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Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET). Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age < 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes. Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p<0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p<0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease > 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS >1 7% vs 13%, p<0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died. Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets. Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.

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.

Background Hispanic patients continue to be underrepresented in clinical trials. To better understand the factors that impact clinical trial participation, we surveyed patients with NHL receiving care at an academic institution on their perspectives on clinical trials, barriers to care, and helpful aids to encourage clinical trial participation. Here we report the findings of the Hispanic patients and non-Hispanic white patients; accrual is ongoing for other cohorts of patients. Methods Consecutive patients ≥ 18 years old with histologically confirmed NHL who received care at MD Anderson Cancer Center in the Texas Medical Center in Houston, Texas were invited to participate regardless of treatment status. A self-administered questionnaire was used to assess patient sociodemographic factors, perceptions and willingness to participate in different clinical trial scenarios as well as participant perceived barriers to care and facilitators of trial participation. The questionnaire included a total of 53 items with an additional 13 demographic items. The questionnaire was available in English and Spanish. Results Of the 1204 patients invited, 316 consented to participate and 285 ultimately completed the survey (participation rate 23.7%). Among the total participants, this cohort included 100 self-identified Hispanic (H) participants and 103 non-Hispanic white (NHW) participants diagnosed with NHL who completed the survey and were included here. The histology of our cohort included Follicular Lymphoma (FL) [35.6%]; Diffuse Large B-cell lymphoma (DLBCL) [18.2%], Mantle cell lymphoma (MCL) [18.7%], T-cell Lymphoma (TCL) [9.4%] Marginal Zone Lymphoma [7.8%]. Compared with NHW participants, Hispanic patients were younger (Median age of 60 vs 66 years), less likely to be male (H 54% vs NHW 66%), less likely to commute more than an hour away from the doctor's office (54% vs 71.8%), had lower household income (income > $100,000 was 32% vs 41.7%) and less likely to have a bachelors' degree or higher (38% vs 50.5%). There were similar prevalence histologies such as DLBCL (H 20% vs NHW 16.5%) and FL (H 36% vs NHW 35%) compared to rarer histologies such as MCL (H 11.1% vs NHW 26.2%) and MZL (H 12% vs NHW 3.9% ) which had disproportional prevalences. Hispanic patients were less likely to have previously participated in a clinical trial (28% vs 51.5%) and less likely to have discussed clinical trials as an option (49% vs 70.9%). A majority of Hispanic (81.0%) and NHW (92.3%) respondents stated that they understood what was meant by a “clinical research study” or “clinical trial” somewhat well or very well. Less than half of Hispanic participants (38.0%) and NHW participants (48.5%) reported being very willing to participate in a cancer clinical trial as their initial course of treatment. The most prevalent concern of both Hispanic and NHW participants respectively was the cost of a clinical trial (34.0%, 22.3%). Other top concerns included distance to the treatment center (32.0%, 13.6%) and frequency of contact with the care team (26.0%, 14.6%). Participants identified access to written materials (69.0%, 60.2%), insurance aid (65.0%, 68.0%), and access to videos (64.0%, 51.5%) as extremely helpful resources that could reduce the burden of participating in a clinical trial. Participants identified that it was most important that a treatment may improve their quality of life by decreasing pain level, increasing activity level, or other symptoms (76.0%, 91.3%). Conclusions Although most Hispanic and NHW participants reported a very good understanding of clinical trials and similar facilitators/barriers for trial participation, Hispanic patients were less likely to have discussed trials as an option with their care teams and less likely to have previously participated in a trial. Evidence-based interventions to address various barriers to clinical trials exist but data on their effectiveness and application is limited. Implementing strategically designed evidence-based interventions to address identified barriers and facilitators will be necessary to improve participation in lymphoma clinical trials.

Introduction: WM is a rare subtype of lymphoma, identified by the presence of IgM paraprotein, infiltration of clonal, small lymphoplasmacytic B cells in the bone marrow, and the somatic mutation, MYD88 L265P, which is observed in over 90% of WM patients. We previously identified two rare variants at 6p25.3 (EXOC2) and 14q32.13 (TCL1) that were significantly associated with an increased risk of WM/LPL (PMID: 30305637). However, the genetic basis for WM/LPL predisposition remains largely unknown. We conducted the largest WM/LPL GWAS to discover further germline susceptibility loci for WM/LPL. Methods: Our meta-analysis discovery set included 1,707 cases and 58,328 controls of European ancestry from the InterLymph Consortium, genotyped on a high-density SNP array and imputed to TOPMed, providing over 10 million common variants for association testing. Germline genetic loci with suggestive significance (P<5x10-6) were selected for replication in four independent sets (570 cases and 771,770 controls; UK Biobank, Copenhagen Hospital Biobank, FinnGen, Mayo Clinic), giving us a total of 2,277 WM/LPL cases and 831,098 controls. Conditional and sensitivity analyses were performed considering family history and sex. A transcriptome-wide association study (TWAS) was performed using FUSION with expression quantitative trait loci (eQTL) data from GTEx and Young Finns Study in whole blood, lymphocytes, and other tissues. Functional annotations were done using FUMA, F-MAGMA, FORGE, and OpenTarget. Colocalization was measured using CoLoC with whole blood gene expression data. Results & Discussion: We identified 11 germline genetic loci associated with WM/LPL risk that replicated and reached genome-wide significance (P< 5x10-8), including the two known loci on 6p25.3 and 14q32.13 and nine novel loci in the following regions: 6p25.3 (n=2 independent loci), 2q37.1, 9p13.2, 6p21.32, 10q23.31, 16q21, 1p31.1, and 15q15.1. Four of the discovered variants showed strong associations with WM/LPL [odds ratios (ORs) >10]. Enrichment was observed for enhancer and promoter elements in B-cells (FDR q < 0.01), and gene-based and colocalization analyses identified several potential biological pathways. Colocalization analyses show the intronic PAX5 risk variant on 9p (OR=1.5, P= 2.3x10-25) associated with whole blood eQTL expression of PAX5, which plays an essential role in regulating lymphoid progenitors to the B-lymphocyte lineage, as well as RP11-297B17.3 (RNA gene, antisense to PAX5). In addition, GWAS have shown this variant is in linkage disequilibrium (LD) with GWAS loci for CD20 on IgD+ CD38- B cell that represents a specific immunophenotype that helps identify and characterize B cells involved with WM and other similar conditions. The 2q37.1 (SP140) locus (OR=1.6, P=1.2x10-33) contains variants linked to chronic lymphocytic leukemia (CLL) and autoimmune diseases, including multiple sclerosis and Crohn's disease. This locus is important in chromatin-mediated gene regulation, suggesting a significant role in the immune system. The specific variant influences exon-skipping and potentially protein expression, altering the gene's function. The variants on 10q23.31 in FAS (OR=1.3, P=4.4x10-13) and 15q15.1 (OR=1.2, P=8.5x10-11) in BCL2 modifying factor (BMF), are in strong LD with known CLL susceptibility variants. The 15q variant is also linked with multiple lymphoid leukemia GW significant SNPs. Sex-specific analyses identified one novel locus at 20q13.33 associated with the expression of ZGPAT and UCKL1 in males (OR=1.9, P=9.5x10-10). TWAS identified associations with CRHR1 and CDKN2A; overexpression of both are shown to be associated with an increased risk of WM/LPL. Expression of CDKN2A has been linked to childhood acute lymphoblastic leukemia, while CRHR1 has been associated with breast cancer risk. Conclusions: Our study, the largest GWAS of WM to date, has identified 11 susceptibility loci, including two previously known and nine novel regions. The findings underscore the genetic complexity of WM, with the PAX5 and SP140 loci implicated in both chromatin-mediated gene regulation and immune system functions. These insights not only enhance our understanding of WM predisposition but also pave the way for future research focused on functional understanding of these loci, potentially leading to new therapeutic strategies.

Introduction: Follicular lymphoma (FL) is the most common indolent subtype of non-Hodgkin lymphoma. Family history is a risk factor. Genome-wide association studies (GWAS) have identified several germline variants, especially within the HLA region, to be associated with an increased risk of FL, but these variants only explain a fraction (16%) of heritability. Here, we present novel findings from GWAS of FL uncovering multiple germline genetic variants contributing to disease susceptibility. Methods: A GWAS was performed comprised of a discovery analysis in 6,508 FL cases and 64,183 controls of European ancestry followed by a replication of the most significant variants (P<5x10-7) in 2,745 FL cases and 782,226 controls from the biobanks of UK, Copenhagen Hospital, FinnGen and Mayo Clinic . At 9,253 FL cases and 846,409 FL free controls imputed genome-wide, this is the largest FL GWAS of European genetic ancestry to date. HLA alleles were imputed, and Class I and Class II signals were analysed at the amino acid level. A transcriptome wide association study (TWAS) was performed using FUSION investigate relationship to expression in GTEx and Young Finns Study in whole blood and cross-tissue . Functional annotations were done using FUMA, F-MAGMA, Open Targets and FORGE. Colocalization was conducted using CoLoC with whole blood gene expression data to understand causal variants. Mendelian randomization (MR) was performed on blood cell traits and leukocyte telomere lengths (LTL) to infer their relationships with FL genetic risk. Results: We replicated the previously published susceptibility loci within and outside the HLA region, finding two additional independent SNPs at two known loci (P < 5 x10-8) and discovered thirteen novel, genome-wide significant loci located at chromosome 2q13, 3p13, 3p24.1,3q13, 3q24.1, 4q31.21, 6p21, 6p22, 7q31, 10p14, 10q22, 10q23, 17q12, 19p13 and 20p11 with P < 5 x10-8. These SNPs were located near genes that show relevance for B-cell biology, such as BCL2L11, FOXP1, CD86, EOMES, IZKF3, PRF1, KLF2 NKX2-2 and HLA Class I and Class II genes. TWAS uncovered a role for H2AX, IGKV2-29, IMP, UBE4A and IKZF3 and provided directionality of effect for associated transcripts. Colocalization analysis corroborated a positive association with IKZF3 expression showing a robust correlation with FL risk variants (posterior probability PP4>0.7). In addition, several genome-wide significant variants in IKZF3 colocalize with eQTLs across tissues. IKZF3 (Aiolos) is part of the Ikaros family of transcription factors, critically important to the regulation of B-cell development and function. Therapeutic strategies leveraging Immunomodulatory imide drugs (IMiDs) to degrade IKZF3 have shown efficacy in multiple myeloma, and we speculate may also have potential benefits in FL by enhancing anti-tumor immunity and disrupting malignant B-cell function. Gene-set analysis showed blood and spleen to be the most relevant tissues for FL risk variants with lymphocyte activation and immune cell type differentiation genes demonstrating enrichment based on gene-ontology terms. Associated traits included allergies, respiratory diseases (e.g., asthma phenotypes), inflammatory bowel diseases, type 1 diabetes (T1D), lipid levels and commonly measured blood cell traits, with some SNPs showing evidence of colocalization with select blood traits. Interestingly, no causal association to blood traits was observed using MR; however, MR analyses did reveal a strong association with LTL. For the HLA loci, FL shows a diverse set of amino acid associations in HLA Class I and Class II genes that extends beyond what is known from autoimmune disease associations, such as rheumatoid arthritis or T1D. Our study also reveals interesting biological insights about FL susceptibility, such as a novel locus intragenic to FOXP1, an activated oncogene preferentially expressed in FL and DLBCL tumors, but rarely observed in Hodgkin's lymphoma. High levels of FOXP1 are known to result in poor survival in FL. Conclusion: This large GWAS of FL has identified multiple susceptibility variants, uncovering interesting gene candidates for further pathophysiological characterization of FL risk and B-cell development. It suggests new biological pathways and genes that could be potential leads for drug development and targeting treatment, in addition to identifying genetically high-risk populations for FL susceptibility.

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: 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 Underserved patient populations characterized by low income, lack of insurance, low levels of education, and minoritized status face significant barriers when accessing clinical trials. To better understand these challenges, patients from a safety-net county hospital were surveyed on their perspectives on clinical trials, barriers to care, and facilitators of participation. Methods Patients ≥ 18 years old with histologically confirmed non-Hodgkin lymphoma (NHL) who received care at Lyndon B. Johnson Hospital, a safety-net county hospital in Houston, Texas, were invited to participate regardless of treatment status. A self-administered questionnaire was used and offered in English or Spanish. The questionnaire included a total of 53 items with an additional 13 demographic items assessing patient sociodemographic factors and knowledge of clinical trials. Questions also addressed barriers/facilitators of trial participation and respondent willingness to participate in a trial based on certain scenarios. Results Of the 136 patients invited to participate, a total of 49 participants diagnosed with NHL consented to the study and all completed the survey (participation rate 36%). Twenty-seven (55%) surveys were completed in Spanish. Participants self-identified as Hispanic (N=35, 71.4%), African American (N=6, 12.2%), non-Hispanic white (N=7, 14.3%), and Asian/Pacific Islander (N=1, 2%). This cohort included Diffuse Large B-cell lymphoma NOS (DLBCL) [32%], Follicular Lymphoma (FL) [28%], Marginal Zone lymphoma (12%). There were several patients with rare histologies such as Burkitt's lymphoma (4.2%); Mantle Cell lymphoma (4.2%), Plasmablastic lymphoma (4.2%) and T-cell lymphoma (4.1%). The majority of participants reported a commute of less than an hour away to the doctor's office (83%) with almost all participants commuting less than 2 hours (98% with 2% missing an answer). Participants were a median age of 55 years old (range 22-80), majority female (51%), less than a bachelor's degree as highest education (91.8%) and earning < $35,000 (49%). Among respondents, 89.8% had not participated in a clinical trial for their cancer. Only 36.7% of respondents reported that they understood what a clinical research study as “somewhat well,” while 30.6% reported their understanding as “not very well.” Regardless, a majority were very willing (38.8%) or somewhat willing (36.7%) to participate in a trial as their initial course of treatment. Respondents' biggest concerns were the cost of a clinical trial (61.2%), not being able to contact the research team with questions (38.8%), and frequency of clinic visits (32.7%). The most helpful resources that participants identified to reduce participation burden were educational resources such as written materials (77.6%), videos (67.3%), an explanation of the study in their language (65.3%), insurance aid (75.5%), and flexible study visit times (65.3%). Notably, 26.5% of participants responded that they believed they had received medication from a doctor as part of an experiment without their permission. When asked which outcome would most influence their decision to participate in a trial, 79.6% of participants rated the possibility of improving quality of life by decreasing pain and increasing activity levels as very important. Fewer patients (55%) rated other outcomes such as types of side effects (55%) and possibility of pain/discomfort (59%) as very important. Conclusions The majority of patients with NHL who participated in this observational study had little or no previous exposure to or understanding of cancer clinical trials. We identified common barriers to participation including out-of-pocket costs, the ability to contact the research team, and the frequency of clinic visits that should be addressed with specific identified resources to reduce participation burden. Interventions guided by these data should be implemented and evaluated to improve clinical trial participation for patients with lymphoma.

Introduction: Clonal hematopoiesis (CH) is a common age-related premalignant condition defined by the presence of an acquired somatic mutation in a gene frequently mutated in myeloid malignancies characterized by a variant allele frequency (VAF) of ≥2%, without fulfillment of other diagnostic criteria for myeloid neoplasm. Incidence of CH increases with age and found in 10%-30% of people > 70 years of age. CH-related mutations confer an increased risk of myeloid neoplasms, cardiovascular diseases, and are linked to inferior survival in solid tumor patients treated with chemo/radiation therapy. Such mutations can act as a driver/amplifier of inflammation, especially through myeloid cells. To distinguish true disease drivers from background genetic events related to aging or environmental factors, we need a deeper understanding of the impact of CH in different tissue microenvironments and under therapeutic pressure for better risk stratification of CH carrier patients. Recent reports suggested high prevalence of CH-related mutations in lymphoma. Current analyses aimed to investigate: i) the prevalence of CH-related mutations in two real-world lymphoma cohorts from Molecular Epidemiology Resource (MER) MER-FL and MER-DLBCL, ii) CH-related mutational landscape in DLBCL and FL, iii) the impact of CH-related mutations on clinical outcomes. Methods: Whole exome sequencing (WES) derived from blood/PBMC from lymphoma patients with paired tumor samples was analyzed to identify CH-related myeloid drivers in 42 previously reported genes. We used Sention-Tnhaplotype2 somatic pipeline with a custom panel of normals from whole blood samples. To avoid tumor contamination, we filtered variants for which VAF in the tumor was higher than that in the germline sample. Other filtering criteria included HIGH/MODERATE impact; read count > 1 in both forward and reverse reads; gnomAD_AF < 0.01. We used the R “survival” package Cox regression implementation for outcome and other statistical analysis. Results: Genomic and clinical data of 507 patients from MER-FL and 383 patients from MER-DLBCL cohorts, with median age of 60 and 64 respectively, were available for analysis. CH-related mutations were present in 17.16% (87/507) in FL and 18.28% (70/383) in DLBCL cohorts with a VAF cut off >2%. The most common CH-related mutations were DNMT3A (5%), CREBBP (2%), TET2 (1%), ASXL1 (1%) and PPM1D (1%) in MER-FL while DNMT3A (5%), TET2 (3%), TP53 (3%), ASXL1 (2%) and PPM1D (1%) in MER-DLBCL cohort. Both the prevalence of CH-related mutations and their average VAF increased with age, consistent with literature. Finally, cox regression analysis suggested that CH-related mutations were associated with significantly inferior overall survival (OS) in both FL and DLBCL cohorts (HR 1.6 p=0.028 and HR 2.3 p=<0.001 respectively); however only in DLBCL this association was significant after age correction (HR 1.8 p=0.008). When separated by individual gene mutations, genes of interest with inferior OS included TP53 (n=4, HR 3.1, p=0.057) in FL and PPM1D (n=3 HR 2.6 p=0.1), TP53 (n=8 HR 2.1 p=0.1) and DNMT3A (n=14, HR=2.0, p=0.048) in DLBCL; however, these estimates did not quite reach statistical significance. Conclusions: Taken together, our exploratory analysis indicates that CH-related mutations associate with worse OS in lymphoma patients, supporting the rationale for evaluation of CH for the risk assessment in lymphoma. Furthermore, DLBCL displays of larger size effect, which may be related to different treatment regimes. Additional studies will be needed to elucidate the interaction between high dose chemotherapy regimes and CH-associated adverse events.