on established criteria. Results. We identified 31 non-BRAFV600E patients treated with SMKI (2 LCH; 20 ECD; 9 RDD). The median age at diagnosis was 61 years (range: 16-76) and 52% were females. The distribution of BRAF mutations was: class I (V600delinsRE [1]), class II (V495A [1], V471F [1], N486_P490del [2], GAB2-BRAF [1], UBR2-BRAF [1], RNF11-BRAF [1], UBTD2-BRAF [1]), and class III (G466E [1], D594A [1]). The only patient with class I mutation received cobimetinib and had PR. Among those with BRAF class II mutations, 2 received vemurafenib and had NR, while 9 received MEK inhibitors (binimetinib, cobimetinib, trametinib) and most responded (3 CRs, 5 PRs). The patient who had NR required dose reductions due to side effects. Both patients with class III mutation did not respond to cobimetinib. The median duration of responses was 19 months (range: 3+ to 45+) and 3 patients progressed subsequently. The distribution of MAP2K1 mutations was: RAF-independent (E102_103del [2]), RAF-regulated (I103N [1], K57T [1], Q56P [3], F53L [1], K57N [1]) and RAF-dependent (Y130C [1], D67N [1]). Both patients with RAF-independent mutations treated with cobimetinib had PRs. All patients with RAF-regulated mutations treated with allosteric MEK inhibitors responded (3 CRs, 5 PRs). Both patients with RAF-dependent mutations treated with cobimetinib responded (1 CR, 1 PR). The median duration of responses was 15 months (2 to 29+) with 3 patients progressing after treatment cessation due to intolerance. The distribution of RAS mutations was: NRAS (Q16R [1]) and KRAS (K117N [3], A146T [1], T581 [1], G13C [1], G12D [1]). Most patients treated with allosteric MEK inhibitors responded (3 CR, 4 PR, 1 NR). The median duration of response was 15 months (5 to 41) and 2 patients subsequently progressed, one of them after treatment cessation. Conclusions. Among patients with histiocytic neoplasms with non-BRAFV600E mutations receiving SMKI, our study found mixed patterns of concordance between pre-clinical predictions and clinical responses. There was concordance of efficacy in the setting of BRAF classes I-III and MAP2K1 RAF-regulated mutations. However, we found discordant findings in patients harboring RAF-dependent and RAF-independent MAP2K1 mutations as well as KRAS mutations as most responded to allosteric MEK inhibitors.

Background: Erdheim-Chester disease (ECD) manifests as multi-organ infiltration of clonal histiocytes with mutations primarily in the mitogen-activated protein kinase (MAPK) pathway. The revised classification of histiocytosis (2016) categorizes ECD with typical bilateral, symmetric osteosclerosis of the lower extremity long bones as classical (C) and as non-classical (NC) if otherwise. The clinical and biological significance of this classification is unclear. This study compared the clinical and genotypic findings of the 2 subtypes within a large cohort of ECD patients. Methods: We included patients seen at our institution since 1990 meeting the following criteria: A) had an ECD diagnosis based on the revised criteria by Haroche J, et al. (Blood 2020;135:1311-1318); B) completed whole-body imaging studies including long bones of the legs. Classification as C-ECD required symmetric osteosclerosis of the distal femur and/or proximal tibia/fibula. Results: A total of 145 patients were enrolled, comprising a male-to-female ratio of 2:1 (66.2% male). C-ECD was diagnosed in 77.2% of cases, and NC-ECD in 22.8%. The median age at diagnosis was similar with 58.5 years (range, 18-82) in C-ECD and 55 years (range, 20-81) in NC-ECD, (p=0.65). The most frequently affected systems included skeletal (81.4%), renal (60.0%), vascular (45.5%), cardiac (40.0%), central nervous (38.6%), sinus (37.2%), pulmonary (36.6%), and adrenal (32.4%). The numbers of organs involved were significantly higher in C-ECD compared to NC-ECD (median 5 vs 3, p<0.01). Higher rates of skeletal (100% vs. 18.2%, p<0.01), adrenal gland (37.5% vs. 15.2%, p=0.02), and sinus (44.6% vs. 12.1%, p<0.01) involvement were observed in C-ECD. Arginine vasopressin deficiency (AVP-D) was exclusively observed in C-ECD (20.7% vs. 0%, p<0.01). NC-ECD had a higher rate of cardiac involvement (69.7% vs. 31.3%, p<0.01). No significant differences were found in other systems. The overall median time between onset of the first symptoms/signs to diagnosis was 15 months with no significant difference between C-ECD and NC-ECD (17.5 vs. 12 months, p=0.18). The median time to diagnosis of ECD in patients with AVP-D was 38.5 months, compared to 12 months without AVP-D (p=0.09). Genetic testing was conducted in 86.2% of patients and B-Raf proto-oncogene (BRAF) alterations were identified in 59.2% of the tested cases. BRAFV600E was more prevalent in C-ECD (61.3% vs. 21.9%, p<0.01), whereas non-V600 mutations were more commonly found in NC-ECD (12.5% vs. 1.1%, p<0.01). There was no significant difference in the frequency of BRAF fusions. NC-ECD patients exhibited a higher rate of MAP2K1 mutations (25.0% vs. 5.4%, p<0.01). Other frequently mutated genes included KRAS (4.0%), NRAS (2.4%), and CSF1R (2.4%), although no significant difference was observed in their frequency between C-ECD and NC-ECD. Testicular involvement appeared to be more common in patients with MAP2K1 mutations (23.1% vs. 8%, p=0.08). Two patients with pathogenic CSF1R mutations both had central nervous system (CNS) involvement. Among C-ECD patients, BRAFV600E conferred a higher rate of CNS involvement (50.9% vs. 25%, p=0.01). No significant difference was observed in NC-ECD patients (71.4% vs 36%, p=0.09). Among NC-ECD cases, MAP2K1 mutations conferred a reduced risk of cardiac involvement (37.5% vs. 79.2%, p=0.03) and no such difference was observed in patients with C-ECD (40% vs 34.1%, p=0.79). The median numbers of organs involved in patients with BRAF, MAP2K1, and KRAS/NRAS mutations were 5, 3, and 3, respectively, with no significant difference. Conclusions: C-ECD affects more organs and more frequently involves bones, adrenal glands, and sinuses. AVP-D was exclusively observed in C-ECD. Conversely, NC-ECD showed a higher prevalence of cardiac involvement. BRAFV600E was more commonly identified in C-ECD, whereas non-V600 mutations and MAP2K1 mutations were more prevalent in NC-ECD. Among C-ECD patients, BRAFV600E was correlated with a greater likelihood of CNS involvement. Conversely, NC-ECD patients with MAP2K1 mutations had a reduced risk of cardiac involvement. This study highlights the distinct clinical and molecular features of C-ECD and NC-ECD, underscoring the importance of subclassifying ECD into classical and non-classical forms. Further studies are needed to explore differences in the clinical outcomes between the 2 forms.

Introduction: Autoimmunity in Rosai-Dorfman disease (RDD) has been reported in several case reports and small case series. The recent consensus RDD guidelines even classify “immune-related RDD” as a distinct entity, but little is known about the prevalence and patterns of autoimmune conditions in this rare disease. We conducted this study to evaluate a large cohort of patients with RDD for concomitant autoimmunity. Methods: We conducted a retrospective review of cases diagnosed with RDD from five referral centers globally. Data pertaining to autoimmunity were captured in terms of serology and a clinical diagnosis of autoimmune disease (AID) and compared to previously reported prevalence of AID and autoimmunity in the general population and in patients with other lymphomas. Results: We included 157 patients diagnosed with RDD from 2003-2023. Median age at the time of RDD diagnosis was 48 years, IQR 35.5-60. This included 103 females (65.6%) and 54 male (34.4%). Racial distribution included 54 Black (34.4%), 52 White (33.1%), 40 Asian (25.5%), 7 Middle Eastern (4.5%) and 4 other (2.5%). 83 patients had multi-systemic disease (52.8%) and 74 had single organ involvement (47.2%). Most common organs involved were skin/subcutaneous tissue (78, 49.7%), lymph nodes (63, 40.1%), bone (54, 34.2%). Tissue next generation sequencing data was available for 100 patients (63.7 %) and showed KRAS mutation (19, 19 %), MAP2K/MEK (13, 13%), other mutations (27, 27 %), and no mutations (41, 41%). Mean ESR at diagnosis of RDD was 28.42 mm/Hr and mean CRP was 19.5 mg/L. In our cohort, 28 patients (17.8%) were diagnosed with an AID. 19 (67.8%) were diagnosed with the AID prior to the diagnosis of RDD. Most common AID was systemic lupus erythematosus (6, 21.4%), rheumatoid arthritis (5, 17.8%), autoimmune hemolytic anemia (3, 10.7%), polymyalgia rheumatica (2, 7.1%). AID was more common in female vs male (64.3% vs 35.7%, p 0.8) and were more commonly seen in patients with multisystem compared to single organ RDD (60.7% vs 39.3%, p 0.3). Mean ESR and CRP at the time of RDD diagnosis in patients with AID were 40.63 mm/Hr and 37.04 mg/L respectively. Autoimmune antibodies were tested in 90 patients (57.3%), of which 43 (47.8%) were positive for atleast one autoantibody which included 15 patients (16.7%) with AID and a positive autoantibody and 6 (6.6%) with AID and negative antibodies (p 0.01). Most common antibodies were ANA (29/83, 34.9%), 42.3% with a titer higher than 1:160. Other antibodies include RF (10/60, 16.67%), anti-neutrophilic cytoplasmic antibody (3/19, 15.8%), double stranded DNA (6/56, 10.7%). Positive Antibodies were more common in female compared to male patients (72% vs 23%, p 0.04) and in patients from China compared to North America (45.7% vs 22.6%, p 0.007). Autoantibody positivity was common in multi-system vs single organ RDD (53.5% vs 46.5%, p 0.9). Mean ESR and CRP in this group of patients were 34.54 mm/Hr and 23.93 mg/L respectively. Median duration of follow up for our cohort was 32 months (IQR 14-65). Five-year survival was 93.4%. There were a total 8 deaths reported in the cohort, none of which were in patients with underlying AID. In a multivariable analysis, AID was associated with race (odds ratio [OR] for Middle Eastern compared with Chinese, OR 7, p=0.02) but other factors like organ involvement, mutational status, sex and age at diagnosis were not significant. Conclusions: Our study reveals a high prevalence of autoimmunity in RDD, both in terms of AID (17.8 %) and positive autoantibodies (47.8 %), which is much higher than the general population rates of approximately 3% and 16% respectively, and higher than patients with non-Hodgkin lymphoma, 7.6% and 39%, respectively. There was a trend toward association of AID with multisystem RDD and among individuals from North America and Middle East compared to China, although auto-antibody positivity was more common in Chinese patients. Mean ESR and CRP at the time of diagnosis of RDD was higher in the patients who had AID. We did not find any statistically significant association between AID and autoantibody positivity with the underlying driver mutation. Nearly half of the patients with RDD who also had AID did not have a positive autoantibody, thereby implying the need of clinical evaluation for rheumatological symptoms rather than empiric serological testing. Overall, this study also highlights the need to explore the biological link between RDD and autoimmunity.

PURPOSE BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective. METHODS We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations. RESULTS Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months. CONCLUSION We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules.