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Abstract Introduction A 2017 survey by the American Society of Hematology found a widespread perceived shortage of classical hematologists in the US, which was compounded by a low trainee interest in the field (<5%) (Masselink LE, Blood Adv 2019). Recently, we reported that among hematologist/oncologists at the 64 National Cancer Institute (NCI)-designated cancer centers with clinical programs, only ~5% identify as classical hematologists, despite 15% of them including classic hematology (CH) patients in their practice (Go LT, Blood Adv, in press). However, there remains limited data on CH consult volumes at NCI-designated cancer centers (West CV, JCO Oncol Pract 2023). This study aimed to evaluate the volume and nature of CH outpatient consults at the Mayo Clinic Comprehensive Cancer Center (MCCC). Methods We reviewed electronic medical records to identify all completed outpatient consults in CH, malignant hematology (MH), and solid tumor oncology at MCCC in Rochester, Minnesota from January 1 to December 31, 2024. Consults were defined as either external or internal referrals for new patients seen in CH outpatient clinic. CH consults were further categorized by referral reasons and the type of physician (CH, MH, or fellow) performing the consultations. CH physicians were defined as those whose clinical practice primarily focuses on non-malignant hematologic conditions; one advanced practice provider (APP) was included in this group. Inpatient consults, electronic consults, and return visits were excluded. Results In 2024, a total of 17,153 outpatient consults were completed. Of these, 13.4% were CH, 30.5% were MH and 56.1% were solid tumor oncology. Among CH consults, the most common referral reasons were abnormal blood counts (68.3%), bleeding disorders (10.6%), thrombosis (11.8%), and other hematologic diagnoses (9.3%). Within abnormal blood counts, the leading indications were anemia (50.7%), thrombocytopenia (15.3%), leukopenia (11.0%), leukocytosis (9.1%), and pancytopenia (7.0%). Among bleeding disorders, the top reasons included suspected bleeding diathesis (49.4%), von Willebrand disease (24.5%), Hemophilia A (4.1%), Factor VII deficiency (3.7%), and platelet qualitative defect (3.4%). Thrombosis-related consults were most often for pulmonary embolism or deep vein thrombosis (43.2%), antiphospholipid syndrome (17.7%), thrombophilia (16.2%), portal vein thrombosis (4.1%), and splenic infarct (2.6%). The top ten referrals for a specific hematologic diagnosis were iron deficiency anemia (29.2%), pulmonary embolism or DVT (13.5%), immune thrombocytopenic purpura (10.3%), von Willebrand disease (6.9%), hemoglobinopathy (5.5%), antiphospholipid syndrome (5.5%), thrombophilia (5.1%), anemia of chronic kidney disease (2.4%), aplastic anemia (1.5%), and hereditary spherocytosis (1.4%). Of the 114 physicians at MCCC during the study period, 55 (48.2%) were medical oncologists, 54 (47.4%) primarily practiced MH, and only 5 (4.4%) were dedicated CH physicians. Despite comprising only 4.4% of the hematology/oncology workforce, CH physicians or fellows completed the majority (86.1%) of CH consults; MH physicians completed 13.8%. Conclusion CH consults represent a substantial portion of outpatient hematology referrals at MCCC, primarily for diagnostic evaluation of cytopenias or thrombotic/bleeding symptoms. However, a striking mismatch exists between CH physician representation (4.4%) and CH consult volume (13.4%). This imbalance has implications for quality, timeliness, and continuity of care for patients with non-malignant hematologic conditions. Our findings underscore the urgent need to expand recruitment and career development pathways in CH to address a huge clinical demand.

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

Abstract Background:Erdheim-Chester Disease (ECD) is a rare, incurable histiocytic neoplasm. Since its recognition in 1930, our understanding of ECD's pathophysiology has evolved. The identification of its clonal nature after 2015 established ECD as a cancer, prompting increased disease awareness and treatment advances. Targeted therapies show promising responses, but changes in ECD mortality over time have not been extensively documented. Methods:A multi-institutional retrospective cohort study analyzed adults with ECD consecutively seen at Mayo Clinic MN, AZ, and FL and the University of Alabama at Birmingham between 2007 and 2024. Clinical and prognostic data were abstracted. Overall survival was estimated using the Kaplan-Meier method and compared to expected survival using U.S. Census data, based on age at diagnosis (by calendar year), date of diagnosis, and sex. Standardized mortality ratios (SMRs) were calculated by dividing the number of observed deaths in the study population by the expected number of deaths using U.S. population data. Risk of death was compared by date of diagnosis (pre- and post-2015) using Cox proportional hazards analysis. Statistical analysis was performed with R software. Results:A total of 159 ECD patients were included (median age 58 years [range 19-82], 65% male). Forty-nine patients were diagnosed between 1990-2014 and 110 between 2015-2024. Median follow-up for the entire cohort was 4.0 years (95% CI: 3.2-4.4). Median follow-up for those diagnosed between 1990-2014 was 10.4 years (CI: 3.2-16.8), compared to 3.5 years (CI: 3.0-4.2) for those diagnosed between 2015-2024. The 5-year overall survival rate was 80% (95% CI: 72-88). Patients with ECD had an increase in mortality over expected, with 28 deaths compared to an expected 11.2, an SMR of 2.5 (95% CI: 1.7-3.6, p<0.001). Of 17 patients with an identified cause of death, death was attributable to ECD in 11 (65%), secondary malignancy in 1 (7%), and unrelated causes in 5 (29%). Cause of death was unknown in 11 patients. Among deaths, 11 (39%) were treated with targeted therapy, 8 (29%) with chemotherapy, and 1 (4%) received both. One patient (4%) received steroids, 1 received immunomodulator and targeted therapy (4%), and 6 (21%) received no disease-directed therapy. Of the patients whose death was related to ECD, 10 (91%) had multisystem disease. For 49 patients diagnosed pre-2015, 14 deaths occurred during the follow-up, significantly higher than the expected 5.2 deaths based on U.S. population data (SMR of 2.7 [95% CI: 1.5-4.4, p=0.001]). Among those diagnosed between 2015 and 2024, 14 deaths occurred, compared to expected 6.1 (SMR of 2.3 [95% CI: 1.3-3.8, p=0.006]). In an age- and sex-adjusted Cox proportional hazards model, diagnosis after 2015 vs. diagnosis prior to 2015 yielded a hazard ratio of 0.59 (95% CI: 0.27-1.31, p=0.19). Conclusion:The mortality rate of ECD patients remains higher than the general population, despite advancements in disease recognition and development of targeted therapies. While our data suggest a possible trend toward improved survival among patients diagnosed after 2015, we did not find statistically significant evidence of decreased mortality compared to those diagnosed prior to 2015. Larger cohorts with longer follow-up periods are needed to draw definitive conclusions regarding mortality.

Abstract Background: In 2022, Medicare alone spent $42.1 billion on prescription drugs, with antineoplastic and classical hematology drugs accounting for 44% and 8% of the total, respectively (2024 MedPAC Data Book). While antineoplastic drugs have been extensively studied, classical hematology drugs have received comparatively little attention. We analyzed US Food and Drug Administration (FDA) approvals of classical hematology drugs over the past 30 years and examined their per-patient costs and annual total US sales. Methods: We identified all classical hematology drugs (those prescribed by hematologist/oncologists for non-malignant indications) approved by the FDA from January 1, 1995 to December 31, 2024, including novel pharmaceuticals (synthesized from chemical compounds), biologics (derived from living organisms), and biosimilars (highly similar, but not identical, to biologics previously approved). Cost estimates for 2024 were based on wholesale acquisition costs (WAC), using annual WAC for continuous-duration treatments and typical course WAC for fixed-duration treatments. WAC and US gross sales data for 2024 were obtained from IPD Analytics (Aventura, FL). Results: A total of 98 classical hematology drugs were approved over the past 30 years—11% in 1995–2004, 26% in 2005–2014, and 63% in 2015–2024. These included pharmaceuticals (36%), biologics (54%), and biosimilars (10%). Six gene therapies received approval: 3 for hemophilia and 1 each for sickle disease, beta thalassemia, and sickle cell disease/beta thalassemia (dual indication). Common categories of indications included bleeding (31%), anemia (30%), neutropenia (9%), and thrombocytopenia (9%). Leading diagnoses were hemophilia (25%), chemotherapy-induced neutropenia (9%), thromboembolism (8%), paroxysmal nocturnal hemoglobinuria (PNH; 7%), anemia of chronic kidney disease (6%), iron deficiency anemia (6%), and immune thrombocytopenia (5%). The median cost for gene therapies was $2.9 million per treatment (range: $2.2 million–$3.5 million). Among non-gene therapies, median costs were $3,000 per course for fixed-duration treatments (range: $64–$378,000) and $467,000 annually for continuous-duration treatments (range: $2,400–$1.8 million). The most expensive fixed-duration treatments targeted hemophagocytic lymphohistiocytosis ($378,000/8-week course), while the most expensive continuous-duration treatments were for hemophilia (median: $630,000/year; range: $270,000–$853,000). Estimated 2024 US gross sales across all drugs exceeded $70 billion. Top-selling indications included thromboembolism ($43.5 billion), hemophilia ($6.9 billion), immune thrombocytopenia ($4.9 billion), PNH ($4.7 billion), chemotherapy-induced neutropenia ($2.8 billion), anemia of chronic kidney disease ($2.0 billion), and iron deficiency anemia ($1.8 billion). Total sales for all gene therapies combined were $143 million. Six drugs have been discontinued (year approved/year discontinued/reason): betrixaban (2017/2020/business), daprodustat (2023/2024/business), fidanacogene elaparvovec (2024/2025/business), oprelvekin (1997/2011/business), peginesatide (2012/2013/safety), and voxelotor (2019/2024/safety). There are limitations to our study. Some drugs have non-classical hematology indications (anticoagulants in atrial fibrillation; luspatercept in myelodysplastic neoplasm) and/or may also be prescribed by non-classical hematologists (erythropoiesis stimulating agents by nephrologists and medical oncologists). We were unable to disaggregate the sales data in these situations. Therefore, the annual sales for certain indications may be overestimated. Conclusions: Classical hematology drugs contribute substantially to US prescription drug spending, with over $70 billion in annual sales and medications for thromboembolism accounting for over half of the costs. Approvals have accelerated over the past three decades, doubling each decade. Biologics and biosimilars now represent two-thirds of approvals. Continuous-duration treatments, particularly for rare hereditary diseases like hemophilia, carry significant financial burden, with annual costs per patient often exceeding $0.5 million. In these conditions, if gene therapies demonstrate durable efficacy, they may prove to be cost-effective alternatives. As more gene therapies are developed, evaluating their long-term value relative to chronic high-cost treatments will be essential for shaping future reimbursement and access strategies.

Abstract Background Secondary central nervous system lymphoma (SCNSL) is a rare but significant complication, affecting approximately 2–10% of patients with diffuse large B-cell lymphoma (DLBCL), often leading to poor outcomes. The CNS-International Prognostic Index (CNS-IPI) remains a widely adopted tool for estimating CNS relapse risk; however, recent advances in molecular profiling and evolving treatment paradigms have challenged the adequacy of CNS-IPI alone in guiding risk assessment. This study evaluates the prognostic relevance of CNS-IPI in conjunction with molecular and clinical factors, specifically cell-of-origin (COO), gene expression, and frontline treatment regimens. The aim is to refine risk stratification and identify patients at highest risk for SCNSL. Method Building on our previous study, we analyzed data from patients with newly diagnosed DLBCL between 2002 and 2023, enrolled in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource. Patients with primary CNS lymphoma, CNS involvement at diagnosis, or who received CNS-directed therapy were excluded. COO was determined using the Hans algorithm and/or Nanostring profiling. Multivariate cause-specific Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for predictors of CNS relapse that were measured at the time of initial DLBCL diagnosis. Cumulative incidence with competing risks and cause-specific Cox models were used to analyze relapse risk. Result We included 2137 patients in our analysis, median age at diagnosis was 63 (IQR 53-72), with 41.6% (n=890) females. The albumin level was below normal in 32.5% (n=350), 64.0% (n=1367) had CNS-IPI of intermediate/high, 37.5% (n=586) had non-germinal center B-cell (GCB) COO, and 14.5% (n=309) were double expressor positive. At a median follow-up of 83 months (IQR 42 -143), 82 (3.8%) SCNSL relapses were observed; the 3 and 5 yrs cumulative incidence for SCNSL from time of DLBCL diagnosis were 3.7% (95% CI 3.0-4.7) and 3.8% (95% CI 3.1-4.8) respectively. In models accounting for death as a competing risk, the 5-year cumulative SCNSL incidence estimate for patients with a CNS-IPI low was 1.5% (95% CI 0.8-2.7), Intermediate was 4.9% (95% CI 3.7-6.4), and high was 6.1% (95% CI 3.8-9.6). The 5-year cumulative SCNSL incidence estimate for patients with non-GCB COO was 5.2% (95% CI 3.6-7.4) compared to 2.4% (95% CI 1.6-3.6; p=0.001) for GCB patients, and the 5-year cumulative SCNSL incidence for double expressor positive patients was 8.6% (95% 5.8-12.6) compared to 1.5% (95% CI 0.8-2.7; p<0.001) for double expressor negative patients. In a multivariable model (including CNS-IPI, COO, double expressor, treatment group, extranodal involvement, and albumin group), CNS-IPI intermediate (HR 2.85 [1.58-5.14]; p<0.001) and high (HR 4.31 [2.15-8.65]; p<0.001), non-GCB COO (HR 2.36 [1.37-4.06]; p=0.002], double expressor (HR 5.56 [2.88-10.73]; p<0.001), and below normal albumin (HR 1.89 [1.02-3.50]; p=0.042) were independently associated with increased risk of SCNSL. The majority of the SCNSL relapse occurred within the first 2 years after DLBCL diagnosis; 81.7% (n=67), with only 6.1% (n=5) occurring after 5 years. For patients who developed SCNSL, the median OS from the time of SCNSL diagnosis was 24 months (95% CI 17-34), with 5 years OS of 31% (95% CI 22-43). These findings are being validated using an external, international cohort, and final analysis will be presented at the time of presentation at ASH. Conclusion In this large, prospectively followed cohort with long-term follow-up data, SCNSL remains a rare but devastating complication of DLBCL, with a 5-year cumulative incidence of 3.8% and it is associated with very poor long-term survival. While CNS-IPI remains a strong predictor of SCNSL risk, our study identifies non-GCB COO and double expressor phenotype as independent, additive molecular risk factors. These findings suggest that current risk stratification tools may underestimate the risk of CNS relapse in molecularly defined high-risk subgroups. Considering the poor outcomes linked to SCNSL and the absence of a connection with frontline treatment types, future research should aim to enhance risk prediction models through molecular profiling and explore prophylactic strategies to reduce the likelihood of SCNSL.

Abstract Background Primary central nervous system lymphoma (PCNSL) is a rare but aggressive non-Hodgkin lymphoma with limited prospective data to guide optimal therapy. This study evaluates real-world treatment patterns and survival outcomes using a large national cohort. Methods We analyzed data from the National Cancer Database (NCDB) for patients diagnosed with PCNSL between 2004 and 2020. Baseline demographics and treatment characteristics were analyzed using descriptive statistics. Survival outcomes were estimated using the Kaplan-Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were constructed to identify independent predictors of overall survival (OS). Results A total of 14,450 patients with PCNSL were included; 14,439 had first-line treatment data available, and 13,390 had survival data. Median age at diagnosis was 67 years (range 18-90), 49.2% were female, and 6.6% were African American. Chemotherapy alone was the modality of treatment for 81.6% (n=11,787), 12.2% (n=1,769) received chemoradiation, 3.8% (n=545) received chemotherapy and underwent autologous stem cell transplant (ASCT) but no radiation, and 2.4% (n=348) received radiation only. The median follow-up time was 73.5 months (95% CI 71.4-75.6), and the median OS for the group was 17.4 months (95% CI 16.2-18.6). Survival differed significantly by age group (median OS: <65 yrs, 46.1 months [95% CI 41.7 -50.6]; 65-79 yrs, 12.5 months [95% CI 11.2-13.7]; ≥80 yrs, 3.2 months [95% CI 2.9-3.5]; p<0.001), by year of diagnosis (median OS: 2004-2009, 11.0 months [95% CI 9.9-12.1]; 2010-2015, 20.0 months [95% CI 17.4-22.6], 2016-2020, 29.7 months [95% CI 26.0-33.4]; p<0.001), and by frontline treatment strategy (p<0.001). Patients treated with chemotherapy followed by ASCT had the longest median OS (not reached), while those receiving radiation alone had the poorest outcomes with a median OS of 3.9 months (95% CI 3.2-4.7); chemoradiation patients had a median OS of 31.8 months (95% CI 27.5-36.1), and chemotherapy only patients had a median OS of 13.9 months (95% CI 12.7-15.1)(p<0.001). African American patients had an inferior outcome with a median OS of 10.2 months [95% CI 7.2-13.1], compared to “other” races with a median OS of 36.9 months [95% CI 27.6-46.1] (p<0.001), although this is more similar to the median outcome for white patients (17.0 months [95% CI 15.8-18.3]). Treatment at an academic center (25.7 vs 11.0 months) and a high case-volume center (defined as >median number of cases per facility) (18.6 vs 10.5 months), and lower Charlson-Deyo comorbidity scores (CDS) (defined as CDS 0-1) (21.7 vs 6.8 months) were also associated with superior OS (p<0.001). In multivariable analysis, increasing age ( 65-79 y.o HR 1.60 [1.52-1.1.68], ≥80 y.o HR 2.95 [2.75-3.17]), CDS≥2 (HR 1.36 [1.28-1.44]), and African American race (HR 1.12 [1.02-1.24]) were adverse predictors of OS (all p<0.001), while treatment strategy (ASCT [HR 0.17], chemoradiation [HR 0.53], chemotherapy only [HR 0.68] compared to radiation alone), more recent year of diagnosis (2010-2015 [HR 0.81], 2016-2020 [0.70]), and treatment at an academic center [HR 0.81] remained predictors of superior OS (all p<0.001). Conclusion In this large national cohort of patients with PCNSL, treatment with chemotherapy followed by ASCT was associated with the most favorable survival outcomes. Patients treated with chemoradiation or multi-agent chemotherapy also demonstrated improved survival compared to those receiving radiation monotherapy or single-agent chemotherapy alone, respectively. Age, comorbidities, race, and treatment at academic centers were also significant independent predictors of OS. These findings highlight substantial disparities in outcomes and underscore the importance of optimizing treatment strategies, improving access to high-intensity therapies, and supporting timely referral to academic or high case-volume centers, particularly for younger and medically fit patients.

Abstract Background: Immune checkpoint inhibitors (ICIs) have been established as standard of care for patients with classical Hodgkin lymphoma (cHL), including relapsed or refractory (r/r) disease. However, ICIs discontinued in some patients due to treatment-related toxicities or disease progression may later be re-initiated. The outcomes of this common clinical practice of ICI re-initiation, or ‘rechallenge,‘ have not been evaluated. Here, we present real-world efficacy and safety data of ICI rechallenge in patients with cHL. Methods: We conducted a retrospective cohort study of patients with cHL treated with ICIs between 2015 and 2024 at Mayo Clinic sites. Patients were identified via institutional records using diagnostic and treatment codes. Included patients were adults ≥18 years with histologically confirmed diagnosis of cHL receiving ≥1 cycle of ICI therapy. Patients in the rechallenge cohort received a second course of ICI therapy following discontinuation of the initial ICI for any reason. The control cohort included patients with ICI discontinuation without subsequent rechallenge. Primary outcomes included progression-free survival (PFS), event-free survival (EFS), and duration of response (DOR), defined respectively as time from first ICI initiation to disease progression, time from first ICI initiation to disease progression, adverse events, treatment change, or death, and time from first recorded response per positron emission tomography–computed tomography until the occurrence of disease progression. Secondary outcomes included overall survival (OS), and incidence and severity of irAEs following ICI rechallenge. Survival outcomes were compared using propensity-score-matched (PSM) cohorts with a proportional Cox model. Results: A total of 145 patients were included. Of these, 30 (21%) underwent ICI rechallenge, while 115 (79%) received no subsequent ICI treatments. The median age was 40 years (interquartile range [IQR] 26-66). Most were male (59%), predominantly nodular sclerosis subtype (71%), Ann Arbor stage III-IV disease (65%), and ECOG ≤ 1 (96%). ICIs were utilized for r/r disease in 66%, with median 6 (IQR 4-13) cycles and follow up of 40.8 months (IQR 21.1–78.1). Patients received median 1 prior line of therapy (IQR 0-2.5). During initial ICI treatment, 34/145 patients (23%) experienced irAEs, including 17 patients (57%) in the rechallenge group and 17 (15%) in the non-rechallenge group. Most irAEs were of grade 1–2 severity, though 10 (30%) experienced grades ≥3 irAEs. irAE severity did not differ between groups. Among patients who underwent ICI rechallenge, the majority (53%) discontinued due to irAEs. The decision to pursue ICI rechallenge was driven predominantly by disease progression (63%). Among the 1:1 PSM cohorts using bone marrow transplant status and the International Prognostic Score, PFS did not significantly differ between rechallenged vs. non-rechallenged groups (HR 1.7, 95% CI 0.60–4.5, p=0.32). Similarly, no difference was noted among the groups in EFS and DOR using 1:3 PSM cohorts using the number of ICI cycles (HR 1.6, 95% CI 0.83–3.0, p = 0.16 and HR 1.6, 95% CI 0.37–7.0, p = 0.53, respectively). In the 1:1 matched cohort, ICI rechallenge was not associated with inferior OS compared to those without rechallenge (HR 1.6, 95% CI 0.48–5.4, p=0.43). irAE occurred in 20%, including pneumonitis (n=2), hepatitis (n=1), and pancreatitis (n = 1). Of the patients who had experienced irAEs during their initial ICI course, only two developed recurrent irAEs of the same type upon rechallenge, both at reduced severity. Overall, 80% of rechallenged patients did not experience any irAE with their second ICI course. Conclusions: ICI rechallenge was not associated with inferior PFS, EFS, DOR or OS compared patients without rechallenge. Among patients receiving ICI rechallenge after irAE, recurrence of same irAE was rare. ICI rechallenge may be a feasible and potentially effective strategy in selected patients with cHL.

Abstract Introduction: Brentuximab vedotin (BV) was approved by the US FDA for relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) in 2011 and for previously untreated advanced stage cHL in 2018. The immune checkpoint inhibitors (ICIs) nivolumab and pembrolizumab were approved for R/R cHL in 2016 and 2017, respectively. These novel agents have significantly changed the landscape of cHL management in recent years. In this study, we analyzed data from the National Cancer Database (NCDB) to investigate whether survival outcomes have improved in the novel agent era (2011 and beyond) for patients with cHL in the US. Methods: Patients diagnosed with cHL between 2004 and 2020 were identified in the NCDB. Those with missing survival data were excluded. Three treatment eras were defined based on the timing of FDA approval of novel agents: Chemo era (2004–2010), BV era (2011–2015), and ICI era (2016–2020). Patient and disease characteristics were compared using the Chi-square test. Survival analyses were conducted using the Kaplan-Meier method and Cox proportional hazards model. Results: A total of 85,488 patients with newly diagnosed cHL were identified: 36,150 in the Chemo era, 27,058 in the BV era, and 22,280 in the ICI era. Compared to the chemo era, the BV and/or ICI eras included slightly more patients aged ≥66 (17.3% vs 17.8% vs 19.5%), male (53.6% vs 54.6% vs 53.8%, p=0.042), Black (11.3% vs 12.9% vs 12.5%), Hispanic (9.0% vs 9.9% vs 10.9%), with Charlson-Deyo score ≥1 (14.2% vs 16.1% vs 17.2%), B symptoms (44.1% vs 46.9% vs 46.9%), treated at academic centers (32.4% vs 35.9% vs 36.4%), on Medicaid (9.5% vs 12.2% vs 13.7%) or Medicare (19.3% vs 20.3% vs 21.7%), and with higher income (≥4th quartile by 2008-2012 standard; 34.5% vs 34.3% vs 36.3%) (all p<0.001 except for sex, noted above). Ann Arbor stage data were not available in the ICI era. There were slightly more patients with advanced-stage disease in the BV era compared to the Chemo era (45.4% vs 40.3%, p<0.001). IPS scores were available for only 2,344 patients, with a similar distribution (0–2 vs 3–7) across the three eras (p=0.957). The median follow-up was 6.9 years (95% CI 6.9-7.0). Overall survival (OS) significantly improved in the novel agent eras: the 5-year OS rate was 79.8% (95% CI, 79.4%–81.2%) for patients diagnosed in the Chemo era, 81.9% (95% CI, 81.9%–82.4%) in the BV era, and 84.1% (95% CI, 83.5%–84.8%) in the ICI era (p<0.001). Statistically significant OS improvements were observed across all subgroups, including age (≤40: 92.8% vs 94.9% vs 96.5%, 41-65: 80.5% vs 81.8% vs 84.4%, ≥66: 41.4% vs 46.6% vs 52.7%), sex (male: 78.0% vs 80.0% vs 81.9%, female: 81.9% vs 84.1% vs 86.7%), race (White: 79.9% vs 81.6% vs 83.7%, Black: 77.2% vs 81.2% vs 84.6%, others: 84.5% vs 87.0% vs 89.3%), ethnicity (Hispanic 79.7% vs 82.3% vs 85.1%, Non-Hispanic 80.0% vs 81.9% vs 84.1%), Charlson-Deyo score (0: 83.5% vs 85.4% vs 87.9%, 1: 62.8% vs 68.2% vs 73.2%, 2: 42.5% vs 52.6% vs 58.3%, 3+: 49.0% vs 54.4% vs 51.7%), B symptoms (yes: 74.7% vs 78.9% vs 81.5%, no: 84.3% vs 85.1% vs 87.5%), treatment facility type (academic: 69.8% vs 74.0% vs 77.1%, non-academic: 66.4% vs 67.6% vs 70.2%, unknown: 92.9% vs 95.0% vs 96.5%), insurance type (private: 89.9% vs 91.2% vs 93.4%, Medicare: 46.5% vs 52.3% vs 57.2%, Medicaid: 79.1% vs 84.5% vs 87.7%) and income level (Q1: 74.1% vs 77.1% vs 81.1%, Q2 77.7% vs 80.1% vs 81.3%, Q3 79.8% vs 81.6% vs 85.2%, Q4: 82.8% vs 84.9% vs 87.0%) (all p<0.001). In multivariate Cox regression analysis adjusting for age, sex, race, ethnicity, Charlson-Deyo score, B symptoms, treatment facility type, insurance type, and income level, diagnosis in the BV era (HR = 0.856; 95% CI, 0.827–0.885; p<0.001) and ICI era (HR = 0.666; 95% CI, 0.636–0.698; p<0.001) was independently associated with improved OS compared to the Chemo era. Conclusions: In this large NCDB-based analysis, survival outcomes for patients with cHL significantly improved in the BV and ICI eras compared to the Chemo era. OS improvement was consistent across all subgroups and remained independent of age, sex, race, ethnicity, Charlson-Deyo score, B symptoms, treatment facility type, insurance type, and income level in multivariate analysis. These findings may reflect the positive impact of BV and ICIs on survival in patients with cHL.

Abstract BACKGROUND Mixed histiocytic neoplasms with overlapping features of Erdheim-Chester Disease (ECD) and Rosai-Dorfman Disease (RDD) are extremely rare and diagnosis may be delayed due to lack of awareness and complex histology features. METHODS We report a case of mixed ECD/RDD misdiagnosed as IgG4-related disease and review the literature. RESULTS A 50-year-old man presented for evaluation of spastic paraparesis in the context of a thoracic dural lesion. Two years prior he developed an inflammatory monoarthritis concerning for rheumatoid arthritis unresponsive to methotrexate. Six months prior he developed leg spasms, gait spasticity, and urinary incontinence. MRI demonstrated a T2 hypointense enhancing epidural mass with spinal cord compression. Epidural biopsy showed fibrosis and non-specific inflammation. Given elevated serum IgG4 (170 mg/dL) and clinical findings, he was diagnosed with IgG4-related disease. He received high dose prednisone and etanercept without radiographic or clinical improvement. He then presented to our institution. Given high concern for RDD, he underwent FDG-PET CT which demonstrated an infiltrative process and FDG avid regions in the upper thoracic spinal cord, paranasal sinus, renal hilum, perivascular abdominal vessels, testicle, and multiple joint effusions. Biopsy of left testicle demonstrated CD163-positive histiocytes which coexpressed S100, cyclin D1, and OCT2, consistent with RDD. Biopsy of the left shoulder synovium demonstrated an atypical CD163-positive histiocytic infiltrate expressing Factor XIIIa, cyclin D1 and S100 (partial), and appeared negative for OCT2, consistent with ECD. The atypical histiocytes in both biopsies were negative for CD1a and BRAF V600E by immunohistochemistry. Genomic sequencing of the testicular tissue demonstrated a MAP2K1 (Q56P) alteration. He was treated with radiation therapy targeting the dural lesion with temporarily worsening symptoms improved with steroids and started on cobimetinib. DISCUSSION This case expands on the phenotypic description of mixed ECD/RDD. Histiocytic neoplasms should be considered in the differential diagnosis of dural based lesions.

262 Background: According to the American Cancer Society, nearly half (47%) of cancer patients and survivors incurred medical debts to pay for cancer care, although most (98%) had health care coverage (2024 Survivor Views Survey). The financial toxicity from high cost of cancer care is itself a risk factor for cancer mortality – hazard ratio of 1.8 among those requiring bankruptcy protection (Ramsey SD, J Clin Oncol 2016). Charity care, also known as financial assistance, plays a vital role in alleviating the medical debt for low-income patients. The Affordable Care Act requires non-profit hospitals to publish charity care policies to maintain their tax-exempt status. We studied the criteria for hospital charity care among NCI-designated cancer centers in the US. Methods: We included all NCI-designated cancer centers with a clinical program as of December 1, 2024. We searched their cancer center websites for charity care eligibility policies in 2024 and obtained the following information: income limit as percentage of the federal poverty guidelines (FPG), eligibility criteria beyond income, and supporting documents required for charity care application. Cancer centers were grouped into the following regions based on US Census classification: Northeast, Midwest, South, and West. Results: We found 64 NCI-designated clinical cancer centers - all non-profit institutions. Charity care policies were readily available. The median income cutoffs for free and discounted care were 200% of the FPG (range, 100%-600%) and 400% of the FPG (range, 200%-800%), respectively. These income cutoffs were similar among the four geographic regions. Most centers (52%) allowed not only uninsured but also underinsured or insured patients experiencing hardship. A minority of the policies (13%) applied different rules for insured patients. Majority of the centers (52%) allowed financial assistance when medical bills exceed a certain hardship limit even if income cutoffs were not met. Only 3 centers (5%) required medical bills to exceed a minimum threshold for eligibility. Residency requirements included US citizenship or permanent residency (27%), state (33%), service area (14%), county (2%), not necessary (11%) or not stated (34%). Most policies (64%) mentioned investigating a patient's assets. Specific documents required for submission included income (98%), pay stub (88%), tax return (84%), asset (73%), proof of residency/citizenship (44%), and bank account (61%). Conclusions: NCI-designated cancer centers apply a relatively uniform range of financial eligibility criteria for free and discounted charity care. Approximately 1 in 4 centers require evidence of US citizenship or permanent residency while 1 in 2 centers restrict eligibility to in-state residents. Future studies into the awareness, accessibility, and utilization of charity care will provide insight into how to optimize this resource for the neediest population.