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Background: Recently, large B-cell lymphomas (LBCLs) have undergone major shifts in classification and treatment paradigm, particularly with the advent of CD19-targeted chimeric antigen receptor T cell therapy (CAR-T). Initially approved as third-line treatment in LBCL in 2017, as of early 2022 CAR-T is indicated for second-line therapy (2L) in patients with relapsed or refractory (R/R) disease within 12 months of frontline treatment or who are not candidates for autologous stem cell transplant (ASCT). Given this quickly changing landscape, we aimed to describe disease characteristics, patterns of care, and survival outcomes in patients with R/R LBCL receiving two or more lines of systemic therapy across modern treatment eras. Methods: We developed a database of patients with R/R LBCL from 8 U.S. academic centers in the Lymphoma Epidemiology of Outcomes (LEO) Cohort study (NCT02736357) and Consortium for Real World Evidence (CReWE). Unlike the SCHOLAR-1 dataset (M Crump et al, Blood 2017), our cohort included any patient receiving 2L, regardless of timing of progression/relapse. For this analysis, eligible patients were aged ≥18 years and received 2L between 2002-2022. Patients with histologic transformation, post-transplant lymphoproliferative disorder, primary CNS lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma, or plasmablastic lymphoma were excluded. Prognostic factors, therapy details (including intent for ASCT and/or CAR-T), and outcomes, including treatment response, event-free survival (EFS), and overall survival (OS), were abstracted for all lines of therapy. Treatment eras were defined as pre-CAR-T (2002-2010), CAR-T available via clinical trial (2011-2017), and post-FDA approval of CAR-T (2018-2022). Results: Of 1760 patients initiating 2L for R/R disease, 1523 were eligible for analysis. Median age at start of 2L was 62 (interquartile range [IQR] 53-70), and 65% were male; 11% were non-White, and 8% were Hispanic. High-grade subtypes comprised 16% of all cases. IPI was available for 1013 patients at time of 2L therapy, with 54% having IPI 3-5. Median time from diagnosis to 2L was 8.7 months (IQR 5.6-18.5), with 834 patients not having achieved complete response (CR) to 1L, 285 patients relapsing <12 months after 1L, and 404 patients relapsing ≥12 months after 1L. The median number of total lines of therapy received was 4 (range 2-18), with 586 and 347 receiving ASCT and CAR-T, respectively, at any line of treatment. At a median follow-up of 48 months from the start of 2L, 926 patients (61%) had died. Progressive lymphoma was the primary cause of death in 75% of deceased patients, with 8% of reported deaths due to therapy. 2L was received at an academic medical center in 83% cases, and 209 patients (14%) received 2L on a clinical trial. ASCT and/or CAR-T was planned at 2L for 989 patients (65%), of whom 463 ultimately received ASCT, 88 received CAR-T, and 21 received allogeneic transplant at 2L. 494 patients were not considered for ASCT or CAR-T at 2L, and 40 were unknown for ASCT/CAR-T intent. Breakdown by treatment era (n = 1518 with available treatment start date) is shown in the Table. Median EFS from start of 2L was 4.2 months (95% confidence interval [CI]: 3.8-4.8). Median OS from start of 2L was 18 months (95% CI: 17-22), and 2- and 5-year OS estimates were 46% (95% CI: 44-49%) and 35% (95% CI: 33-38%), respectively. EFS and OS improved significantly for patients initiating 2L between 2011-2017 compared to 2002-2010. However, EFS and OS in the 2018-2022 era remained similar to 2011-2017 (Figure). Conclusions: To our knowledge, this study is the first-ever large-scale attempt to describe patterns of care and outcomes in LBCL 2L in the modern era, inclusive of all treatment approaches. The rich and unique LEO CReWE dataset captures evolving practice approaches over time in terms of both intent for and receipt of cellular therapies. Likely reflecting the rapid development of many novel immune effector cell products and bispecific antibodies, we observed increased enrollment on 2L clinical trials in the 2018-2022 period, including a substantial proportion of patients receiving CAR-T in 2L. Importantly, survival increased in treatment eras during which CAR-T was available. Ongoing analyses of factors associated with improved survival will be presented at the meeting.

Background: We previously reported thatearly events in follicular lymphoma (FL), defined as progression of disease within 24 months (POD24) or early transformation to a more aggressive histology, are significantly associated with increased risk of lymphoma related death. To refine clinical management, the FLIPI24 prognostic model was developed to predict the risk of early events after starting immunochemotherapy (IC) (Maurer et al, 2022). The FLIPI24 model was found to be significantly superior to standard clinical models for prediction of both event-free survival at 24 months (EFS24) and overall survival (OS) in internal and external validation sets of patients receiving IC. We sought to evaluate the prognostic ability of the FLIPI24 model in patients with FL not receiving IC. Methods: The cohort consists of prospectively enrolled patients in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and the multicenter Lymphoma Epidemiology of Outcomes (LEO) Cohorts. Data were collected from medical records by standard protocol with all events verified by medical record review. Eligible patients were those diagnosed with grades 1-3A FL and initiated observation, rituximab monotherapy, radiation, or other non-IC therapy. The FLIPI24 model utilizes 5 continuous variables: age (linear 60-90 years with inflection at age 75), HGB (linear 8-17 g/dL), WBC (linear 4-11x10 9/L), LDH/ULN (linear 0.5-5), and B2M (linear 1-10 mg/L). FLIPI24 risk is grouped as follows: low risk (≤10%], low-average risk (10-15%], average risk (15-20%], high risk (20-40%], very high risk (>40%) for an early event. EFS was defined as time from diagnosis to progression, relapse, (re)treatment, histologic transformation, or death due to any cause. OS was defined as the time from diagnosis until death from any cause. Cox models and Kaplan Meier curves were used to evaluate association between FLIPI24 and EFS or OS. Results: 1542 patients initiating non-IC management approaches at diagnosis from 2002-2020 were identified. 51% were >60 years (IQR 52-70), and 49% were male. Most patients (86%) had FL grade 1-2. 61% of patients met any criteria for high tumor burden per GELF, BLNI, or GITMO based on available variables. Treatment approaches were 833 observation (54%), 315 rituximab monotherapy (20%), 186 radiation (12%), and 208 other non-IC approaches (14%). At median follow-up of 58 months, EFS24 was 73.8% (95% CI: 71.6%, 76.1%), 5-year OS was 90.9% (95% CI: 89.3%, 92.5%) and 253 (16%) patients died. The FLIPI24 score identified poor outcomes among patients with high/very high-risk score (FLIPI24 >20%), with median EFS of 1.8 years (95% CI, 1.3, 3.28) and 5 year OS of 65.1% (95% CI: 55.9-75.8) (Figure 1). When evaluating patient subsets, for patients with high tumor burden (defined based on available variables) and high/very high-risk score, median EFS was 1.6 years and 5 year OS was 64.6% (95% CI: 54.9%-76.1%). Among patients with low tumor burden FL and high/very high-risk score, median EFS was 2.0 years (95% CI: 0.84-NA) and 5 year OS was 66.2% (95% CI: 42.4%-100%). Patients undergoing observation with high/very high-risk score similarly had shortened median EFS of 1.53 years (95% CI: 1.25-NA) and 5 year OS of 68.9% (95% CI: 56.4%-84.1%). The FLIPI24 had superior concordance for OS (c=0.726) compared to the FLIPI (c=0.646) when evaluated in patients not treated with IC. Results were comparable in the subsets of patients observed (c=0.706 vs 0.596) and receiving rituximab monotherapy (c=0.764 vs 0.721). Conclusion: The FLIPI24 model has been previously validated to provide an individual risk score at diagnosis for the likelihood of experiencing an event within 24 months from starting IC. Here we demonstrate that a high FLIPI24 score predicts for poorer outcomes following non-IC strategies including observation, treatment with radiation, and rituximab monotherapy. The FLIPI24 has better prognostic performance for OS than FLIPI in this non-IC population. High FLIPI24 in patients not treated with IC identifies a patient population who should be considered for IC and/or novel frontline therapies when feasible.

Introduction Survival rates for people with mantle cell lymphoma (MCL) have improved in recent years. Among the potential factors accounting for this improvement is the approval of multiple new therapies over the past two decades, including bortezomib, bendamustine, ibrutinib, lenalidomide, acalabrutinib, and zanubrutinib. We hypothesized that the availability of multiple agents with non-overlapping mechanisms of action would result in significant improvements in overall survival following first-line therapy. Methods Patients diagnosed with MCL between 2002 and 2017 were identified using the SEER-Medicare linked database. Selected patients were >65 years of age at the time of diagnosis with MCL. Lines of therapy were determined using billing codes, with inpatient/outpatient claims used for traditional agents and Medicare Part D dataset used for oral agents. Next lines of therapy were defined based on claims for new anticancer agents separated from the end of the prior line by some certain number of days. Sensitivity analyses were performed varying the number of days between therapies. Overall survival (OS) was defined as initiation of initial therapy to death, while OS2 was defined as time from initiation of second-line therapy to death. Time to next therapy 1 (TTNT1) was defined as time from start of first-line therapy to death or start of second-line therapy, whichever came first. Cox models and Kaplan-Meier (KM) survival curves were generated for time-to-event analyses. Analyses were stratified by categories of years of first- and second-line therapies corresponding to eras of key drug approvals (e.g., 2002-2005, 2006-2009, 2010-2013, >2013). Results In total, 4,832 patients were included, among whom 3,840 patients (79.5%) had claims for first-line regimens and 1,648 (34.1% of total and 42.9% of patients with first-line regimens) had second-line regimens. Of the 4,832 patients, the majority were male (67.4%), White (94.6%), and non-Hispanic (94.7%), with good performance status (74.8%) and a Charlson Comorbidity Index <2 (64.8%). The median age at diagnosis was 75 (IQR 70-81). Patients with first- and/or second-line regimens did not differ significantly from the entire population of 4,832 patients with MCL in terms of baseline characteristics. In the first-line setting, use of bendamustine-rituximab (BR) increased from 2.3% of patients treated in 2006-2009 to 49.5% in 2014-2017. Similarly, use of single-agent BTK-inhibitors (BTKi) increased from nonexistent in patients treated in 2010-2013 to 13.8% in 2014-2017. In the second-line setting, use of single-agent BTKi similarly increased from 2.6% of those treated in 2010-2013 to 44.9% in 2014-2017. Median OS for the 3,840 patients with fist-line regimens was 4.4 years (95% CI, 4.1-4.5); median OS for those receiving first-line therapy in 2002-2005 was 3.5 years (3.1-3.9), compared to 3.7 (3.4-4.0), 4.5 (4.2-5.0), and not reached (4.8-NR) among those treated in 2006-2009, 2010-2013, and 2014-2017, respectively. Patients treated in 2014-2017 had significantly improved OS compared with those in 2002-2005 (log rank p<0.0001). Median TTNT1 overall was 2.5 years (2.4-2.6); median TTNT1 was 3.2 years (2.9-3.5) vs 2.3 years (2.1-2.6) for patients who received first-line therapy in 2014-2017 compared to 2002-2005 (log rank p<0.0001) ( Figure A). In addition, there was a significant difference across KM curves for OS2 stratified by categories of years of second-line therapy, with median OS2 of 2.5 (2.0-3.2) in patients treated in 2014-2017 compared to median OS2 of 2.1 (1.7-2.5) in 2010-2013 ( Figure B). Discussion In this analysis, we observed improvements survival of MCL patients over time, along with similar improvements in outcomes following first-line therapy, which may correlate with increased BR and BTKi use as first-line agents. Unexpectedly, improvements in survival following first-line therapy were considerably more modest. Potential explanations include lack of data from recent years during which we expect continued increased utilization of oral therapies vs unique impact of repeated therapies in the elderly. Overall, these data support the need for ongoing development of first- and subsequent-line therapies in MCL.

Background: The goal of clinical trial eligibility criteria is to identify a population of patients that have high risk disease or have unmet needs with standard of care therapy. Frontline trials of diffuse large B-cell lymphoma (DLBCL) include patients with International Prognostic Index (IPI) scores of 3-5 as a way to identify a high risk population. Trials typically include patients with IPI score=2, and sometimes IPI score=1, to expand the eligible patient population. However, broader patient populations must be balanced by the potential inclusion of low-risk patients with excellent outcomes to standard of care therapy, leading to potentially underpowered trials. IPI is a sum of dichotomous variables which makes implementation easy but can result in heterogeneity in outcomes within IPI scores. This heterogeneity may be caused by unequal prognostic information across IPI variables, loss of information within IPI variables due to the use of cutoffs, as well as information captured by variables that are not included in the IPI. In prior modeling of outcomes in DLBCL (Maurer et al, AJH 2016), we identified that: i) LDH has a strong prognostic ability beyond the upper limit of normal (ULN) and ii) bulky disease is an independent variable for prognosis. Here we evaluate if the presence of either of these two variables, easily captured at diagnosis within the current standard clinical work-up, can identify a high-risk subset of patients within the population of those with IPI scores of 1-2. Methods: Patients with newly diagnosed lymphoma were enrolled within 6 months of diagnosis in the LEO Cohort at 8 academic medical centers from 2015-2020 and prospectively followed. Inclusion criteria for this analysis was aggressive B-cell lymphoma typically included in frontline trials (e.g. DLBCL, high grade B-cell lymphoma, FL3B), IPI 1-5, frontline therapy with rituximab and anthracycline-based chemotherapy, stage II-IV disease and ages 18-80 years. Event-free survival (EFS) was defined as the time from diagnosis until progression, initiation of 2 nd line therapy, or death due to any cause; EFS was evaluated at 24 months (EFS24). Very high LDH was defined as LDH>1.3xULN based on prior modeling (Maurer et al, AJH 2016) and bulky disease was defined as maximum tumor diameter (MTD) of 7cm or greater. IPI 1 and 2 were first evaluated separately and then combined due to similar outcomes in patients with very high LDH and/or bulky disease. High risk IPI1-2 was defined as the presence of either bulky disease and/or very high LDH within an IPI score of 1-2. Confirmation was performed in a similar cohort of patients enrolled in the Iowa/Mayo SPORE Molecular Epidemiology Resource (MER) from 2002-2015; bulky disease was defined using a 10cm cutoff per availability in MER data collection forms. Results: 1560 patients from LEO were analyzed; median age was 64 years (IQR: 54-71), 42% were female and 83% had stage III/IV disease; subtype was DLBCL, NOS in 1335 (86%). IPI was 1-2 in 766 patients, 3 in 496 patients and 4-5 in 298 patients ( table). 391 (51%) with IPI1-2 had either bulky disease and/or very high LDH (high risk IPI1-2) and 375 had low-risk IPI1-2. EFS24 in high risk IPI1-2 (71.6%, 95% CI: 67.2-76.3) was significantly inferior to IPI1-2 without bulky disease or very high LDH (85.2, 95% CI: 81.7-88.9 logrank p=0.0035, figure) and similar to patients with IPI3 (70.7%, 95% CI: 66.8-74.9). Consistent results were observed in 1014 patients analyzed in the MER using a higher cutoff for bulky disease (10cm) due to data availability ( table). Patients with high risk IPI1-2 had significantly shorter diagnosis to treatment interval (DTI) in both the LEO (per-week OR=0.83, 95% CI: 0.77-0.88) and MER (per-week OR=0.77, 95% CI: 0.68-0.87) cohorts compared to low risk IPI1-2, both p<0.0001). In sensitivity analysis, LEO results were similar when performed in the subset of patients with DLBCL, NOS. Conclusion: The presence of either bulky disease and/or very high LDH at presentation identifies a high-risk subset of patients with IPI 1-2 that have similar outcomes to patients with IPI 3 disease. These simple criteria can be easily implemented within existing clinical trial diagnostic work-ups. Future trial designs in frontline aggressive B-cell lymphoma should include patients with IPI 3-5 and patients with IPI 1-2 with either bulky disease and/or very high LDH to better define a high-risk population of patients for clinical trial eligibility.

Background: Understanding the symptoms and quality of life (QOL) over time of adults with follicular lymphoma (FL) is important for treatment decision-making and clinical management. However, there are limited population-level data on the long-term QOL of adults with FL. We aim to describe the real-world, long-term QOL of adults with newly diagnosed FL up to 5/6 years after diagnosis. Methods: We used the Mayo Clinic/Iowa Molecular Epidemiology Resource (MER) and the multi-institutional Lymphoma Epidemiology of Outcomes (LEO) to identify adults with grade 1-3A FL who completed QOL surveys at baseline and follow-up. Participants with lymphoma were prospectively enrolled within 9 months of diagnosis in the MER cohort from 2002-2015 and within 6 months of diagnosis in the multi-institutional LEO cohort study across 8 cancer centers from 2015-2020. The LEO/MER cohort studies systematically collected information on disease status, QOL, health behaviors, and functional assessment. Treatments, disease relapses, and deaths were verified by medical record review. Treating physicians determined clinical management. QOL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G) at years 1, 2, 3, and 5/6 post-diagnosis. A higher FACT-G total score (range 0-108) indicated better QOL across 4 subscales (range): physical (0-28), social/family (0-28), emotional (0-24), and functional (0-28) well-being. We categorized participants based on their frontline management at time of diagnosis: “observation” (surveillance), “treatment” (systemic treatment with immunotherapy +/- chemotherapy), and “local” (radiation) groups. We employed a generalized linear mixed model to evaluate and compare the changes in QOL scores (as a continuous variable) from baseline for the observation, treatment, and local groups, adjusting for sex, race/ethnicity, age, FLIPI risk, and cohort (i.e., LEO or MER). We also evaluated QOL changes by FLIPI risk. Results: Our study included 1,544 participants with FL and QOL data. At the time of enrollment, median age was 61 years (range 19-91), 88% were non-Hispanic White, and 49% were female. Based on initial management, 529 (34%) were in the observation group, 880 (57%) were in the treatment group, and 135 (9%) were in the local group. FLIPI risk was high for 17% in the observation group, 29.3% in the treatment group, and 3% in the local group. The mean (standard deviation) baseline FACT-G total score was lowest in the treatment group with the following baseline scores: 86 (13) for the observation group, 83 (14) for the treatment group, and 88 (12) for the local group (Table 1). The observation and local groups reported a greater worsening of their baseline FACT-G total score vs the treatment group at both the 2-year (-1.2, -0.8 vs +1.8, respectively) and 5/6 year (-5.4, -6 vs. -1.6, respectively) timepoints (Figure 1). This appeared to be driven by worsened physical and functional well-being in the observation (-1.3, -2.2, respectively) and local (-0.9, -2.4, respectively) groups vs the treatment group (0, -0.3, respectively). These differences were statistically significant between the observation vs treatment groups. There were no statistically significant differences in the other subscales, i.e., social/family and emotional well-being, by frontline management. Social/family well-being decreased across all groups by 5/6 years (-2.3 in observation, -2.2 in treatment, and -3 in local, p<0.05). Regardless of FLIPI risk, the total FACT-G scores decreased within each FLIPI risk group at 5/6 years (-4.4 for low, -3.8 for intermediate, and -4.9 for high, p<0.05). This was primarily due to worsened social/family well-being (-2.4 for low, -2.2 for intermediate, and -3 for high, p<0.05) at 5/6 years. There was no statistically significant difference in QOL between FLIPI risk groups. Conclusion: This is one of the first and largest studies with real-world longitudinal QOL data for FL. Our study suggests that frontline systemic treatment initially improved QOL and resulted in a lower degree of QOL decline over time. Social/family well-being decreased over time regardless of frontline management or FLIPI risk. Further research is warranted to explore the impact of timing and specific systemic treatments on QOL, incorporate the patient/caregiver experience to address social/family well-being, and identify the clinical significance of our findings.

Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras. Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2). In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2). In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2). In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2). In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort. Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.

Background: Shorter diagnosis to treatment interval (DTI) has been shown to be associated with more aggressive disease features and inferior outcomes in diffuse large B-cell lymphoma (DLBCL; Maurer et al, JCO 2018). Additional confirmatory studies have also shown that DTI is related to tumor volume (Alig et al, JCO 2021) and molecular phenotype (Aluaij et al, Blood 2023). Here we evaluate DTI in a large multicenter cohort of patients prospectively enrolled and followed as part of the Lymphoma Epidemiology of Outcome (LEO) cohort. Methods: Patients were enrolled within 6 months of diagnosis at one the 8 LEO cohort academic medical centers in the United States between 2015 and 2020. Patients in this analysis had aggressive B-cell lymphoma (BCL) treated with anthracycline-based chemotherapy. DTI was defined as the initial lymphoma biopsy date until the start of initial chemotherapy; patients with DTI between 0-100 days were evaluated. Short DTI was defined as DTI ≤ 14 days (DTI≤14) as previously described in prior publications (e.g. Maurer et al, JCO 2018) and confirmed via examination of functional forms via splines. Event-free survival (EFS) was defined as the time from start of treatment until progression/relapse, retreatment, or death due to any cause. Overall survival (OS) was defined as the time from start of treatment until death due to any cause. Results: 2565 patients with aggressive B-cell lymphoma were evaluated. Median age was 62 years (IQR 51-71) and 1469 (57%) were male. 297 patients (12%) were self-reported non-White race and 314 patients (12%) were self-reported Hispanic or Latino. The majority had DLBCL, NOS subtype (N=1927, 75%), while 227 (9%) had high-grade BCL with MYC and BCL2 and/or BCL6 rearrangements (HG, DH) and 90 (4%) had high-grade BCL NOS (HG, NOS). Clinical characteristics are summarized in the table. At median follow-up of 49 months (IQR 36-68), 800 patients (31%) had an event and 578 patients (23%) died. EFS at 24 months (EFS24) was 76% (95% CI: 74-77). Median DTI across all subtypes was 21 days (IQR 12-33) and 845 patients (33%) had DTI≤14. Patients with DTI≤14 were significantly younger (median age 59 years) but there was no association between DTI and gender, race, or ethnicity. Patients with DTI≤14 were more likely to have HG, DH or HG NOS subtypes, ECOG PS 2-4, advanced stage, elevated LDH, CNS involvement, B symptoms, and bulky disease ( see table). Patients with DTI≤14 were more likely to receive R-EPOCH-based or intensive therapies (41%) and less likely to receive 1L therapy on a clinical trial (3.8%) compared to DTI>14 (26% and 10.1%, respectively). Consistent with previously reported data, DTI≤14 was associated with inferior EFS (HR=1.62, 95% CI: 1.41-1.87, figure), OS (HR=1.73, 95% CI: 1.47-2.04), and EFS24 (OR=1.93, 95% CI: 1.60-2.38). The association between DTI and outcomes remained significant after stratifying for subtype (EFS HR=1.68, 95% CI: 1.46-1.94; OS HR=1.78, 95% CI: 1.50-2.10) and adjustment for IPI (EFS HR=1.43, 95% CI: 1.24-1.65; OS HR=1.47, 95% CI: 1.24-1.74). In subset analysis, DTI≤14 was significantly associated with inferior outcomes within the subtypes of HG, DH (EFS HR=2.70, 95% CI: 1.82-4.01; OS HR=2.97, 95% CI: 1.92-4.60); HG, NOS (EFS HR=2.07, 95% CI: 0.93-4.60; OS HR=2.36, 95% CI: 1.03-5.43); and DLBCL, NOS (EFS HR=1.51, 95% CI: 1.27-1.78; OS HR=1.52, 95% CI: 1.45-1.85). Analysis was limited in other subtypes due to number of events. Notably, within the subset of patients with DTI>14, there was no significant difference in EFS between subtypes for DLBCL, NOS (EFS24=80%, EFS HR=ref), HG, DH (EFS24=73%, EFS HR=1.26, 95% CI: 0.92-1.73) and HG, NOS (EFS24=83%, EFS HR =0.84, 95% CI: 0.40-1.78), logrank p=0.29; similar results were observed for OS (p=0.22). Conclusions: Patients requiring early initiation of therapy for aggressive B-cell lymphoma represent a distinct population of patients with more aggressive clinical features and inferior outcomes. In patients with longer DTI, high grade subtypes had similar outcomes to DLBCL, NOS. Efforts should be made to include patients with anticipated short DTI in clinical trials and translational studies to fully capture the spectrum of patients with aggressive B-cell lymphoma.

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

Background: High Grade B cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements(R) was introduced as an entity in 2016 by the WHO revised 4 th edition. In 2022, both the WHO 5 th edition (beta version) and the International Consensus Classification (ICC) separated DHL- BCL2 (+/- BCL6-R)from DHL- BCL6 given differences in biology . However, while the ICC has maintainedDHL- BCL6 as a provisional entity, the WHO has removed the category, thus removing the requirement to FISH for BCL6-R in this setting. Clinical data on DHL- BCL6 is much more limited, as these cases represent only 10-20% of DHL and have been combined with BCL2-R cases in prior studies. Outcomes are variable in retrospective studies with no consistent data on prognosis or optimal therapeutic strategies. By retaining the category of DHL-BCL6 as a provisional entity, the ICC emphasized the need for further, multicenter, prospective studies evaluating the clinical and biological features of this disease. We herein report a comprehensive comparison of clinical characteristics and outcomes in patients with DHL- BCL6 compared to diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS); DLBCL with MYC rearrangement only; DHL- BCL2; and HGBL, NOS in a large, multicenter, prospective cohort of patients from Lymphoma Epidemiology of Outcomes (LEO). Methods: Adult patients with newly diagnosed large B-cell or HGBL were enrolled within 6 months of diagnosis at one the 8 LEO cohort academic medical centers in the US between 2015 and 2020. Baseline characteristics were abstracted at the time of diagnosis per protocol. Based on FISH data patients were further sub mgrouped into DLBCL, NOS (without MYC rearrangement); MYC-R DLBCL, NOS; HGBL, NOS; DHL- BCL2 and DHL- BCL6. Event-free survival (EFS) was defined as the time from diagnosis until progression/relapse, retreatment, or death. Overall survival (OS) was defined as the time from diagnosis until death due to any cause. Results: A total of 1526 eligible patients were identified during this time period. All FISH data was available at the time of diagnosis and the choice of treatment was based on physician discretion. Median age at diagnosis was 63 years (IQR 53-72), with 148 (10%) patients in the AYA category, and 128 (8%) patients > 80 years. 58% (891) were male, 11% self identified as Hispanic or Latino, and 7% as Black/African American. The median diagnosis to treatment interval (DTI) was 20 days (IQR 12-32), and 33% had DTI < 14 days. The FISH-based subgroups were MYC-negative DLBCL, NOS (N=1146, 75%), MYC-R DLBCL,NOS 227 (N = 96, 6%), DHL- BCL2 (N=154, 10%), DHL- BCL6 (N=38, 3%), and HGBL, NOS (N=92, 6%). When available, COO by Hans algorithm was 92% GCB in DHL- BCL2 and 50% GCB in DHL- BCL6. Clinical characteristics can be found in the table. At a median follow-up of 49 months (IQR 36-67), 490 patients (32%) had an event and 356 patients (23%) died. EFS at 24 months (EFS24) was 75% (95% CI: 73-77). Patients with DHL- BCL6 were younger at diagnosis (median 60 years), had more extranodal site involvement (40%), more often stage III/IV disease (70%), and more often treated with a higher intensity regimen than R-CHOP (69%) compared to DLBCL,NOS and MYC-R DLBCL. DHL- BCL6 also had fewer patients that were males (47%), with DTI <=14 days (33%), NCCN IPI ≥ 4 (45%), elevated LDH (53%) than HGBL, NOS and DHL- BCL2. The 2-year EFS and OS rates were noted to be significantly better in the DHL- BCL6 (EFS 79%, 95% CI: 67-93; OS 92%, 95% CI: 84-100) as compared to DHL- BCL2 (EFS 58%, 95% CI: 50-66; OS 70%, 95% CI 63 - 78) and HGBL, NOS (EFS 74%, 95% CI: 65-84; OS 74%, 95% CI: 65-84 ), (Figure 1) but were comparable to that of DLBCL, NOS (EFS 78%, 95% CI: 76-81; OS 87%, 95% CI: 86-89). Conclusions: Our data support separating DHL- BCL6 from DHL -BCL2 as these patients form a unique subgroup with some clinical characteristics comparable to both DLBCL, NOS as well as HGBL, NOS and DHL- BCL2 subtypes. In this cohort, clinical outcomes are more comparable to DLBCL, NOS than DHL- BCL2 or HGBCL, NOS. More frequent use of intensive chemotherapy in DHL- BCL6 compared with DLBCL may account for this finding, although larger multicenter studies are needed. Our results support continued identification of DHL- BCL6 in the clinical setting to better understand optimal therapy and biology of this cohort.

Introduction: Histologic transformation (HT) from follicular lymphoma (FL) to an aggressive lymphoma is infrequent but has unfavorable outcomes. Sarkozy et al. (J Clin Oncol, 2019) reported that approximately half of FL-related deaths within the first decade of diagnosis occurred following HT. Our recent analysis showed heterogeneous outcomes with median overall survival (OS) of 61 months (Day et al., ASH, 2022). Prognostic tools post HT would be clinically useful but development has been limited by small cohort sizes. Factors previously associated with outcomes following HT have included age, time to progression, prior therapy, anthracycline exposure, and early HT. Utilizing the Lymphoma Epidemiology of Outcomes (LEO) Consortium of Real World Evidence (CReWE), we describe patterns of care and evaluate other prognostic factors following HT. Methods: This multicenter observational cohort consists of prospectively enrolled patients in the LEO Cohort, and patients with HT retrospectively identified at LEO centers. Patients diagnosed with biopsy proven grade 1-3A FL at diagnosis, and a subsequent biopsy showing HT to an aggressive lymphoma (FL grade 3B, diffuse large B cell lymphoma [DLBCL], or high-grade B cell lymphoma [HGBCL]) between 2002-2022, were eligible for the study. Patients with a component of FL grade 3B, DLBCL, or HGBCL at diagnosis were excluded. HGBCL was defined as double or triple hit or another aggressive subtype. OS was defined as the time from HT until death from any cause and calculated via Kaplan-Meier. Associations between clinical factors at time of HT and/or diagnosis and OS were evaluated using Cox models. Cause of death was evaluated using a competing risk approach. Results: Overall, 328 patients were confirmed with HT during the study period, 41% were female, and the median age at HT was 63 years (interquartile range [IQR] 56-70). The median time from diagnosis to transformation (TDT) was 35 months (IQR 12-66). At HT, 88% had advanced stage disease (III-IV) and LDH was elevated in 49%, while few patients exhibited B symptoms (5%) and ECOG performance status was >2 in 9%. 23% did not receive systemic therapy prior to HT. For those with prior therapy, the median time from prior therapy to HT was 15 months (IQR 7-39). The most frequent treatment regimens following HT were CD20-CHOP (42%), followed by platinum-based salvage therapy (20%), R-EPOCH (10%), CD20-Benda (8%), R-Mono (4%), and R-Gem-Ox (3%). 50 (15%) patients underwent consolidation with autologous stem cell transplant, 3 underwent allogeneic transplant (30 platinum-based, 15 CD20-CHOP, 5 R-EPOCH, 3 Other), and 2 received CAR T-cell therapy (Figure 1). After median follow-up of 85 months from HT, 170 patients had died; 5-year OS was 52% and median OS was 65 months (95% CI: 55-107). Among 160 patient deaths, cause was most often lymphoma-related (progression, n=107 [63%]; therapy-related, n=14 [7%]) compared to non-lymphoma (n=20, 13%) or missing/unknown causes (n=29, 17%). Clinical factors at the time of HT that were associated with worse OS include: ECOG PS >2, age ≥70, IPI 3-5, and shorter TDT (<24 months), hemoglobin <10 g/dl and elevated LDH. A transformation to HGBCL was also associated with inferior OS (Table 1). OS did not significantly differ by gender, BMI, stage, presence of B-symptoms, absolute lymphocyte count, number of extranodal groups, presence of bulky disease at HT, or response to prior FL treatment. Factors at the time of FL diagnosis that were associated with decreased OS after HT included FLIPI score 3-5 (high risk), FLIPI 2 (moderate risk), and FL grade 3A at diagnosis. Exposure to any systemic therapy for FL prior to HT was associated with shorter OS, with the worst outcomes in patients receiving an anthracycline prior to HT. POD24 to frontline immunochemotherapy was associated with inferior OS after HT (Table 1). Conclusions: Patterns of care in Transformed FL are heterogeneous and vary greatly in intensity. These data confirm previous reports that age, early HT, and any systemic therapies prior to HT are negative prognostic indicators for OS. At HT elevated LDH, low hemoglobin, POD24 status, poor performance status, and HT to HGBCL were associated with poor outcomes following HT. These data provide a basis for future prognostic indices to identify patients with highest risk of lymphoma related mortality for whom study of novel treatments is greatly needed.