Nowakowski, Grzegorz S.

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.

Introduction Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is very aggressive, with a historically low complete response (CR) rate (Blood. 2017; 130[16]:1800-1808). Recent research has focused on achieving complete and durable responses in this population, which translate to improvements in overall survival (OS) and progression-free survival (PFS). Results from the randomized, global, phase 3 ECHELON-3 study (NCT04404283) demonstrated a statistically significant and clinically meaningful improvement in OS, PFS, and objective response rate with brentuximab vedotin (BV) combined with lenalidomide (Len) and rituximab (R; BV+Len+R) vs placebo+Len+R in patients (pts) with R/R DLBCL after ≥2 prior systemic therapies. Here, we present subgroup analyses in pts with a best overall response (BOR) of CR (n=67). Methods Pts in the study were randomized (1:1) to receive BV (1.2 mg/kg) or placebo every 3 weeks, in combination with R (375 mg/m2) and Len (20 mg) once daily. In these subgroup analyses, eligible pts had a BOR of CR and some ended study treatment and received any subsequent anticancer therapy. BOR was assessed by investigators according to the Lugano 2014 classification. Duration of response was defined as the time from the start of the first documented CR to the first documented tumor progression per Lugano 2014 or death. Pts who initiated a subsequent nonpalliative anticancer therapy were censored at the most recent prior response assessment. Subsequent nonpalliative anticancer therapies were defined as any systemic therapy received after the end of study treatment. P values are descriptive. Results Of the 112 pts in the BV+Len+R group, 45 (40.2%) had a BOR of CR. Of the 118 pts in the placebo+Len+R group, 22 (18.6%) had a BOR of CR. The median duration of CR was 18.9 months (95% CI, 11.1 months-not estimable [NE]) with BV+Len+R vs not reached (NR) with placebo+Len+R (hazard ratio [HR], 0.527; 95% CI, 0.200-1.389; P=.1891). The median time to CR was 1.58 months (range, 1.2-7.3 months) with BV+Len+R and 1.61 months (range, 0.7-4.6 months) with placebo+Len+R. With a median follow-up of 14.3 months, the median OS in pts with a BOR of CR was 31.5 months (95% CI, 20.3 months-NE) in the BV+Len+R group vs NR in the placebo+Len+R group (HR, 1.044; 95% CI, 0.331-3.298; P=.9407). Median PFS in pts with a BOR of CR was 21.5 months (95% CI, 12.6 months-NE) in the BV+Len+R group vs NR (95% CI, 5.4 months-NE) in the placebo+Len+R group (HR, 0.6333; 95% CI, 0.256-1.567; P=.3198). Results of NR in the placebo+Len+R group are likely attributable to limited follow-up and small sample size. Additional data on baseline characteristics of pts who had CR will be presented. Of the 45 pts with CR in the BV+Len+R group, 42 (93.3%) received no subsequent anticancer therapy. Of the 22 pts with CR in the placebo+Len+R group, 17 (77.3%) received no subsequent anticancer therapy. Conclusions BV doubled the CR rate in pts with R/R DLBCL compared with placebo, and outcomes in pts with CR were durable, with only 6.7% of pts treated with BV+Len+R receiving subsequent systemic anticancer therapy, compared with 22.7% of pts treated with placebo+Len+R receiving subsequent therapy. Overall, BV+Len+R demonstrated a survival benefit in the ECHELON-3 study and is a promising option to achieve complete and durable responses in third- or later-line therapy for pts with R/R DLBCL.

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.

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: Financial toxicity (FT), or the negative impact of medical expenses experienced by patients, is a known adverse effect of cancer treatment that result in worse health outcomes for patients. However, there is limited literature investigating FT in lymphoma with even less data on predictors such as age, gender, and socioeconomic factors. As lymphoma treatment options expand, it is vital to understand the impact of these treatments on patients' financial well-being. We investigate FT through patient reported outcomes from the Lymphoma Epidemiology of Outcomes (LEO), a large multi-institution prospective cohort study of non-Hodgkin lymphoma (NHL). Methods: Patients with newly diagnosed NHL were enrolled into the LEO cohort from 2015-2020. Clinical, pathology and treatment data were abstracted from medical records, and participants were offered self-administered surveys at enrollment and selected follow-up time points. Participants were included if they completed at least four of six survey questions on FT adapted from the Medical Expenditure Panel Survey (MEPS) within the first year after diagnosis. Questions focused on either material hardship (unable to cover costs; file for bankruptcy; borrow money; work extra job or hours) or psychological stress (worried about paying large medical bills). We evaluated FT as answering positively to any question (any vs none). Associations with FT were evaluated using chi-squared tests. All analyses were performed using R (v4.2.2). Results: 3202 patients completed at least four survey questions relating to FT. Mean age at diagnosis was 62 years (18-94), 56% were male, and majority identified as white (90%). Characteristics associated with FT are reported (p<0.001). FT was more likely in younger patients: 18-25 years (64%, 30/47), 26-44 years (73%, 299/313), and 45-64 years (58%, 799/1375) as compared to those 65-79 years (36%, 459/1272) and ≥80 years (35%, 69/195). FT was highest in patients without a high school diploma (54%, 45/84), followed by patients with a high school diploma (52%, 209/402), and an associate's degree (57%, 358/627). It was lowest in patients with a bachelor's (45%, 224/296) or post-graduate degree (39.6%, 216/545). Higher FT was seen in those receiving disability income (65%, 47/72); whereas less FT was seen in retired patients (36%, 299/828). FT rates inversely correlated with income: 65% for income < $21,000 (184/283), 61% for $21,000- $39,999 (224/370) and 60% for $40,000-$65,999 (293/491). Lower FT noted for income range of $66,000-$106,000 (47%, 323/681) or > $106,000 (37%, 324/872). Patients separated from a partner (82.9%, 19/23) had the highest FT, followed by patients living with a partner (64%, 48/75), divorced (56%, 103/184), and never married (53.4%, 79/148). Patients who were married (47%, 793/1672) or widowed (41%, 60/146) reported the lowest FT. Higher FT was reported in DLBCL (55%, 631/1146), MCL (55%, 172/315), and TCL (53%, 119/226) when compared to FL (44%, 327/746), MZL (44%, 137/316), and other NHL (44%, 200/453). This is likely related to treatment as more FT was seen in patients who received an anthracycline and/or alkylator containing therapy (54%, 1066/1963) versus non-systemic (43%, 120/278) and observation (35%, 168/483). In multivariable analyses, FT strongly correlated with age at diagnosis, household income, and treatment type. The odds ratio and 95% confidence intervals for the most significant category within each variable are as follows: age per 1 year (0.96, [0.95-0.97]), income > $106,000 vs < $21,000 (0.28, [0.21-0.38]), and observation vs anthracycline and/or alkylator (0.56, [0.44-0.71]). Conclusion: Nearly 50% of patients with lymphoma experience FT, seen as material hardship and psychological stress, within the first year of diagnosis. Patients with a younger age (18-44), less education, and lower household income reported higher levels of FT; whereas those who were retired or married/widowed reported lower FT. Lymphoma subtypes that require more anthracycline and/or alkylator containing therapy imposed higher FT. Understanding these risk factors can help clinicians identify patients who may benefit from additional resources during lymphoma management.

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: Epcoritamab (epcor) is a first-in-class CD3xCD20 bispecific antibody (bsAb) approved for the treatment of 3L+ LBCL and follicular lymphoma. In the single-arm, phase 1/2, EPCORE NHL-1 trial (NCT03625037), epcor given until disease progression or unacceptable toxicity, demonstrated deep and durable responses, a median overall survival (OS) of 18.5 months, and a manageable safety profile in R/R LBCL. A second CD3xCD20 bsAb given as fixed-treatment duration, glofitamab (glofit), also demonstrated durable responses, conferring a median OS of 11.5 months in the pivotal study. Understanding how long-term outcomes compare among bsAb agents remains an important knowledge gap. With over 2 years of follow-up, in the absence of a head-to-head study, it is now relevant to compare the efficacy of these agents via indirect comparison. This study evaluated OS, progression-free survival (PFS), and duration of complete response (DoCR) of epcor vs glofit in R/R LBCL using data from the respective pivotal trials. Methods: Two analyses were conducted to compare the efficacy of epcor and glofit. First, a matching-adjusted indirect treatment comparison (MAIC) was conducted using published OS and PFS data from the full cohort of the glofit pivotal trial (12.6 months of follow-up, Dickinson et al, 2022) and the epcor pivotal trial (EPCORE NHL-1). Piece-wise hazard ratios (HRs) were calculated when proportional hazards assumptions were not met. Baseline characteristic prognostic variables were selected based on literature, clinical judgement, and empirical statistical testing and were adjusted between epcor and glofit cohorts. Second, in sensitivity analyses, indirect comparisons were conducted using an updated analysis of glofit with longer follow-up that included DoCR, together with OS and PFS data starting at cycle (C) 3 with 32 months of follow-up (Hutchings et al, ASH 2023). Sensitivity analyses with longer follow-up could not be adjusted because glofit pt baseline characteristics were not presented. Aggregate OS and PFS curves for glofit were derived from subgroups of pts with complete response/partial response/no response (CR/PR/NR) at C3 (Hutchings et al, ASH 2023). Aggregate epcor OS and PFS curves were similarly derived for pts with CR/PR/NR at C3 without prior disease progression. Weighted Cox proportional-hazards models were used to estimate the OS and PFS HRs between the 2 comparators. The DoCR comparison included all glofit and epcor pts achieving CR. All comparisons used EPCORE NHL-1 data with a median of 37.1 months of follow-up. Results: Pts enrolled into the pivotal trials of epcor and glofit were comparable by several key baseline characteristics before adjustment: age ≥65 y; male gender; Ann Arbor disease stage III-IV; primary refractory disease; refractory to most recent anti-CD20 therapy; previous chimeric antigen receptor T-cell therapy (CAR T); refractory to CAR T; and previous autologous stem cell transplant (ASCT). MAIC analysis revealed no significant difference in OS benefit from C1 until month 6 (HR 1.08, 95% CI 0.71, 1.64; P=0.72), but a demonstrable OS advantage from 6 months onward (HR 0.60, 95% CI 0.37, 0.98; P=0.04) in favor of epcor. An OS comparison starting at C3 with longer glofit follow-up demonstrated a consistent survival advantage in favor of epcor (HR 0.68, 95% CI 0.46, 1.01; P=0.05). The proportion of pts who received CAR T or ASCT subsequent therapy were similar for epcor and glofit (CAR T: 7.0% vs 8.9%; ASCT: 6.4% vs 6.3%) (National Institute for Health and Care Excellence Glofit Single Technology Appraisal, 2023). The MAIC analysis showed comparable PFS between epcor and glofit (HR 1.06, 95% CI 0.79, 1.41; P=0.71), although there was substantial censoring in the glofit PFS curve due to immature follow-up. With longer follow-up in the analysis starting at C3, with less censoring, the glofit PFS curve remained similar to the epcor PFS curve from C3 until month 6 (HR 0.67, 95% CI 0.42, 1.07; P=0.10), where separation of the PFS curves were observed favoring epcor (HR 0.56, 95% CI 0.33, 0.97; P=0.04). Median DoCR was longer for epcor (36.1 months) vs glofit (26.9 months). Conclusion: These indirect treatment comparisons suggest that epcor may provide an overall survival benefit over glofit through longer PFS with more mature follow-up, potentially driven by longer DoCR. Survival data with longer follow-up in the full glofit cohort are needed to confirm these findings.

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.