Habermann, Thomas M.

Background: Splenic marginal zone lymphoma (SMZL) is a rare indolent disease with a median overall survival (OS) of more than 10 years, although a proportion of patients may develop aggressive histology transformation. In a previous report from this large, international dataset, the 10-year cumulative incidence of transformation was 17% (95% 13-21) and in another study of 186 patients, the 10-year cumulative incidence was 14%Click or tap here to enter text.. In this report, we focus on risk factors for transformation as well as clinical characteristics and outcomes of transformed SMZL (tSMZL). Patients and methods: Adults diagnosed with SMZL in 2000-2018 were identified through regional or nationwide population-based registries or from hospital registries. Only patients likely to have SMZL as defined by Matutes et al. were included. Those with discordant lymphoma and/or transformation at diagnosis were excluded. Medical records were reviewed by local clinicians with experience in hematology/oncology, and detailed information on clinical characteristics, treatment lines, and outcomes was collected. Only histologically confirmed high-grade transformations (HT) were included. OS was defined as the time from transformation to death or censoring at last follow-up. Additional analyses stratified by treatment exposure prior to HT and treatment of HT were conducted. Multivariable Cox analyses were performed to determine clinicopathological features associated with transformation and OS. Results: Out of 940 patients with SMZL, 111 developed HT during a median follow-up of 9.1 years. The median time from diagnosis to HT was 3.4 years with an interquartile range of 1.6-7.4 years. Median age at HT was 71 years. Patients with HT shared similar baseline characteristics to those without in terms of age at diagnosis (66.4 vs 67.6), f:m ratio (1.5 vs 1.1) and ECOG ³2 (7.2% vs 7.4%). The 5-yr OS from the time of HT was 42% (CI 95%, 32-54). Of the 111 patients with tSMZL, a complete treatment history from SMZL diagnosis until HT was available for 88 included in the following analyses. By the time of HT, 46 had not received any prior systemic therapy (37 only splenectomy, 9 no therapy), 6 patients had received rituximab alone or combined with splenectomy, and 36 patients had received chemotherapy alone or as part of combined modality treatment. In a uni- and multivariable models for HT, we assessed age, treatment at diagnosis, sex, extra-hilar lymphadenopathy, and extranodal involvement. In both the uni- and multivariable model, age >70 (HR 1.9, 95% CI: 1.1-3.4), immediate treatment including splenectomy (HR 2.0, 95% CI: 1.05-3.6), and extra-hilar lymphadenopathy (HR 1.9, 95% CI: 1.1-3.3) were associated with higher HT hazard, while extranodal involvement (HR 0.23, 95% CI: 0.06-0.84) was associated with a lower HT hazard. At the time of first-line treatment, multivariable analysis revealed similar results and with no association between risk of transformation and treatment strategy (i.e splenectomy alone, rituximab monotherapy or chemotherapy with /without rituximab or splenectomy, and other). At the time of HT, patients who had been previously treated with chemotherapy had an inferior 5-year OS of 24% (95%CI: 13-44%) versus 54% (95%CI: 41-71%) for those who had not received chemotherapy prior to HT. In contrast, there was no difference in the survival of patients that transformed less than or more than 24 months from diagnosis with 5-year OS after HT of 35% (95%CI 20-60%) and 45% (95%CI, 33-61%) respectively. In a multivariable Cox regression analyses of age at time of HT, sex, time since last treatment <24 months, chemo-exposure in previous treatment lines and anthracycline-containing therapy (+/-R) at the time of HT, only prior chemo-exposure was borderline associated with poorer OS (HR 1.8, 95%CI: 0.9-3.5). Conclusion: Patients with SMZL face a notable risk of developing tSMZL over time. Patients in need of immediate treatment at first SMZL diagnosis, age >70 and extrahilar lymphadenopathy had a higher risk of tSMZL and outcomes at the time of HT were poor if patients had been exposed to prior chemotherapy after adjustment for age, sex, and time since last treatment.

Introduction: Outcomes from multidisciplinary lymphoma tumor boards in the molecular era are limited, and the effects of transitioning to virtual formats during the COVID-19 pandemic are not well-documented. This study evaluates how the transition of the Mayo Clinic Lymphoma Tumor Board to a virtual format has impacted its effectiveness and operations. The board, part of the International Mayo Clinic Care Network (MCCN), involves case presentations, subspecialist reviews, and collaborative recommendations. Methods: The Mayo Clinic Lymphoma Tumor Board, an integral part of the Mayo Clinic Care Network (MCCN), conducted a comprehensive review of lymphoma cases from 2014 to 2024. The board's review process involves a structured approach including the presentation of clinical case details, radiology and hematopathology findings, proposed treatment options, relevant literature review, and discussions. From 2014 to 2024, the Mayo Clinic Lymphoma Tumor Board reviewed a total of 722 patients. The review process involves a multidisciplinary team, including physicians, pharmacists, clinical research associates, and trainees. Recommendations and changes related to radiology interpretation, pathologic diagnosis, and treatment approaches were documented and tracked prospectively. In March 2020, the board transitioned to a virtual format due to the COVID-19 pandemic. This shift allowed for remote participation and continued collaborative review while maintaining the board's structured approach and documentation practices. Results: In a total of 722 patients, changes in care were identified in 423 patients, including 287 with newly diagnosed lymphoma and 136 with relapse or refractory disease. Among those who experienced changes, 94 had diffuse large B-cell lymphoma, 49 had follicular lymphoma, 39 had marginal zone lymphoma, 36 had classical Hodgkin lymphoma, and 29 had mantle cell lymphoma. Prior to the COVID-19 pandemic, 431 patients were analyzed, with 217 (50.3%) experiencing changes. A total of 268 changes were documented among these patients. Changes in radiologic interpretation occurred in 9 patients (2.1% of 431 total patients). Pathologic diagnosis changes were noted in 42 patients (9.7%). Additional testing was recommended for 73 patients (16.9%), and clinical management was altered for 144 patients (33.4%). After transitioning to a virtual format, 291 patients were reviewed post-COVID, with 206 (70.8%) having recommended changes. The total number of change recommendations was 322, reflecting increases across all components compared to previous data, with adjustments for varying numbers of patients reviewed. Specifically, radiologic interpretation changes occurred in 21 patients (7.2%), pathologic diagnosis changes in 57 patients (19.6%), additional testing recommendations for 85 patients (29.2%), and clinical management alterations in 159 patients (54.7%). Conclusion: Transitioning to a virtual format in the Mayo Clinic Lymphoma Tumor Board's continued to demonstrate the effectiveness, with increased changes in diagnostic interpretations and clinical management. These results illustrate the potential of virtual tumor boards to improve collaborative decision-making and adapt to evolving clinical needs.

Background: Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is a commonly utilized chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), especially for patients ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor T cell therapy (CAR T). R-GemOx is used as a comparator arm in several active phase III clinical trials for R/R DLBCL, including the POLARGO (polatuzumab vedotion and R-GemOx), STARGLO (glofitamab and GemOx), SUNMO (mosunetuzumab and polatuzumab vedotin), LOTIS-5 (loncastuximab tesirine and rituximab), and EPCORE DLBCL-1 (epcoritamab) studies. However, real-world data are limited to understand the patterns of use and outcomes of R-GemOx in the US. Methods: We developed a retrospective multicenter US cohort (known as LEO CReWE) of patients with R/R DLBCL and other aggressive B-cell lymphomas at the eight US academic centers participating in the LEO Cohort Study (NCT02736357). Patients first diagnosed with DLBCL (including transformed and high-grade B-cell lymphoma) from 2007 - 2022 who received second line (2L) or later therapy for R/R DLBCL with R-GemOx were included. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Index line of therapy was defined as the first receipt of R-GemOx therapy in the 2L or later setting. Intent for CAR T and/or ASCT was evaluated at each line of therapy based on medical records at the time of treatment initiation. Subgroup analyses were pre-planned in groups of special interest, including those treated with R-GemOx without intent for ASCT or CAR T, those treated as a bridge to CAR T, and those aged 70 and older. Results: 183 patients with R/R DLBCL treated with R-GemOx were included. At time of initiation of R-GemOx, median age was 68 years (range 21-88), with 71 patients (39%) aged 70+ and 18 (10%) aged 80+. Many patients had high risk features including 13% with high grade B-cell lymphoma and 56% with IPI 3 or greater. 21% had an ECOG performance status of 2 or greater. Patients received a median of 2 lines of therapy prior to the index line of R-GemOx (range 1-7). 52% of patients did not achieve a complete response (CR) to first-line therapy, and 20% relapsed <12 months from an initial CR. In all patients receiving R-GemOx, the overall response rate (ORR) was 45% (29% CR). At a median follow-up of 39 months, median EFS was 2.3 months (95% CI: 1.8-3.2), with 12-month EFS of 21% and a 24-month EFS of 15%. Median OS was 13.5 months (95% CI: 9.6-18.1), with a 12-month OS of 52% and a 24-month OS of 38%. In patients treated without intent for ASCT or CAR T, ORR was 33% (18% CR). Median EFS was 2.0 months (95% CI: 1.6-2.5) with 12- and 24-month EFS of 14% and 9%, respectively. Median OS was 9.5 months (95% CI: 6.6-16.1) with 12- and 24-month OS of 45% and 29%, respectively. In patients receiving R-GemOx as bridging to ASCT or CAR T, ORR was 57% (35% CR). 35% received CAR T and 14% received ASCT, while the remainder did not receive the intended therapy as part of this line. Median EFS was 3.6 months (95% CI: 1.8-5.2) with 12- and 24-month EFS of 28% and 25%, respectively. Median OS was 17.4 months (95% CI: 13.4-NR); 12- and 24-month OS were 61% and 50%, respectively. In patients aged 70+, ORR was 53% (33% CR). Median EFS was 2.3 months (95% CI: 1.6-5.2), with 12- and 24-month EFS of 20% and 18%, respectively. Median OS was 13.9 months (95% CI: 8.6-30.2); 12- and 24-month OS were 57% and 39%, respectively. Conclusion: This study represents the largest reported cohort of patients treated with R-GemOx in US academic centers to date. The ORR of 45% and CR rate of 29% CR, as well as median EFS and OS of 2.3 and 13.5 months, respectively, are consistent with findings from previous phase II studies; these results highlight that responses to R-GemOx are not durable and the vast majority of patients require additional therapy. This study demonstrates real-world evidence of the efficacy of R-GemOx in a large cohort of patients with R/R DLBCL from the US over a long period, including both transplant-eligible and -ineligible patients, and patients treated in the CAR T era. These data aid in providing a benchmark for active clinical trials in the rapidly evolving landscape of R/R DLBCL therapies and allow potential comparison to a real-world cohort of patients with a broad range of clinical characteristics.

Introduction: Hyaline-vascular type unicentric Castleman disease (HV-UCD) is a classic variant of Castleman disease, characterized by localized lymph node hyperplasia. Due to its rarity, there have been few systematic reports summarizing its clinicopathological features globally. Also, its pathogenesis remains unelucidated. The present study aims to provide a detailed clinicopathological and transcriptomic analysis of HV-UCD to enhance the understanding of its underlying mechanisms at a molecular level. Methods: We conducted a clinicopathological analysis of 51 HV-UCD cases and performed whole transcriptome analysis on frozen lymph node specimens from four cases. Differentially expressed genes (DEGs) and Gene Ontology (GO) analyses were performed to identify significant pathways and biological processes involved in HV-UCD, with reactive lymphoid hyperplasia as control. Results: The mean age of HV-UCD patients was 42.8 years, with no significant gender differences. The most common sites involved were the abdominal cavity (n = 18, 35.3%), mediastinum (n = 11, 21.6%), and retroperitoneum (n = 9, 17.6%), with an average size of the lesions being 4.8 cm. Histologically, 33.3% of cases exhibited “dysplastic follicular dendritic cells (dFDCs)” characterized by multinucleation or large nuclei within and outside follicles, positive for follicular dendritic cells (FDC) markers. DEGs analysis compared to reactive lymphoid hyperplasia revealed significant upregulation of genes related to FDCs and angiogenesis. Notably, the placental growth factor (PGF), a proangiogenic factor and a member of the VEGF family, demonstrated significant overexpression. GO analysis identified significant enrichment of genes involved in angiogenesis, cell adhesion, tissue architecture, and humoral immunity. Discussion: This large cohort of HV-UCD cohort provides potentially novel clinicopathological insights. Gene expression analysis demonstrated increased expression of FDC-related genes, suggesting a pivotal role of FDCs in HV-UCD pathogenesis. The differences in the gene profiles related to angiogenesis may contribute to the distinct mechanisms and histological features of HV-UCD and iMCD-TAFRO, where HV-UCD is associated with hyalinization of vascular walls and iMCD-TAFRO is characterized by angiogenesis with endothelial cell swelling. Conclusion: The present results suggest the crucial role of FDCs in HV-UCD pathogenesis from the molecular features. Currently, there are no objective diagnostic markers for HV-UCD. Identifying these markers may lead to a clearer understanding of the disease pathophysiology and improve diagnostic accuracy for HV-UCD. Further investigation is warranted to verify the findings.

Introduction: Patients with non-Hodgkin Lymphoma (NHL), especially adolescents and young adults, can face late effects from treatment, including decreased fertility. Due to time constraints prior to treatment initiation and sometimes financial limitations, implementing fertility counseling and referral-based guideline care remains challenging. We aim to understand the occurrence and predictors of fertility counseling and preservation in patients with NHL in the Lymphoma Epidemiology of Outcomes (LEO) cohort study. Methods: The LEO cohort prospectively enrolled newly diagnosed patients with NHL from 2015-2020 at 8 academic medical centers in the US. Clinical. Treatment data were abstracted from medical records, pathology was reviewed and classified by a LEO pathologist, and participants completed a self-administered questionnaire. Participants were then prospectively followed to identify outcomes and collect additional patient reported data, including a survivorship questionnaire at follow-up 3 years (FU3) after diagnosis that included items on fertility counseling and preservation. The questionnaire contained two fertility questions analyzed: whether healthcare providers discussed the impact of lymphoma treatment on fertility, and whether providers discussed the process of fertility preservation. This analysis was based on participants aged 18-50 years at enrollment and who completed the fertility questions at FU3. Women who had undergone natural or procedural menopause and men who had undergone vasectomy pre-treatment were excluded. We estimated the association of demographic and clinical factors with fertility preservation using odds ratios (ORs) and 95% confidence intervals (CI) from univariate and multivariable logistic regression models. Results: Seventy-seven patients were included in the analysis: 36 females (46%) and 41 males (53%). The median age of diagnosis was 40 years (IQR 30-45), and 36 (47%) participants were in the age 18-39-year category. Participant self-identified race/ethnicity was 69% non-Hispanic White, 22% Hispanic, 4% Black and 3% Asian. Sixty (78%) patients were treated with alkylators, 12 (15.6%) with non-alkylators, and 5 (6.5%) with radiation. Fifty-five (71%) of the patients were classified as having aggressive lymphoma, with follicular, extranodal marginal zone, primary cutaneous follicle center, and nodal marginal zone B-cell lymphoma defined as indolent and remaining subtypes aggressive. Around 6% of female patients underwent fertility preservation after lymphoma diagnosis, compared to 12.2% of male patients. All the patients who had undergone fertility preservation after lymphoma diagnosis were in the 18-39-year age group. On univariate analysis, females were more likely to have undergone fertility toxicity and preservation discussions compared to males, with 72% of females and 59% of males recalling a discussion regarding fertility (OR 1.8, 95% CI 0.7-4.9, p=0.21). Those age 18-39 were significantly more likely to have undergone fertility discussion compared to those aged 40-50 (OR 10.2, 95% CI 3.3-39.2, p<0.001). Patients treated with alkylating therapy were significantly more likely to undergo fertility discussion when compared to those on non-alkylating therapy (OR 9.0, 95% CI 2.3-45.5, p<0.01). In addition, 75% of those with aggressive lymphoma compared to 41% of patients with indolent lymphoma had fertility discussion (OR 4.2, 95% CI 1.5-12.4, p=0.01). White patients were significantly less likely than Hispanic, Black and Asian patients to have fertility discussion (OR 0.2, 95% CI 0.04-0.6, p<0.01). In the multivariable analysis, alkylating therapy (OR 8.9, 95% CI 1.6-66.7) and age 18-39 years (OR 10.9, 95% CI 2.9-55.3) remained significant predictors of fertility discussion; White race was also trending towards significance (OR 0.2, 95% CI 0.04-1.0, p=0.08). Aggressive lymphoma subtype was not a significant predictor of fertility discussion. Conclusions: In this cohort of lymphoma survivors 3 years post-diagnosis, we found that Hispanic patients, those diagnosed at a younger age and exposed to alkylating chemotherapy agents were significantly more likely to undergo discussions regarding the effects of lymphoma treatment on fertility. Our study highlights the importance of all cancer patients of childbearing age having the opportunity to address fertility concerns during clinic visits.

Background: The Optimized Hemophagocytic Lymphohistiocytosis (HLH) Inflammatory (OHI, Zoref-Lorenz et al, Blood, 2022) index, defined by the combined elevation in serum soluble CD25 (sCD25) and ferritin, has emerged as a promising prognostic tool for patients with newly diagnosed hematologic malignancies, demonstrating superior performance in predicting 500-day mortality compared to HLH-2004 criteria. However, previous studies were retrospective, with a substantial proportion (65%) of patients suspected clinically to have HLH. We evaluated the performance of the OHI index in an unselected, prospective cohort of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. Methods: We analyzed the predictive utility of the OHI index in 331 newly diagnosed DLBCL patients enrolled from 2002-2015 in the prospective Iowa/Mayo Molecular Epidemiology Resource cohort. Ferritin and sCD25 levels were quantified in pre-treatment serum samples using R&D ELISA kits. OHI values were also optimized based on 500-day mortality in the cohort using receiver operating curve analysis with internal validation. Patients were classified as OHI+ using the original and newly optimized thresholds for sCD25 and ferritin. The primary endpoint was 500-day survival, and the secondary endpoints were event-free survival (EFS) at 24 months (EFS24), EFS, and overall survival (OS). The predictive capability of the OHI index was evaluated using logistic regression to determine odds ratios (OR) and 95% confidence intervals (CI) for 500-day mortality and EFS24, as well as Cox regression to calculate hazard ratios (HR) and 95% CIs for EFS and OS. Results: The median age at diagnosis of the 331 patients was 63.5 years (interquartile range, 54.5-74), and 168 (51%) were male. Using the original thresholds (sCD25 3,900 U/mL and ferritin 1,000 ng/mL), 4.2% of patients were OHI+, with a more than 5-fold higher 500-day mortality risk compared to OHI- patients (OR=5.6; CI 1.6-17, p<0.001). After optimizing thresholds for sCD25 (2,400 U/mL) and ferritin (250 ng/mL) to predict 500-day mortality, 23.6% were OHI+ and the OHI+ group had a 9-fold higher 500-day mortality risk (OR=9.2; CI 4.0-24, p<0.001), with 31% mortality in the OHI+ vs 5% in the OHI- group. OHI+ patients exhibited more B-symptoms (35% vs 20%, p=0.027), elevated LDH levels (76% vs 34%, p<0.001), poorer performance status (Eastern Cooperative Oncology Group 2+: 38% vs 12%, p<0.001), and more advanced stage disease (Stage IV: 57% vs 38%, p<0.001), although the frequency of a high International Prognostic Index (IPI) was not statistically different between the groups (IPI 3-5: 44% vs 36%, p=0.28). After adjusting for age and IPI, OHI+ remained a strong predictor of 500-day mortality (OR=5.0; CI 1.9-13, p=0.001). Further adjustment for the cell of origin did not impact the results. The association of OHI+ status with 500-day mortality was similar in IPI 0-2 (OR=5.8; CI 1.2-29, p=0.033) and 3-5 (OR=6.8; CI 0.6-73, p=0.11). OHI+ patients were also more likely to not achieve EFS24 (45% vs 13%), with a 3-fold greater risk after adjusting for age and IPI (OR=3.2; CI 1.5-6.5, p=0.0018). The OHI index also retained its predictive ability over longer-term follow-up (median 9.8 years for living patients) for both OS (HR=2.0; CI 1.0-4.0, p=0.040) and EFS (HR=2.2; CI 1.1-4.3, p=0.030) after adjusting for age and IPI. Cytokine profiling using multiplex ELISA identified elevated inflammatory markers in OHI+ patients, underscoring the role of systemic inflammation in prognosis. The distribution of cytokines was significantly different between the groups, with consistently higher means in the OHI+ vs OHI- group, including IL1a (1,628 vs 759 pg/ml, p=0.008), CCL2 (1,020 vs 724 pg/ml, p=0.028), CXCL10 (165 vs 53 pg/ml, p<0.0001), and CXCL9 (380 vs 150 pg/ml, p<0.0001). Conclusions: While the original OHI index for prediction of 500-day mortality was validated in this unselected cohort of newly diagnosed DLBCL patients, optimization of the OHI thresholds identified a larger OHI+ group (24%), enhanced the identification of hyperinflammation, improved predictive ability for early (500-day) mortality, and predicted EFS24 status and long-term OS. This underscores the clinical relevance of the OHI index, supports the need to evaluate disease-specific thresholds, and suggests its potential for use in routine management and as enrollment criteria in clinical trials for novel therapies.

Background: Indolent non-Hodgkin lymphomas (iNHL) are incurable and disproportionately affect adults age >65 in whom frailty and functional impairment can impact disease management. The Vulnerable Elders Survey (VES-13) is a 13-item screening tool that incorporates age, self-rated health, physical function limitations, and functional disabilities to identify vulnerable older community-dwelling adults. Adults with a VES-13 score of >3 have a fourfold increased risk of death or functional decline over 2 years as compared to adults with a score <3 (Saliba et al, JAGS 2001). Our team previously showed that VES-13 >3 was associated with a higher risk of 1-year mortality in NHL (OR 3.26, 95% CI 2.15-4.96, Fama et al, ASH 2019), including in adults age <65. In this study, we determined whether VES-13 scores >3 were associated with quality of life (QOL) changes in adults with iNHL across the age spectrum. Methods: We used the Lymphoma Epidemiology of Outcomes (LEO) Cohort Study to identify adults enrolled from 2015-2020 with grade 1-3A follicular and marginal zone lymphoma (FL, MZL) who completed the VES-13 at enrollment and QOL surveys at enrollment and follow-up. The LEO Cohort Study enrolls participants within 6 months of diagnosis and collects information on disease status, QOL, health behaviors, and patient-reported functional assessment. For this analysis we included QOL measured using the Functional Assessment of Cancer Therapy-General (FACT-G) at years 1 and 2 post-enrollment. The FACT-G total score was the sum of 4 subscales (range): physical (PWB, 0-28), social/family (SFWB, 0-28), emotional (EWB, 0-24), and functional (FWB, 0-28) well-being. A higher FACT-G total score (range 0-108) indicated better overall QOL. VES-13 scores ranged from 0 (lowest risk for death or decline) to 10+ (highest risk). Generalized linear mixed models evaluated changes in QOL from baseline based on VES-13 score >3 (vulnerable) vs <3 (non-vulnerable), within groups by age at enrollment >65 and <65. Results: Our study included 1,186 participants: 42% age >65, 54% female, 84% non-Hispanic White, 10% Hispanic, 3.3% Black, and 1.4% Asian/Pacific Islander. Most (68%) were diagnosed with FL. FLIPI was high risk for 20%, and MALT-IPI was high risk for 23%. In the VES-13 <3 group, the mean (SD) baseline FACT-G total score was 86.5 (12.0), PWB 21.0 (3.5), SFWB 24.3 (4.3), EWB 18.8 (3.7), and FWB 22.3 (4.9). In the VES-13 >3 group, the mean (SD) baseline FACT-G total score was 70.4 (16.5), PWB 15.4 (5.6), SFWB 22.3 (5.5), EWB 17.5 (4.5), and FWB 15.3 (6.4); all significantly lower than the VES-13 >3 group (all p<0.01). In adults <65, 63 (9%) had a VES-13 >3, which was associated with a significant improvement from baseline in PWB at years 1 and 2 when compared to VES-13 <3 (changes in baseline PWB were 2.1, 2.9 for VES-13 >3 vs 0.2, 0.1 for VES-13 <3, all p<0.05). Similarly, we observed improvement in FWB from baseline at years 1 and 2 in the VES-13 >3 vs <3 group (2.4, 2.9 vs 0.4, -0.1, respectively all p<0.05). The VES-13 >3 group had a decline in their EWB at 1 year vs the VES <3 group (-0.5 vs 1.2, respectively, p=0.003). At year 2, total FACT-G improved from baseline in the VES-13 >3 group (5.6 for VES-13 >3 vs -0.5 for VES-13 <3, p=0.002). SFWB changes from baseline did not differ between groups. In adults >65, 83 (17%) had a VES-13 >3, which was associated with a significant improvement from baseline PWB (1.3, 1.5 for VES-13 >3 vs. 0.1, -0.1 for VES-13 <3), FWB (3.3, 2.2 for VES-13 >3 vs. 0.5, 0.1 for VES-13 <3), and total FACT-G score (5.2, 3.4 for VES-13 >3 vs. 1.0, -0.4 for VES-13 <3) when compared to VES-13 <3 at years 1 and 2 (all p<0.05). SFWB and EWB changes from baseline did not differ between groups. While there was improvement from baseline PWB and FWB in the VES-13 >3 group, QOL scores across all subscales remained below the VES-13 <3 group in the study period for both age groups. Statistical significance was maintained in models adjusted for baseline characteristics, including initial treatment strategy (observation, systemic, vs local) for both age groups. Conclusion: Although the vulnerable group reported worse QOL throughout the study period compared to the non-vulnerable group, survivors in the vulnerable group saw greater improvement in their physical and functional well-being at 1- and 2-years post-diagnosis. Additional analyses are underway to identify drivers of improvement in physical and functional well-being in vulnerable adults diagnosed with iNHL.

Background Advancements in imaging techniques, diagnostic procedures, and increased routine health care visits are anticipated to lead to a higher number of patients with an incidental diagnosis of cancer, including the most common lymphoma DLBCL. In parallel, multiple cancer early detection (MCED) blood assays are emerging to screen for cancer in asymptomatic, average risk individuals. Assays that use methylated DNA markers (MDM) are of special interest and have been shown to detect evidence of DLBCL in the blood in 80% of DLBCL cases (Witzig TE et al ASCO 2022). While these MDMs are candidates for inclusion in MCED assays, the impact of early detection of lymphoma in general and DLBCL specifically remains controversial. Since the outcomes for patients with an incidental diagnosis of DLBCL have not been previously studied and to give further insight to the early detection question, we investigated clinical characteristics and outcome differences between patients with DLBCL found incidentally and those with symptoms or obvious signs of disease that led them to seek medical evaluation. Methods We conducted a retrospective analysis of newly diagnosed DLBCL patients enrolled into the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence from 2002-2015. We reviewed the medical records of the Mayo component to assign a mode of diagnosis (incidental vs symptomatic). We examined disease characteristics and impact on event-free survival (EFS) and overall (OS) survival according to the mode of diagnosis. EFS was the time from diagnosis to relapse, progression, retreatment, or death from any cause. OS was defined as the time from diagnosis to death from any cause. Results 1140 patients with DLBCL (90.6%), high grade B cell lymphoma (2.4%) or primary mediastinal B cell lymphoma (7.0%) were reviewed; 85 (7.5%) patients presented incidentally (incidental group), while 1055 (92.5%) presented with a lymphoma-related symptom or sign, e.g., palpation of a lump/mass, B symptoms and/or other symptoms caused by the lymphoma such as abdominal pain (symptomatic group). In the incidental group, 67.5% (65/85) of patients were diagnosed after an incidental finding on imaging or diagnostic/surgical procedure, 14.1% (12/85) were diagnosed after an incidental lab finding, and 9.4% (8/85) were diagnosed after a clinical health care professional incidentally identified a lump/mass. Compared to the symptomatic group, patients with incidental diagnosis were older at diagnosis (median age 66 vs 63 years, P=0.01) and more likely to present with an earlier stage I/II (62.4% vs 38.9%, P<0.001). Patients who presented with symptoms were more likely to have ≥ 1 extra-nodal site involvement (29.8% vs 15.5%, P=0.005), elevated LDH level (55.4% vs 40.8%, P=0.01), and high-risk IPI score (13.7% vs 5.9% P=0.03) compared to the incidental group. The median diagnosis to treatment interval (DTI) was significantly longer in the incidental group (21 days, IQR 12-34) compared to the symptomatic group (15 days, IQR 9-24) (P = 0.0014). The median follow-up time was 152.3 months in the incidental group and 123.7 months in the symptomatic group. We observed no difference in early failure rates as measured by failure to achieve event-free status at 24 months (EFS24) for incidentally vs symptomatic diagnosis (25.9% vs 31.9%, P=0.25). There was no difference in EFS between the two groups in univariate (HR=1.08, 95%CI=0.8-1.45) or multivariable analysis adjusted for IPI (aHR=0.97, 95%CI=0.72-1.31). There was also no difference in OS in univariate (HR=0.98, 95%CI=0.72-1.34) or multivariable analysis adjusted for IPI (aHR=0.87, 95%CI=0.64-1.19). Conclusion In this large cohort of aggressive B-cell lymphoma, incidental diagnosis occurred in only 7.5% of cases and these patients had earlier stage, lower IPI score, lower LDH levels and less extranodal involvement. These differences in clinical characteristics did not translate into EFS or OS differences. Our findings are the first to describe presentation and outcomes of incidentally diagnosed DLBCL and provide data regarding what investigators may find with MCED assays. Finding more early stage DLBCL patients with lower tumor burden may influence type of treatment, enable the use of fewer chemotherapy cycles, and avoid symptoms and complications of advanced stage disease such as tumor lysis syndrome and organ compression.

Background: FL3B is the least common among FL subtypes, accounting for 5-10% of cases. Almost half of FL3B tumors have concurrent diffuse large B cell lymphoma (DLBCL) in the diagnostic tissue biopsy, while FL3B rarely coexists with FL1-2 or FL3A. Several lines of evidence suggest that FL3B displays distinct biological and clinical characteristics resembling aggressive DLBCL rather than the indolent FL1-3A. Accordingly, DLBCL anthracycline-containing regimens, such as R-CHOP, are the mainstay of therapy for FL3B with or without coexisting DLBCL. However, while some studies show that R-CHOP therapy in FL3B was associated with 5-year overall survival (OS) rate of 54%, others report outcomes comparable to FL3A with 79-90% survival. Additional controversy involves the clinical implication of pure FL3B (FL3Bp) vs FL3B with concurrent DLBCL (FL3Bc). Thus, it remains unclear if FL3B clinically resembles DLBCL or lower-grade FL and whether FL3Bp has a different prognosis from FL3Bc. To address these questions, we performed a pooled study of two large prospective multicenter study cohorts to compare the clinical characteristics and outcomes of newly diagnosed FL3B with FL1-2, FL3A and DLBCL patients, all of whom were uniformly treated with frontline R-CHOP. Patients and Methods: Weevaluated 469 newly diagnosed patients with FL1-2 (n=216), FL3A (n=170) and FL3B (n=83) who received R-CHOP within 6 months of diagnosis and 739 de novo DLBCL (GCB n=455 and non-GCB n=284) who were prospectively enrolled into the Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts between 2002 and 2021. FL3B cases were designated as FL3Bc and FL3Bp based on the presence or absence of coexisting DLBCL, respectively. Histologic diagnosis was determined by an expert pathologist at each participating center and centrally reviewed. Event free survival (EFS) and OS were defined as time from diagnosis to progression, relapse, retreatment or death, and early progression defined as failing to achieve EFS at 24 months (EFS24). Associations between clinical features and EFS or OS were evaluated using Kaplan Meier curves and Cox proportional hazards models unadjusted and adjusted for age and FLIPI (comparisons with FL1-2 and FL3A) or IPI (comparisons with DLBCL). Results: The median age was 61 years (range, 18-94 years). Among FL3B patients, 21 (25%) had FL3Bc and 62 (75%) FL3Bp. Baseline characteristics and outcomes were broadly similar between the two FL3B subtypes. We then compared all FL3B patients to those with lower-grade FL. Patients with FL3B showed similar clinical features to those with FL1-2 and FL3A, with exception for a lower tumor burden. After R-CHOP, FL1-2 patients had an inferior EFS (HR 2.13 95%CI 1.31-3.46) than those with FL3B, whereas there was no difference compared to FL3A. OS was similar across all FL grades. Although FL1-2 patients failed to achieve EFS24 more frequently than FL3B and FL3A (34% vs 18% and 15%, p<0.001), FL3B patients who did fail EFS24 had almost three folds higher risk of subsequent mortality (HR 2.84 95%CI 1.35-6.01) than other FLs. At 5-year follow-up, FL3B patients had twice the risk of relapse with an aggressive subtype (i.e., DLBCL, high-grade B-cell lymphoma) than those with FL1-2 and FL3A, who instead often recurred with indolent disease (i.e., FL1-2, FL3A; p<0.001). We further compared FL3B patients to those with DLBCL classified based on cell-of-origin into GCB and non-GCB subtypes. At diagnosis, patients with FL3B had more favorable clinical features than those with GCB and non-GCB DLBCL. Compared to FL3B, patients with non-GCB DLBCL had an inferior EFS (HR 1.73 95%CI 1.07-2.79) and OS (HR 2.04 95%CI 1.11-3.75), while those with GCB DLBCL did not show a significant difference in EFS (HR 1.41 95%CI 0.88-2.25) or OS (HR 1.69, 95%CI 0.93-3.06) likely due to insufficient statistical power. Patients with FL3B failed EFS24 less frequently than patients with GCB or non-GCB DLBCL (17% vs 25% and 32%; p=0.01). Among patients who failed EFS24, those with FL3B had a similar subsequent OS as both GCB (HR 1.41 95%CI 0.73-2.72) and non-GCB DLBCL (HR 1.27 95%CI 0.65-2.47). Conclusions: We report that FL3Bp and FL3Bc appear clinically similar. While most FL3B patients have a prognosis comparable to FL1-2 and FL3A, 18% exhibit aggressive behavior with poor outcome reminiscent of DLBCL. Future studies with a larger population will be needed to confirm our findings.

Introduction: Diffuse large B cell lymphoma (DLBCL) patients experience favorable outcomes following frontline immunochemotherapy, however, 30-40% of patients will exhibit primary refractory disease or relapse (rrDLBCL). Recent studies have expanded upon well-defined characteristics of newly diagnosed DLBCL (ndDLBCL) to elucidate genomic landscapes underlying rrDLBCL; yet, high-throughput examination of resistance and relapse mechanisms within rrDLBCL subtypes, including the newly defined dark zone signature (DZsig) addition to cell of origin (COO), have yet to be described. To expand upon the current tumor etiology and define subtype-specific driving mechanisms, we describe a multi-omic analysis leveraging clinical and biologic variables in rrDLBCL. Methods: Tumor biopsies (N=228) collected at the time of relapse were obtained from n=85 participants in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource (MER), n=73 in the Mayo Clinic Biobank, and n=38 from CC-122-DLBCL-001 or n=32 CC-122-ST-001 trials. Tumor samples were analyzed by WES (n=158) or WGS (n=70) and by RNAseq (n=145). Comparative analysis against ndDLBCL MER samples (N=444) utilized WES (n=404) and RNAseq (n=321). Chi Square or Fisher's exact test was used for enrichment analysis of categorical variables, while Wilcoxon or Kruskal-Wallis test was used for continuous variables. Results: rrDLBCL samples were enriched for ABC (46% vs 33% in ndDLBCL, p=0.01), and fewer GCB (27% vs 40%, p=0.006). Amongst rrDLBCL patients, variance in overall survival (from time of original diagnosis; log-rank p=0.001) was observed between COO subtypes, with poor outcomes in patients with DZsig (median 15.0 mo) and GCB (36.5 mo) compared to ABC tumors (74.4 mo). Patients with progression or relapse within 6 months featured a more even COO distribution (ABC - 22%, GCB - 34%, DZsig - 28%) than patients with early (6-24 mo; 51%, 22%, 22%) or late relapses (>24 mo; 62%, 19%, 4%), which were predominantly ABC. Comparing mutation frequency within subtypes, rrDLBCL GCB tumors were enriched for B2M (41% vs 15% in ndDLBCL, p=0.002), EP300 (19% vs 7%, p=0.059), CIITA (19% vs 5%, p=0.02), PRKCB (11% vs 2%, p=0.035), CD79B (11% vs 0%, p=0.004), and CD83 (8% vs 1%, p=0.049) mutations, and CNV events including gains at 8q24.21 (MYC locus; 48% vs 14%, p<0.001) and 18q21.33 (BCL2, TCF4 locus; 36% vs 15%, p=0.021), and losses at 17p13.1 (TP53 locus; 40% vs 19%, p=0.035). rrDLBCL DZsig tumors featured enrichment for BCL6 (22% vs 3%, p=0.025), and SPEN (17% vs 3%, p=0.062) mutations and 2q22.2 losses (LRP1B locus; 20% vs 0%, p=0.019). Despite differential mutation and CNV profiles, gene expression analysis revealed minimal variance within COO subtypes in rrDLBCL and ndDLBCL, however upregulation of lymphoma driving genes including MYBPC2 (LogFC=1.68, FDR<0.001), MYOM2 (LogFC=1.33, FDR=0.007), MYC (LogFC=0.61, FDR=0.04), and CELSR2 (LogFC=0.53, FDR=0.02) were observed in ABC rrDLBCL. Increased frequency of LymphGen classifier A53 was observed in ABC (43% vs 17%, p=0.005) and GCB (40% vs 14%, p=0.009) rrDLBCL. Using CIBERSORTx to infer lymphoma microenvironment (LME) cell type abundance, an LME-depleted class was evident in rrDLBCL tumors, including reduction of CD8+ T cells (effect size (r)=-0.78, p<0.001) and T follicular helper cells (r=-0.48, p=0.012) in GCB rrDLBCL and reduction of T follicular helper cells (r=-0.43, p=0.023) and Tregs (r=-0.32, p=0.065) in DZsig rrDLBCL. Significance: We present an update to the genomic landscape of rrDLBCL, highlighting GCB and DZsig tumors with differential biology and advanced clinical course. Our data supports increased implementation of sequencing efforts in rrDLBCL to more broadly evaluate relapse mechanisms, with optimism that a more detailed understanding of r/r disease may guide trials for targeted treatment strategies. For example, rrDLBCL patients may be strong candidates for MYC pathway targeting agents (BETi), or a Lenalidomide-based regimen (R2 or Tafa-Len), as Lenalidomide has been shown to reprogram the LME via PD-L1 expression in addition to downregulation of MYC and MYC target genes. Or, due to enrichment of variants affecting anti-apoptotic proteins including BCL6 or BCL2 in DZsig and GCB rrDLBCL, a venetoclax-based therapeutic may be considered. Further targeted strategies should be considered as development of a more personalized approach remains an unmet need.