ABSTRACT:Castleman disease (CD) is a heterogeneous group of lymphoproliferative disorders anatomically classified by distribution (unicentric CD [UCD], oligocentric CD [oligoCD], or multicentric CD [MCD]). Human herpes virus 8-negative MCD is called idiopathic MCD (iMCD), which includes clinical subtypes with varying phenotypes and responses: TAFRO (thrombocytopenia, anasarca, fever, renal dysfunction and/or reticulin fibrosis, and organomegaly), IPL (idiopathic plasmacytic lymphadenopathy), and not otherwise specified. OligoCD has recently emerged as an intermediate form between UCD and MCD, with unclear clinical behavior, and IPL has not been validated in a Western cohort. We retrospectively analyzed 217 patients with CD evaluated at our institution between January 2004 and August 2024. Survival probabilities were compared using log-rank tests. Overall, 57% had UCD, 20% had oligoCD, and 23% had iMCD. Patients with oligoCD and iMCD more frequently exhibited systemic symptoms than those with UCD. Patients with oligoCD and iMCD had significantly shorter event-free survival (EFS) of 8.9 and 2.3 years, respectively, than those with UCD (not reached; P< .001 and P< .02). Among iMCD subtypes, iMCD-IPL demonstrated a longer EFS than iMCD-TAFRO (P = .02), with no deaths during the follow-up periods. The results validate oligoCD and iMCD-IPL as new subtypes in this Western cohort. The survival outcome in oligoCD was intermediate between UCD and iMCD, with only a subset of patients with oligoCD requiring systemic therapy. iMCD-IPL had a favorable survival outcome in this US cohort, similar to what has been reported in non-Western countries. Tailoring treatment strategies to disease subtypes and vigilant monitoring of oligoCD for progression may improve survival outcomes in CD.

High-dose methotrexate (HDMTX) is a key treatment for lymphoma with central nervous system involvement. Whether incorporating cystatin C into glomerular filtration rate estimation improves methotrexate (MTX) clearance prediction remains unclear. We aimed to evaluate whether cystatin C-inclusive glomerular filtration rate equations improve MTX clearance prediction and to explore the relationship between MTX exposure and acute kidney injury (AKI) in adult patients with lymphoma receiving HDMTX. This was a prospective single-center study performed on 80 adult patients with lymphoma receiving HDMTX (1.5–8 g/m2) over a 4-h infusion. A population pharmacokinetic model was constructed using data from 80 administrations of HDMTX and 427 serum MTX concentrations. The population pharmacokinetic model estimated MTX concentrations were included in a logistic regression to assess the relationship between MTX exposure and AKI. A two-compartment model best described the pharmacokinetic data, with baseline albumin and CKD-EPI creatinine-cystatin C (eGFRCr-CysC) as significant covariates on clearance. Seventeen patients (21

BACKGROUND:Although some vaccines seem to be associated with a lower risk of lymphoma, their impact on outcomes is largely unknown. METHODS:Data from a large prospective lymphoma cohort study were utilized to estimate associations of self-reported history of vaccination against hepatitis A, hepatitis B, influenza, and yellow fever with event-free survival (EFS) and overall survival (OS) using Cox proportional hazard models. RESULTS:None of the vaccines were associated with EFS [hazard ratio (HR) 0.77-1] or OS (HRs 0.96-1.04). Similarly, there were no significant associations between the vaccines and outcomes for each lymphoma subtype. CONCLUSIONS:Prior vaccination against selected viruses was not associated with EFS or OS among patients with lymphoma. IMPACT:We did not find evidence for an impact of prior vaccination on lymphoma prognosis.

BACKGROUND AND PURPOSE:4 Gy in 2 fractions has grown in use for indolent B-cell lymphomas because of its tolerance and convenience. However, local progression occurs in 30% of patients. In 2020, we introduced 8 Gy in 2 fractions with the hypothesis that this would improve control compared to 4 Gy in 2 fractions. MATERIALS AND METHODS:We conducted a retrospective review of 121 patients (137 sites) with indolent lymphoma treated with either 4 Gy or 8 Gy in two fractions between 2013 and 2024 at a single institution. Local control and complete response were primary endpoints, assessed using imaging and clinical exam. Competing-risks analysis and Cox models were applied. RESULTS:Median follow up for the overall cohort, 4 Gy cohort, and 8 Gy cohort was 2.9 years, 6.6 years, and 2.0 years respectively. Local progression occurred in 26% of sites treated with 4 Gy versus 7% with 8 Gy, and after appropriate censoring via univariate analysis, local control was superior with 8 Gy (HR 2.97, p = 0.044). Complete response at one year was also higher with 8 Gy (81%) than 4 Gy (57%) (HR 0.54, p = 0.001). On multivariable analysis, nodal sites of disease were independently associated with a higher rate of local recurrence, regardless of dose (HR 3.33, 1.13-8.86, p = 0.016). CONCLUSION:Increasing the dose from 4 to 8 Gy was associated with a higher rate of local control while maintaining the convenience of 2 fractions. Further maturation of this data and results of ongoing prospective studies are needed.

Background: A summary of pharmacist-based practices and preferences regarding the prevention and management of high-dose methotrexate (HDMTX) toxicity in patients with lymphoma does not exist. The objective of the study was to describe current practices surrounding management of HDMTX therapy. This was done through a self-administered, web-based, cross-sectional survey of hematology/oncology pharmacists to ascertain practices and individual attitudes about HDMTX therapy management. Responses were summarized with descriptive statistics. Response comparisons were made using Chi-square or Fisher's exact test for categorical data, and Kruskal-Wallis test for variables on the Likert scale. A total of 175 pharmacists provided 116 eligible surveys [68 (59%) complete responses and 48 (41%) partial responses] for analysis. The Cockcroft-Gault estimated creatinine clearance formula was the most preferred method (61%) to estimate kidney function and determine HDMTX dosing. Respondents would proceed with HDMTX therapy until the predicted risk of AKI, or AKI stage 2 or 3, exceeded 50% and 20%, respectively. Preferred treatment modifications for a high predicted AKI risk after HDMTX exposure included additional prehydration, HDMTX dose reduction, and increased kidney function monitoring, although levels and degrees of agreement varied. Respondents indicated that serum cystatin C-based GFR estimates lacked evidence, accuracy, and practicality in HDMTX therapy management. There was limited familiarity with cell cycle arrest biomarker use during HDMTX therapy. Glucarpidase was considered time-sensitive and highly effective; however, acquisition cost represented a barrier to use, and the optimal dose was felt to be unknown. In conclusion, there is significant heterogeneity in supportive practices and beliefs about the optimal management for patients with lymphoma receiving HDMTX therapy.

162 patients with relapsed secondary central nervous system lymphoma (R-SCNSL) (median age, 65 years; male, 59.9%) including central nervous system (CNS)-only (n = 120) and concomitant CNS/systemic relapse (n = 42) were retrospectively analyzed. Overall, 21.9% of patients were classified as high risk according to the CNS International Prognostic Index (CNS-IPI). Several biological and clinical features were significantly associated with leptomeningeal involvement, including double- or triple-hit (DHL/THL) status, MYC rearrangement, negative BCL6 expression by IHC, bone marrow involvement, and concomitant R-SCNSL. Multivariable analysis showed that leptomeningeal involvement independently predicted inferior OS and was associated with a 98% increase in the hazard of death compared with parenchymal relapse (HR = 1.98, 95% CI: 1.20-3.26, p = 0.008). Based on anatomical localization, R-SCNSL was classified into four subtypes: parenchymal-only involvement (parenchymal-CNS [P-CNS], 68/42%) and parenchymal involvement plus systemic relapse (parenchymal-concomitant [P-concomitant], 17/10.5%); and leptomeningeal with or without parenchymal involvement (leptomeningeal-CNS [LM-CNS], 52/32.1%) and leptomeningeal with systemic relapse (leptomeningeal-concomitant [LM-concomitant], 25/15.4%). This anatomical classification significantly impacted OS and PFS (p < 0.001). Two-year OS and PFS were 58.2% and 29.1% for P-CNS, 32.4% and 17.7% for P-concomitant, 22% and 13.9% for LM-CNS, and 7.1% and 0% for LM-concomitant, respectively. ASCT showed a trend toward improved survival among patients with a response (CR/PR) in a 4-month landmark analysis. These findings support the clinical application of the anatomical classification in the management of R-SCNSL.

Limited-stage mantle cell lymphoma (MCL) is rare, and optimal management remains undefined due to limited representation in clinical studies. We conducted a large population-based analysis using the National Cancer Database (NCDB) to evaluate overall survival (OS) in patients with Ann Arbor stage I–II MCL diagnosed between 2004 and 2015. Initial treatment was categorized to chemotherapy alone, radiotherapy (RT) alone, or combined chemotherapy plus RT (Chemo+RT), and outcomes were further stratified by stage and era of diagnosis (2004–2009 vs 2010–2015) to account for advances in systemic therapy, such as the adoption of bendamustine-rituximab for frontline therapy and the availability of Bruton tyrosine kinase inhibitors (BTKis) for relapsed disease. Among 2,428 patients included, median OS for the entire cohort was 8.1 years. Chemo+RT was associated with superior OS compared with chemotherapy alone or RT alone (median OS 11.2 vs 7.4 vs 8.0 years, respectively; P<0.001). This survival benefit was observed in both stage I and stage II disease and in both eras. On multivariable analysis, treatment with chemotherapy alone (hazard ratio [HR] 1.50) or RT alone (HR 1.33) were independently associated with inferior OS compared with Chemo+RT. In this largest real-world analysis of limited-stage MCL to date, combined chemoimmunotherapy and RT was associated with a clinically meaningful survival benefit, including in the modern treatment era. These findings suggest that combined-modality therapy may be preferred for appropriately selected patients with limited-stage MCL.

Abstract The purpose of this study was to explore epigenetic dysregulation resulting from deleterious SPEN mutations in diffuse large B cell lymphoma (DLBCL). Truncating (tr) SPEN mutations are among defining variants in LymphGen:BN2 and DLBclass:C1. We previously found SPEN mutations enriched in DLBCL that failed to reach EFS24, and inferior survival was observed in SPEN-tr vs all other BN2 and C1. Differential gene expression (DEG) in these groups identified >1000 DEGs including upregulation of IKZF3 and BCL2 and downregulation of MHC-II, overall suggesting an alternative, aggressive biology for a subset of BN2/C1 cases generally thought to have favorable outcomes. In healthy cells, SPEN is a dynamic epigenetic regulator with roles in chromatin formation and as a NOTCH co-repressor. We hypothesized that loss of SPEN reprograms the epigenetic landscape to drive the aggressive phenotype in affected DLBCL. Methods: OCI-LY3 cell line with CRISPR/Cas9-induced SPEN-tr mutations was analyzed by ATAC and RNA-seq. Diagnostic DLBCL FFPE tumor biopsies from the Molecular Epidemiology Resource (MER) were analyzed by 850k/EPIC methylation array (n=164). SPEN-depleted OCI-LY3 cells displayed significant (|Log2FC|>2) peaks of open (n=3083) and closed (n=1729) chromatin indicative of systemic epigenetic reprogramming, with enriched peaks (FDR<0.01, |Log2FC|>2) converging on pro-survival and immune evasion (ATP11C, BCL11B, RAG1/2 genes) and negatively enriched for cell cycle and apoptotic pathways (CDK6, TP63, CD80 genes). Chromatin accessibility featured enrichment for TCF3/4 and ZEB1 binding motifs and depletion of EBF1, REL, and NFKB1/2 motifs (FDR<0.0001, |Z-score|>5), suggesting a shift to an activated, post-germinal center program (via open TCF3/4 motifs) with reduced reliance on NF-kB signaling. Footprinting analysis further revealed decreased occupancy at NFKB2 and REL/B motifs, and reduced occupancy at HES1 with elevated occupancy at Rbpjl motifs (p<0.05, |Score|>0.2) indicating downregulation of NF-kB is in favor of non-canonical Notch transcription programming. Merging gene expression and accessibility, gene-peak concordance was observed for elevated CXCR4 and IL6 expression and decreased SOCS1, CD274 (PD-L1), and CCND1 expression (FDR<0.01, |Log2FC|>1), suggesting expression programs feature uncontrolled JAK/STAT signaling (via high IL6, low SOCS1) with immune evasion mechanisms independent of PD-L1. By methylation array, strong epigenetic reprogramming was observed in SPEN-tr DLBCL (n=8), where differential methylation analysis vs WT (n=146), vs BN2 (n=4), and vs C1 (n=15) samples revealed hypermethylation signatures (p<0.05, |FC|>1) indicative of reduced cell-cell signaling and antigen presentation pathways (including HLA-A/G/H). In conclusion, SPEN-depletion triggers systemic epigenetic reprogramming to enhance immune evasion and non-canonical Notch target genes. SPEN-tr DLBCL should be considered with heightened risk estimation and as prime candidates for personalized treatments beyond standard therapy. Citation Format: Janek S. Walker, Joseph P. Novak, Abigail R. Dropik, Zilin Xianyu, Michelle K. Manske, Matthew J. Maurer, Eric Mou, Rebecca L. King, Stephen M. Ansell, Thomas M. Habermann, Thomas E. Witzig, James R. Cerhan, Anne J. Novak. Deleterious SPEN mutations induce epigenetic reprogramming to promote survival and enhance immune evasion pathways in an aggressive subset of BN2/C1 DLBCL tumors [abstract]. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7(3_Suppl):Abstract nr A006.

Family history of haematological malignancy (FHHM) reflects inherited susceptibility to non-Hodgkin lymphoma (NHL), but its prognostic significance remains poorly understood. We used a cohort study of 1994 NHL patients to evaluate associations between FHHM and clinical outcomes across lymphoma subtypes. We estimated associations, adjusted for sex and lymphoma-specific prognostic index, of self-reported FHHM in a first-degree relative with overall survival (OS), event-free survival (EFS) and lymphoma-specific survival (LSS) using multivariable Cox regression models and with failure to achieve EFS at 24 months (EFS24) using logistic regression. FHHM prevalence was 12.8%, and the median follow-up among survivors was 12.0 years. FHHM was not associated with OS. In subtype-specific analyses, FHHM was associated with inferior LSS (hazard ratio [HR] = 1.98, 95% confidence interval [CI] 1.11-3.53) in follicular lymphoma (FL); this association and the association with EFS24 failure strengthened among those treated with front-line immunochemotherapy (EFS24 failure odds ratio = 2.57, 95% CI 1.08-5.99; LSS HR = 2.68, 95% CI 1.09-6.58). In mantle cell lymphoma, FHHM was associated with inferior EFS (HR = 1.70, 95% CI 1.02-2.85). Interaction testing did not demonstrate significant heterogeneity of FHHM effects by lymphoma subtype. FHHM may be associated with adverse outcomes in select NHL groups, particularly FL. These findings warrant further investigation of germline and environmental factors potentially contributing to more aggressive FLs.

Introduction: Head and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy, particularly in the recurrent or metastatic setting after progression on multimodality therapy. Activating health reimbursement arrangement (HRAS) mutations occur in approximately 4–8% of HNSCC and represent a potentially actionable target. Tipifarnib, an oral farnesyltransferase inhibitor, has demonstrated promising activity in HRAS-mutant tumors but is not commercially available despite prior Breakthrough Therapy designation. Case Report: We report the case of a 48-year-old woman with recurrent, treatment-refractory oral cavity squamous cell carcinoma who experienced a dramatic and durable response to tipifarnib. Following initial treatment, she developed rapid locoregional recurrence requiring tracheostomy. Her disease progressed through multiple lines of therapy. Comprehensive next-generation sequencing of recurrent tumor tissue revealed an HRAS mutation. Given lack of response to prior checkpoint inhibitors, compassionate use of tipifarnib was initiated. The patient experienced a near-complete response within two months and achieved a complete response by 12 months and continues to remain disease free almost two years after therapy initiation with excellent functional recovery and manageable toxicity limited primarily to neutropenia. Conclusion: This case highlights the transformative potential of precision oncology in refractory HNSCC. Broader access to HRAS-targeted therapies and prospective validation of molecular predictors are urgently needed to improve outcomes in this molecularly defined subset.

Family history of hematologic malignancy (FHHM) is an established risk factor for developing lymphoma, but studies examining associations between self-reported FHHM and lymphoma prognosis during the recent treatment era are limited. Utilizing a prospective cohort study, we evaluated associations between FHHM and prognosis for common lymphoma subtypes, including diffuse large B-cell (DLBCL), follicular (FL), marginal zone (MZL), mantle cell (MCL), Hodgkin (HL), and T-cell (TCL) lymphomas. We used the Mayo Clinic component of the Molecular Epidemiology Resource, a prospective cohort study of newly diagnosed lymphoma patients enrolled from 2002 to 2015. Self-reported FHHM (HL, NHL, leukemia, or multiple myeloma) in a first-degree relative was obtained via questionnaire. Primary outcomes were overall survival (OS) and event-free survival (EFS; time from diagnosis to disease progression, initiation of second-line therapy, or all-cause death). Secondary outcomes were failure to achieve 24 months of event-free survival (EFS24; associated with aggressive disease and poor outcomes) and lymphoma-specific survival (LSS; time from diagnosis to death from lymphoma or lymphoma treatment-related complications). We used multivariable Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of FHHM with OS, EFS, and LSS, and logistic regression to estimate odds ratios (ORs) and 95% CI for the association with failure to achieve EFS24. All models were adjusted for sex and a lymphoma subtype specific prognostic index. The cohort consisted of 650 DLBCL, 679 FL, 291 MZL, 178 MCL, 254 HL, and 196 TCL patients. The prevalence of FHHM ranged from 9.7% in TCL to 14% in FL. FHHM was not associated with OS in any subtype, but MCL patients with FHHM showed an inferior EFS (HR=1.70, 95% CI 1.02-2.85; p=0.04). For EFS24, FHHM was associated with failure to achieve EFS24 only in FL (OR=1.57, 95% CI 0.99-2.48; p=0.05). Similarly, FHHM was associated with inferior LSS in FL patients (HR=1.98, 95% CI 1.11-3.53; p=0.02). In a treatment subgroup analysis of FL patients, the FHHM associations with failure to achieve EFS24 (OR=2.48, 95% CI 1.04-5.74; p=0.04) and inferior LSS (HR=2.68, 95% CI 1.09-6.58; p=0.03) strengthened among those treated with frontline immunochemotherapy (IC). In summary, there were no evidence of associations between FHHM and OS across lymphoma subtypes, but MCL patients with FHHM displayed inferior EFS. FL patients with FHHM were more likely to not achieve EFS24 and to ultimately die of their lymphoma or a lymphoma treatment-related complication. This finding was stronger in more aggressive FL requiring frontline IC. This novel finding would suggest that genetic or environmental factors associated with FHHM may underlie pathways that impact disease aggressiveness and early clinical failure in FL. George Cholack, Raphael Mwangi, Thomas M. Habermann, Verena Hinder, Rosalie Griffen, Dennis Robinson, Andrew L. Feldman, Thomas E. Witzig, Stephen M. Ansell, Brian K. Link, Yucai Wang, Carrie A. Thompson, Susan L. Slager, Matthew Maurer, Anne J. Novak, James R. Cerhan. Family history of hematologic malignancy and prognosis across lymphoma subtypes: Novel association with poor outcomes in follicular lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7344.

Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma with poor outcomes using standard chemotherapy. In this multi-institutional retrospective study, we analyzed 39 cases of ALK+ LBCL identified at six US academic centers from 2002 to 2024, with treatment including conventional cytotoxic regimens in frontline and biologically informed and nonchemotherapy-based strategies in the relapsed setting. Ninety-two percent of patients received frontline anthracycline-based chemotherapy; 43% received intensified regimens, and 15% underwent upfront autologous stem cell transplantation (ASCT). Despite these approaches, outcomes remained poor. At a median follow-up of 5.4 years, median event-free survival (EFS) was 0.6 years (95% CI, 0.4-0.9), and median overall survival (OS) was 1.5 years (95% CI, 1.3-NR). One- and five-year EFS rates were 28% and 17%, while corresponding OS rates were 72% and 42%, respectively. Advanced stage and high IPI scores were associated with inferior outcomes. Twelve patients received ALK inhibitors, with alectinib showing more durable responses than crizotinib. Lenalidomide and immune checkpoint inhibitors also demonstrated activity, including durable complete responses. Five patients underwent allogeneic stem cell transplantation, with three achieving sustained remission. In conclusion, our findings highlight the limited benefit of chemotherapy, even when intensified or followed by ASCT, and support the integration of biologically targeted therapies, which may have contributed to improved OS in our cohort compared to historical outcomes. Prospective, collaborative studies are needed to better understand disease biology and define optimal use of modern therapies in this rare lymphoma.

ABSTRACT:Although follicular lymphoma (FL) typically follows an indolent course, patients with FL who experience early events, such as transformation or progression, have increased risk of death related to lymphoma. The FL24Cx is an algorithm based on a 45-target gene expression profiling (GEP) assay, which was developed and trained using 265 formalin-fixed, paraffin-embedded tissue samples on a reliable platform to predict, at the time of diagnosis, whether a patient will experience an event within 24 months. The modeling also confirmed and relied upon previously reported synergy between immune response (IR) gene expression signatures IR1 and IR2. Once locked, the 5-factor logistic regression FL24Cx model was independently validated in a retrospectively assessed cohort of 232 patients from 2 immunochemotherapy-treated arms of SWOG Cancer Research Network S0016 phase 3 clinical trial, in which it assigned 169 patients to the low-risk group with 29 events before 24 months (17.2%) and 63 patients to the high-risk group with 24 events before 24 months (38.1%). The relative risk of an event within 24 months after registration among patients who were classified into the high-risk group relative to patients who were classified into the low-risk group was 2.2 (95% confidence interval, 1.41 to 3.51). An up-front GEP biomarker, such as the FL24Cx, rigorously validated in a clinical laboratory and with a clinically relevant turnaround time, could identify and steer enrollment of patients at high risk for early events in clinical trials, thus enabling timely interpretation of such trials and increasing the pace of innovation.

Intensified chemoimmunotherapy regimens are often used in young patients with double-hit and triple-hit lymphoma (DHL/ THL) despite no survival benefit compared to R-CHOP. Favorable retrospective reports on the application of CODOX-M/IVAC-R are subject to selection bias as only young fit patients can tolerate this treatment. We conducted a retrospective analysis to investigate outcome differences between CODOX-M/IVAC-R and DA-EPOCH-R in DHL/THL patients aged 60 years or younger. One hundred and thirteen patients were identified; CODOX-M/IVAC-R (N=49) and DA-EPOCH-R (N=64). Eighty percent (39/49) achieved complete (CR) after completing CODOX-M/IVAC-R compared to 58% (37/64) with DA-EPOCH-R. The median follow-up was 5.3 years and 3.3 years for the CODOX-M/IVAC-R and DA-EPOCH-R group respectively. CODOX-M/IVAC-R demonstrated superior event-free survival (EFS) on univariate (hazard ratio [HR]=0.54, 95% confidence interval [CI]: 0.31-0.97) and multivariable analysis adjusted for age, BCL translocation (BCL2 vs. BCL6 vs. both), International Prognostic Index score and receipt of autologous stem cell transplant (adjusted HR [aHR]=0.52, 95% CI: 0.29-0.93); however there was no significant influence on OS (aHR=0.92, 95% CI: 0.46-1.84). The 1, 2 and 5 years EFS in the CODOX-M/IVAC-R group was 68.3%, 64.1% and 61.5%, respectively compared to 52.4%, 48.9% and 39.5%, respectively in the DA-EPOCH-R group. Primary refractory disease or relapse (R/R) occurred in 33% (16/49) of CODOX-M/IVAC-R and 54% (35/64) of DA-EPOCH-R recipients, and produced median OS of 10.3 months and 33.7 months, respectively, indicating poor outcomes in the CODOX-M/IVAC-R subgroup with R/R disease. More patients were able to receive subsequent salvage therapies in the DA-EPOCH-R group. No patients died of regimen toxicity and the rates of central nervous system relapse and therapy related hematologic neoplasms were similar in both groups.

7075 Background: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, aggressive peripheral T-cell lymphoma arising primarily from γδ T-cells. It carries a poor prognosis and resists conventional chemotherapy. Most reports on HSTCL are case-based. This study comprehensively analyzes a large cohort, evaluating treatment strategies and survival outcomes. Methods: This retrospective study included patients (pts) with pathologically confirmed HSTCL diagnosed between 2000-2024, consecutively seen at Mayo Clinic MN. Clinical, pathological, genomic, and treatment-related data were extracted when available. Descriptive statistics were used to summarize baseline characteristics. Time-to-event analyses, including Kaplan-Meier estimates, median overall survival (OS), and survival time estimates were conducted from the date of diagnosis. Results: A total of 20 patients with newly diagnosed HSTCL were included, with a median age of 57 years (range: 35-71). The cohort was predominantly male (70%) and non-Hispanic (93%). Molecular data was available for five patients, revealing abnormalities in STAT5B, MLL3 deletion, TP53, EZH2, TERT, and NF1 E291D . The median follow-up was 27.6 months (m) with a median OS of 17.6 m (95% CI: 11.2 - NA). First-line treatment was anthracycline-based in 68% of pts and non-anthracycline-based in 32%, with higher response rates in the latter group (50% vs.83%). Although non-anthracycline regimens showed a trend toward improved 3-year OS (100% vs. 29%) the difference was not statistically significant (p = 0.16). Achieving a complete response to first-line therapy was also associated with a trend towards a better 3-year OS compared to refractory disease (80% vs. 50%, p = 0.17). Most pts (79%) underwent hematopoietic stem cell transplant (HSCT), primarily allogeneic, with only one receiving autologous HSCT. First-line therapy before HSCT was evenly distributed between anthracycline (55%) and non-anthracycline (45%) regimens. HSCT recipients had significantly higher 3-year OS than non-recipients (83% vs. 33%, p = 0.017). Notably, the patient with a TP53 mutation has remained in remission for over a year post-allogeneic HSCT. Conclusions: HSTCL predominantly affects younger pts, with nearly half dying within a year. Allogeneic HSCT, rarely used in other NHL subtypes, improved survival. Non-anthracycline regimens and achieving CR trended toward better outcomes. Our study, leveraging a sizable cohort, highlights the need for targeted research and novel therapies to improve HSTCL management. Summary of survival outcomes in HSTCL. Characteristics Median OS (y) 3-Year OS (95% CI) 1.48 [0.93- NA] 46% [0.26 - 0.81] Transplant Transplant NA [NA - NA] 83% [0.58 - 1.00] No Transplant 1.02 [0.93 - NA] 33% [0.07 - 1.00] Treatment Anthracycline Based 1.02 [0.36 - NA] 29% [0.11 - 0.73] Non-Anthracycline Based 4.61 [NA- NA] 100% [1.00 - 1.00]

Parameters detected by positron emission tomography (PET) are not included in the usual predictive indices for follicular lymphoma (FL). Data are lacking regarding PET extranodal (EN) factors that predict outcomes in FL. PET scans from 258 patients with untreated grade 1 to 3A FL included in the E2408 randomized phase 2 trial were reviewed. Validation of the prognostic significance of PET factors identified in a previous retrospective study was performed. PET factors with a significant impact on survival outcomes were combined with significant FL International Prognostic Index 2 (FLIPI-2) factors to evaluate the predictive value of a PET-based prognostic index. Presence of ≥2 EN sites and skin/soft tissue involvement on PET were validated as predictors of overall survival. These factors were combined with all FLIPI-2 factors except "positive bone marrow biopsy" to form a PET-based prognostic score. This novel score identified a group of patients at high risk of progression of disease at 24 months. This PET-based score did not perform better than the traditional FLIPI-2 on additional analysis. Presence of ≥2 EN sites and skin/soft tissue involvement on PET predict poor outcomes in untreated FL. Further studies should be performed to determine the validity of a PET-based prognostic index in FL.