Abeykoon, Jithma P.

Lin et al. report the long‐term follow‐up of a phase II trial involving 95 adult patients with Langerhans cell histiocytosis (LCH), investigating the combination of methotrexate and cytarabine (MA). After a median follow‐up of 6.5 years, the study showed high response rates, with 90% overall response; 55% of patients free from an event such as disease progression, poor response or death; and 93% of patients were alive, though nearly half experienced febrile neutropenia. This prospective study helps fill gaps in understanding adult LCH treatment, indicating that fixed‐duration chemotherapy can yield durable responses despite its associated risks. It emphasizes the importance of personalized treatment decisions, considering both fixed‐duration chemotherapy and continuous targeted agents based on patient and disease‐specific factors.Commentary on: Lin et al. Long term follow‐up of methotrexate and cytarabine in adult patients with Langerhans cell histiocytosis. Br J Haematol 2025; 206:576‐584.

AbstractBackgroundCrystal‐storing histiocytosis (CSH) is a rare form of histiocytosis with intralysosomal accumulations of immunoglobulins or paraproteins that aggregate as crystals. Central nervous system (CNS) involvement of CSH is uncommon but should be considered in cases of persistent parenchymal enhancement on neuroimaging.MethodsWe describe one local case of CNS CSH and 10 additional cases identified by literature review.ResultsAmong 11 CSH patients, lesions involved either the dura (2/11) or brain parenchyma (9/11). Two cases had leptomeningeal enhancement. One case had spinal cord involvement. Two cases were associated with marginal zone lymphoma; one case was associated with an immunoglobulin A‐plasma cell dyscrasia. Eight of 11 cases had outcome data available: 7/8 cases had clinical and/or radiological improvement and 1/8 had radiological stability.ConclusionsCentral nervous system involvement of CSH is rare. Potential cases should be comprehensively evaluated for lymphoma or myeloma with positron emission tomography/computed tomography (CT) of the body or alternatively, CT of the chest, abdomen, pelvis and nuclear bone scan, bone marrow biopsy, serum protein electrophoresis, and cerebrospinal fluid protein electrophoresis. Treatment is targeted toward the underlying malignancy.

Abstract Magnesium (Mg) is an essential element involved in cellular metabolism. We demonstrated that in patients with diffuse large B-cell lymphoma (DLBCL) undergoing autologous stem cell transplant (SCT), those with a serum Mg < 2.0 mg/dL at the time of transplant had worse outcomes. In this study, we aimed to learn the prognostic value of low serum Mg in patients with untreated DLBCL. We analyzed serum from 408 patients and tested 2 Mg cutpoints—low (<1.7 mg/dL) and low normal (<2.0 mg/dL), a range we found associated with lower survival in the SCT group. We found 3% of patients with low levels and 23% with low normal levels. Low normal serum Mg levels were associated with a higher stage at diagnosis, more extranodal involvement, higher international prognostic index score, lower overall survival (OS), and event-free survival. These data warrant testing Mg replacement to a target of >2.0 mg/dL to learn if survival can be improved.

Abstract Disclosure: J. Hewlett: None. S. Mohan: None. C.J. Davidge-Pitts: None. J. Abeykoon: None. R. Go: None. D.Z. Erickson: None. Objective: Erdheim-Chester Disease (ECD) is a multisystem histiocytic disorder which can infiltrate the pituitary gland, often leading to endocrine dysfunction. Central Arginine Vasopressin Deficiency (cAVP-D) commonly affects ECD patients, and those harboring BRAFV600E are reported to have an increased risk. Insufficient data exist about the risk associated with other mutations, and if cAVP-D or pituitary imaging improves with targeted therapies (TT). Methods: We conducted a review of a prospectively maintained database of adults with ECD treated at a tertiary center between 1992-2023. Objectives of this study were to identify mutations associated with cAVP-D and assess for improvement in cAVP-D (remission of disease or decrease in dose of desmopressin) or pituitary gland involvement (via MRI imaging) following TT for ECD. Results: Of 148 patients with ECD, the majority were male (98, 66.2%) and the mean age at diagnosis was 56.5 years [range: 19-82]. Median length of follow-up was 24 months (95% CI, 17 to 27). Of 121 (81.8%) patients with molecular testing results, 89 (73.6%) harbored a somatic mutation. 67 of 89 (75.3%) carried BRAF mutations, with BRAFV600E in 61 (91.0%) and missense mutations/fusions in 6 (9.0%). 22 of 89 (24.7%) patients harbored other somatic mutations, with MAP2K1 in 13 (14.6%) being the most common. 35 (23.6%) patients were diagnosed with cAVP-D, and the median onset of polyuria and polydipsia prior to diagnosis of ECD was 51 months (95% CI, -120 to -6). Molecular testing was performed in 28 patients with cAVP-D: 17 (60.7%) harbored BRAF mutation and 3 (10.7%) MAP2K1 mutation. There was no significant association between the presence of cAVP-D and MAP2K1 (p=0.69, 95% CI, -0.08 to 0.21). The association between cAVP-D and BRAF did not reach statistical significance (p=0.07, 95%CI, -0.03 to 0.38). Additionally, there was no association between BRAF and timing of cAVP-D symptoms before ECD diagnosis (p=0.08, 95% CI -163.4 to 10.3). Pituitary MRI was available in 32 patients with cAVP-D (91.4%) showing infundibular involvement in 17 (53.1%) and loss of the posterior bright spot in 5 (15.6%). 28 (80%) patients with cAVP-D received systemic therapy, 18 (64.3%) of whom received TT. One patient with cAVP-D was able to discontinue desmopressin. Improvement of pituitary MRI was noted in 7 (21.9%), among whom 4 received TT, 2 received systemic non-TT, and 1 was lost to follow-up. There was no significant MRI improvement associated with TT (p=0.67, 95% CI -0.30 to 0.42). Conclusion: In this large cohort of patients with ECD, of whom the majority underwent molecular testing, we identified no association between MAP2K1 mutation and cAVP-D, and no impact of TT on the clinical course or MRI findings associated with cAVP-D. BRAF mutation carriers were more likely to have cAVP-D and more likely to have onset of symptoms closer to ECD diagnosis, but the results did not reach statistical significance. Presentation: 6/2/2024

152 Background: The American Society of Clinical Oncology (ASCO) started the Diversity in Oncology initiative in 2017. Minority representation in the US oncology physician workforce was the subject of a recent series of ASCO State of the Oncology Workforce in America snapshots (1). However, Asian minority representation was not mentioned in any of these reports. Our objective was to determine the proportion of Asian workforce in various oncology specialties inclusive of physician and non-physician practitioners as well as physician trainees. Methods: We searched the web for publicly available data on Asian representation among US oncology adult (A) and pediatric (P) practitioners and trainees. Major data sources included the 2020 US Census, Association of American Medical Colleges, Accreditation Council for Graduate Medical Education, and professional societies. Practitioners included hematologists/oncologists (H/O), gynecologic oncologists (GYNO), radiation oncologists (RADO), surgical oncologists (SURGO), hematopathologists (HP), oncology nurse practitioners (ONP), oncology physician assistants (OPA), and oncology nurses (ON). Trainees included fellows (F) and residents (R). For reference, we obtained similar data on US population, medical students (MS), adult internal medicine residents (AIMR), gynecology residents (GYNR), pediatric residents (PR), pathology residents (PATHR), surgery residents (SURGR), nurses (RN), nurse practitioners (NP), and physician assistants (PA). For a snapshot of the oncology workforce, data from 2020-2022 were used. Whenever available, we obtained serial data for trainees over the years. Results: A snapshot of the proportions of Asians based on their professions is shown (Table). While Asians comprise only 6.2% of the US population, between 14.7% to 32.1% of physician practitioners in various oncology subspecialties are Asian. Moreover, between 17.9% to 35.3% of oncology physician trainees and 26.7% of medical students are Asian and these proportions have remained stable from 2005 to 2022. Data are unavailable for HP, SURGO, and non-physician practitioners except for OPA (7.0%) and RN (7.2%). Conclusions: Asians comprise a large segment of the US oncology workforce. While only 1 in 20 people in the US are Asians, between 1 in 3 and 1 in 5 oncology physician practitioners and trainees are Asians. Data are limited for non-physician practitioners. Asian minority representation should be highlighted and considered as an example of success in diversity. 1. JCO Oncol Pract 2020-2022. Snapshot of Asian representation among oncology trainees and practitioners in the US. Trainees 2022 A-H/O-F 35.3% AIMR 35.9% 2022 P-H/O-F 20.0% PR 22.0% 2022 RADO-R 26.4% MS 26.7% 2022 GYNO-F 17.9% GYNR 14.9% 2022 HP-F 20.0% PATHR 26.6% 2022 SURGO-F 21.2% SURGR 19.2% Practitioners 2021 A-H/O 32.1% OPA 7.0% 2021 P-H/O 20.4% RN 7.2% 2021 RADO 25.9% HP/SURGO/ONP/ON NA 2020 GYNO 14.7% US Census 6.2%

Abstract Currently, the role of DNA methylation in the immunoglobulin M (IgM) monoclonal gammopathy disease spectrum remains poorly understood. In the present study, a multiomics prospective analysis was conducted integrating DNA methylation, RNA sequencing (RNA-seq), and whole-exome sequencing data in 34 subjects (23 with Waldenström macroglobulinemia [WM], 6 with IgM monoclonal gammopathy of undetermined significance [MGUS], and 5 normal controls). Analysis was focused on defining differences between IgM gammopathies (WM/IgM-MGUS) compared with controls, and specifically between WM and IgM-MGUS. Between groups, genome-wide DNA methylation analysis demonstrated a significant number of differentially methylated regions that were annotated according to genomic region. Next, integration of RNA-seq data was performed to identify potentially epigenetically deregulated pathways. We found that pathways involved in cell cycle, metabolism, cytokine/immune signaling, cytoskeleton, tumor microenvironment, and intracellular signaling were differentially activated and potentially epigenetically regulated. Importantly, there was a positive enrichment of the CXCR4 signaling pathway along with several interleukin (interleukin 6 [IL-6], IL-8, and IL-15) signaling pathways in WM compared with IgM-MGUS. Further assessment of known tumor suppressor genes and oncogenes uncovered differential promoter methylation of several targets with concordant change in gene expression, including CCND1 and CD79B. Overall, this report defines how aberrant DNA methylation in IgM gammopathies may play a critical role in the epigenetic control of oncogenesis and key cellular functions.

7533 Background: Maintenance treatment (rx) with lenalidomide (R) improves overall survival (OS) in multiple myeloma (MM). We report a retrospective cohort of patients (pts) with second primary B-cell acute lymphoblastic leukemia (ALL) diagnosed after R-rx for MM. Methods: We included pts who were exposed to at least 1 yr of R for MM rx prior to ALL dx. After approval by institutional review board, data were collected by chart review at participating centers using Redcap. OS was the primary endpoint. We used BlueSky statistics v10.3.1 for analysis. Results: Analysis included 33 ALL pts diagnosed from 2014-2022 at 7 sites. 52% pts were female. Median follow up was 9.6 yrs (95%CI,7.6-11.8) from MM dx and 3.2 yrs (CI, 2.1-4.7) from ALL dx. Pt characteristics at MM dx are given in Table. Induction rx included: proteasome inhibitor (PI) +immunomodulatory drug (IMiD) (43%), PI+alkylator (24%), IMiD (18%) & others (15%). 50% pts received autologous stem cell transplantation (ASCT). Median OS from MM dx was 11.2 yrs (CI, 8.9-NR). Time from MM dx and initial R rx to ALL dx were 5.0 yrs (range, 2.4-18.5) and 4.4 yrs (2.2-10.6) respectively. Median duration of R exposure before ALL dx was 3.8 yrs (1.6-10.4). Table shows characteristics of pts at B-ALL dx and genetic classification based on karyotyping (n=30), ALL FISH (n=28), chromosomal microarray (n=5) and next-generation sequencing (n=5). 31 pts received ALL-directed rx while 1 pt was initially managed with close observation as the pt attained CR on stopping R ( Lakshman et al; ASH 2019 ). Rx was unknown in 1 pt. Initial rx included: hyper-CVAD+/- rituximab- 49%, pediatric inspired protocols-18%, reduced intensity rx for frail pts- 21% and others- 12%. Response to first line rx were: CR- 56%, CRi- 28%, induction failure- 16%. 32% pts attained measurable residual disease (MRD) negativity. 48% pts underwent SCT for ALL. 14 pts died during follow up. 3-yr OS from ALL-dx was 50% (CI, 33%-76%). 3 pts required rx for MM after ALL diagnosis (2 had allo-SCT for ALL before MM relapse). Conclusions: Most pts had standard risk MM and were exposed to R for several years prior to dx of B-ALL, characterized by high incidence of hypodiploid karyotype; IKZF1 loss and TP53 deletions/mutations were detected in a subset of pts.MRD-adapted timely discontinuation of R in standard risk MM may decrease risk of second primary ALL. [Table: see text]

e23554 Background: Follicular dendritic cell sarcoma (FDCS) is a low-grade neoplasm arising from follicular dendritic cells. Its diagnosis is challenging due to its extreme rarity, and the optimal management remains unknown. Methods: We conducted a retrospective study of FDCS patients (pts) seen at Mayo Clinic, MN since 2018. Time to event analyses were done from the time of diagnosis. Results: Ten pts with FDCS were identified (Table). The median age was 60 years (range, 38-76) and 5 were males. Abdominal pain was the most common presenting symptom (30%) followed by constitutional symptoms, shortness of breath, and vision change. In 3 pts, the diagnosis was incidental. The 2 most common primary locations were abdomen/pelvis (50%) and mediastinum (30%). Six pts (60%) presented with advanced disease and 3 (30%) had Castleman’s disease. Most (60%) had advanced disease. Six pts had Epstein-Barr virus in situ hybridization and all tested negative. Seven pts had next generation sequencing and 5 (83%) had genetic alterations detected with CDKN2A/B alterations being most frequent (3 pts, all with advanced disease). The median follow up was 4.3 years (range, 0.2-13.3). In the 4 patients with localized disease, 3 underwent complete surgical excision resulting in complete remissions (CRs). The one who received radiation had a partial remission (PR). The median time to progression after 1st line treatment was 4 months (all with advanced disease). All 3 pts who died had advanced disease and 2 had CDKN2A/B alterations. Conclusions: In FDCS, localized diseases managed by surgical excision with or without radiation can achieve long term remissions. Advanced diseases generally do not respond to multimodality therapy including immunotherapy but can have disease stabilization with variable survival. CDKN2A/B mutations were common and potentially associated with a worse outcome. Better understanding of the impact of the FDCS mutational landscape on prognosis may provide novel approaches to therapy. [Table: see text]

PURPOSE Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88 L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively ( P < .0001). CONCLUSION Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.