Maurer, Matthew J.

PURPOSE: This study assessed the long-term quality of life (QOL) of patients with aggressive lymphoma subtypes treated with autologous hematopoietic cell transplant (autoHCT) compared with those without history of transplant. METHODS: Patient-reported QOL measures were prospectively gathered from patients enrolled in the Iowa/Mayo Specialized Program of Research Excellence Molecular Epidemiology Resource cohort with aggressive lymphoma subtypes. QOL was measured using the Functional Assessment of Cancer Therapy-General (FACT-G), Functional Assessment of Chronic Illness Therapy–Fatigue Scale, State-Trait Anxiety Inventory (STAI), and Profile of Mood States instruments and with a numeric rating scale for overall QOL and spiritual QOL. The autoHCT group and no HCT groups were compared at 3 years (FU3) and 6 years (FU6) after lymphoma diagnosis. RESULTS: In total, 980 patients with lymphoma (106 autoHCT and 874 no HCT) diagnosed between 2002 and 2013 were included for analysis. The mean FACT-G total score was similar in the autoHCT and no HCT groups at FU3 (89.9 v 90.1, P = .64) and also at FU6 (91.5 v 89.6, P = .44). No differences between the autoHCT and no HCT groups were identified in the FACT subscales. The STAI identified lower anxiety in the autoHCT group by mean STAI1 (state) at FU3 (30.1 v 33.4, P < .01) and by mean STAI2 (trait) at FU6 (30.1 v 33.5, P = .02). No other clinically meaningful differences were identified between the two groups using the other QOL instruments. CONCLUSION: Patients remaining in remission at 3 and 6 years after diagnosis had a high level of QOL with no significant differences associated with history of treatment with autoHCT.

The poly(ADP-ribose) binding protein CHFR regulates cellular responses to mitotic stress. The deubiquitinase UBC13, which regulates CHFR levels, has been associated with better overall survival in paclitaxel-treated ovarian cancer. Despite the extensive use of taxanes in the treatment of ovarian cancer, little is known about expression of CHFR itself in this disease. In the present study, tissue microarrays containing ovarian carcinoma samples from 417 women who underwent initial surgical debulking were stained with anti-CHFR antibody and scored in a blinded fashion. CHFR levels, expressed as a modified H-score, were examined for association with histology, grade, time to progression (TTP) and overall survival (OS). In addition, patient-derived xenografts from 69 ovarian carcinoma patients were examined for CHFR expression and sensitivity to paclitaxel monotherapy. In clinical ovarian cancer specimens, CHFR expression was positively associated with serous histology (p = 0.0048), higher grade (p = 0.000014) and higher stage (p = 0.016). After correction for stage and debulking, there was no significant association between CHFR staining and overall survival (p = 0.62) or time to progression (p = 0.91) in patients with high grade serous cancers treated with platinum/taxane chemotherapy (N = 249). Likewise, no association between CHFR expression and paclitaxel sensitivity was observed in ovarian cancer PDXs treated with paclitaxel monotherapy. Accordingly, differences in CHFR expression are unlikely to play a major role in paclitaxel sensitivity of high grade serous ovarian cancer.

Abstract Background: Differences in outcomes between clinical trial and real-world populations in follicular lymphoma (FL) may be partially explained by differences in characteristics between clinical trial and real-world patients. We hypothesized that certain eligibility criteria may be responsible for populations with distinct demographic/clinical characteristics. In this study, we compiled a list of eligibility criteria from front-line FL trials and evaluated their impact on the potentially eligible FL patients derived from two national cohort studies. We also evaluated whether criteria were duplicative and whether liberalizing criteria might enlarge the pool of eligible patients. Methods: Eligibility criteria were abstracted from 21 first-line clinical trials in FL in the FLASH database. We identified FL patients in two prospective cohort studies: Molecular Epidemiology Resource (MER) and Lymphoma Epidemiology of Outcomes (LEO). Descriptive statistics were used to characterize patients included and excluded by various eligibility criteria. Chi-square tests and two-sample t-tests were used to compare categorical and continuous variables, respectively. To study the relative impact of individual criteria, we used a step-wise approach to quantify the number of additional patients excluded with each individual criterion after applying other criteria. Results: Eligibility criteria included in at least one-third of studies included stage (present in all 21 trials), renal function (18), HIV/AIDS status (17), performance status (16), history of other malignancies (16), hepatic function (16), and cardiac function (15), other serious health conditions (13), pregnancy status (10), neuro/psych function (10), age (10), metabolic disease status (9), CNS involvement (9), birth control (8), pulmonary function (8), WBC count (8), HBV status (8), platelet count (7), measurable disease (7), HCV status (7), active infection status (7), and CD20 status (7). We included 738 patients with newly diagnosed FL undergoing first-line therapy from MER and 703 patients from LEO. In MER, the median age was 60 years; 87% were White vs 2% non-White, 80% were non-Hispanic vs 2% Hispanic, and 68% were stage III/IV. In LEO, the median age was 60 years; 88% were White vs 11% non-White, 87% were non-Hispanic vs 11% Hispanic, and 67% were stage III/IV. Exclusion criteria impacting more than 10% of patients included stage (31 in LEO vs 29% in MER), self-reported serious health conditions (17 vs 31%), prior cancer diagnosis (14 vs 11%), performance status (10%), and platelet count (10%). Patients excluded due to the following criteria tended to be older: renal function (median 70 vs 60 years in MER), prior malignancy (67 vs 58 years), and self-reported serious health conditions (66 vs 58 years). This pattern was consistent in LEO (Table). No eligibility criteria significantly impacted race/ethnicity. Given the potential for multiple eligibility criteria to exclude the same patients, we used a step-wise approach to evaluate the impact of individual criteria on patients remaining after exclusion by the larger group of criteria, and whether liberalizing criteria impacted patient numbers and/or demographics. We found that only self-reported serious health conditions significantly impacted numbers (excluding 43% of patients), whereas hematologic parameters and performance status excluded only 5 and 1% of patients, respectively, with no impact on age or race/ethnicity. We also found that liberalizing stage requirement from III-IV to II-IV could increase enrollment by 14% in MER (12% in LEO), and liberalizing platelet requirement from ≥150,000 to ≥100,000 could increase enrollment by 11% (15% in LEO). Moreover, liberalizing eligibility criteria had no impact on age or race/ethnicity of the patient pool or on EFS (Figure). Conclusions: We found that excluding patients with prior malignancies, poor renal function, and self-reported serious health conditions appears to inadvertently exclude older patients. Other serious health conditions appeared to exclude a significant number of patients but did not impact patient demographics. Liberalizing certain criteria, including stage and platelet requirement, could potentially increase trial accrual, but would not likely correct the older patient deficit. These findings may serve in developing consensus eligibility criteria for future first-line FL trials. Figure 1 Figure 1. Disclosures Flowers: Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; National Cancer Institute: Research Funding; Allogene: Research Funding; Biopharma: Consultancy; Cellectis: Research Funding; EMD: Research Funding; Genentech/Roche: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Genmab: Consultancy; Iovance: Research Funding; Guardant: Research Funding; Burroughs Wellcome Fund: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Amgen: Research Funding; Xencor: Research Funding; Nektar: Research Funding; SeaGen: Consultancy; Ziopharm: Research Funding; TG Therapeutics: Research Funding; 4D: Research Funding; Acerta: Research Funding; Denovo: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Morphosys: Research Funding; Adaptimmune: Research Funding; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Kite: Research Funding; Janssen: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Link: MEI: Consultancy; Novartis, Jannsen: Research Funding; Genentech/Roche: Consultancy, Research Funding. Friedberg: Acerta: Other: DSMC ; Bayer: Other: DSMC ; Novartis: Other: DSMC . Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Seattle Genetics: Consultancy; NCI: Research Funding; Verastem: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; NIH grants: Research Funding; University of Miami: Current Employment. Nastoupil: Bayer: Honoraria; Gilead/Kite: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; ADC Therapeutics: Honoraria; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Janssen: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; Caribou Biosciences: Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; MorphoSys: Honoraria. Maurer: Nanostring: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; BMS: Research Funding. Cerhan: NanoString: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding. Martin: ADCT: Consultancy.

Abstract Background: Event-free survival at 24 months (EFS24) is an important clinical endpoint in newly diagnosed diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 with frontline immunochemotherapy have minimal loss of lifetime compared to age- and sex-matched general population. However, the prognostic role of EFS24 in mantle cell lymphoma (MCL) has not been well studied, possibly due to the perception of continued relapse pattern and poor survival outcome of MCL historically. A recent study from our group demonstrated evolving frontline therapy pattern from 2002-2009 ("Era 1") to 2010-2015 ("Era 2") which was associated with improved EFS and overall survival (OS) in Era 2. In the current study, we sought to explore the prognostic role of EFS24 in the two eras. Methods: Patients with newly diagnosed MCL from 9/2002 through 6/2015 were identified from Molecular Epidemiology Resource (MER), a prospective cohort study of the University of Iowa/Mayo Clinic Lymphoma SPORE. OS was defined as time from diagnosis (or the EFS24 defining event where applicable) to death from any cause and was analyzed using the Kaplan-Meier method. Expected OS accounting for age and sex was generated in R by using the general US population as the reference group. Observed versus expected OS was summarized by using standardized mortality ratio (SMR) and 95% confidence intervals (CI) of observed to expected deaths. Cumulative incidence of lymphoma-specific death was analyzed using Gray's test, with deaths from all other causes treated as competing events. Results: A total of 343 patients were included, 175 from Era 1 (median follow-up 13.0 years) and 168 from Era 2 (median follow-up 6.9 years). Age, sex and simplified MIPI score were similar between the 2 groups. Patients diagnosed in Era 2 had better OS, with a 5-year OS of 68.4% vs 59.2% (simplified MIPI-adjusted hazard ratio 0.68, 95% CI 0.50-0.93). Patients diagnosed in both eras had inferior OS compared to the general population, with an SMR of 3.26 (95% CI 2.70-3.89, P&lt;0.001) in Era 1 and 2.63 (95% CI 2.03-3.36, P&lt;0.001) in Era 2. Patients diagnosed in Era 1 who achieved EFS24 (n=98) still had inferior OS compared to the general population, with an SMR of 2.23 (95% CI 1.67-2.92, P&lt;0.001) (Figure 1A). In contrast, for patients diagnosed in Era 2 who achieved EFS24 (n=99), no evidence of OS difference was found compared to the general population, with an SMR of 1.31 (95% CI 0.78-2.07, P=0.31) (Figure 1B). The primary cause of death after diagnosis was lymphoma-related for patients diagnosed in both eras. The 5-year rate of lymphoma-related death was 28.8% in Era 1 and 20.5% in Era 2. In patients who were diagnosed in Era 1 and achieved EFS24, the primary cause of death after achieving EFS24 remained to be lymphoma-related, with a 5-year rate of 19.8% compared to 6.2% for lymphoma-unrelated causes (Figure 1C). In contrast, in patients who were diagnosed in Era 2 and achieved EFS24, the rate of lymphoma-related death was no longer higher than that of lymphoma-unrelated death, with a 5-year rate of 2.1% vs 5.5%, respectively (Figure 1D). In a sensitivity analysis restricted to only patients who received standard frontline immunochemotherapy, similar results were obtained. For example, in patients who achieved EFS24, the SMR compared to the general population was 2.89 (95% CI 2.00-4.04, P&lt;0.001) in Era 1 and 0.89 (95% CI 0.43-1.64, P=0.82) in Era 2. The 5-year rates of deaths due to lymphoma-related vs lymphoma-unrelated causes were 20.7% vs 6.2% in Era 1 and 1.3% vs 4.9% in Era 2. Conclusions: MCL survival outcome has improved for patients first diagnosed in the more recent era (2010-2015, compared to 2002-2009), likely due to improved frontline therapy as well as better salvage treatments (such as lenalidomide and BTK inhibitors). In the more recent treatment era, patients who achieved EFS24 had survival approaching the age- and sex-matched general population. In addition, these patients had a low risk of dying from lymphoma and were more likely to die from other causes. Longer follow-up (e.g., in Era 2) and external validation in other series are necessary to confirm the prognostic role of EFS24. With more efficacious salvage treatment options and likely continued improvement of OS in MCL, EFS24 may become an important clinical endpoint in frontline therapy of MCL. Figure 1 Figure 1. Disclosures Wang: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Nanostring: Research Funding. Link: Novartis, Jannsen: Research Funding; Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy. Farooq: Kite, a Gilead Company: Honoraria. Paludo: Karyopharm: Research Funding. Witzig: Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding; Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Habermann: Seagen: Other: Data Monitoring Committee; Tess Therapeutics: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding; Genentech: Research Funding. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: CD20 antibody plus alkylator and/or anthracycline based immunochemotherapy (IC) is a standard frontline therapy for patients with follicular lymphoma (FL) with 10-year event-free survival (EFS) and overall survival (OS) rates of approximately 50% and 80% respectively in long-term follow-up of clinical trials. Currently available clinical prognostic indices for FL have been designed using PFS and OS endpoints. Early events, commonly defined as progression of disease within 24 months (POD24) or early transformation to a more aggressive histology, are associated with inferior outcomes and increased risk of death due to refractory FL. Timely identification of the minority of patients with elevated mortality risk might enhance clinical management and research strategies. The FLIPI24 Consortium was created to develop a clinical prognostic index using early events as the primary endpoint. We report the outcomes for the pooled cohort and investigate the implications of therapy patterns on potential model development. Methods: Individual patient data were pooled and harmonized from 11 prospective observational cohorts from Europe, North America, and Australia. Patients who were diagnosed with grades 1-3A FL and initiated frontline IC were eligible. EFS was defined as time from start of IC to progression, relapse, retreatment (2nd line), histologic transformation, or death due to any cause. Early events were defined using status at 24 months from start of IC. OS was defined as time from start of IC to death due to any cause. Kaplan Meier curves and Cox proportional hazards models were used to evaluate outcomes by clinical features and therapy types. Results: 9006 patients were abstracted and harmonized, 6111 patients initiated frontline IC between 2002 and 2018 and were included in this analysis. Median age at diagnosis was 61 years (IQR 52-69) and 50% were male. Complete FLIPI data were available in 5637 patients (92%) and 46%, 32%, and 22% were low, intermediate, and high risk, respectively. IC type was 3079 R-CHOP or like (50%) , 1529 R-CVP or like (25%), 918 R-bendamustine (B-R) or like (15%), and 585 fludarabine or other alkylator based IC (10%); 3187 received CD20 antibody maintenance (52%). Patients receiving R-CHOP were younger, more frequently grade 3A, and more frequently had elevated LDH; differences in other characteristics by IC type were not clinically meaningful. At median follow-up of 42 months (IQR 17-72), 2647 patients (43%) had an event (any) and 1494 patients (25%) died. Median survival after an early (non-death) event was 49 months (95% CI: 41-58); 5-year OS was 46% (95% CI: 43-49) compared to 89% (95% CI: 88-90) in patients without POD24. Across all IC types, EFS estimates at 2 and 10 years from start of IC were 80% (95% CI:79-81) and 49% (95% CI:48-51) and OS estimates were 92% (95% CI: 91-92) and 70% (95% CI: 69-72), respectively. FLIPI was highly associated with both EFS (c-statistic=0.61) and OS (c-statistic=0.65) from the initiation of IC (both p&lt;0.0001). There were significant differences in EFS and OS by IC type (both p&lt;0.0001) and use of maintenance was associated with prolonged EFS in landmark analyses at both 6 and 12 months from initiation of IC (both p&lt;0.0001). Treatment patterns changed significantly over the study timeframe. Use of B-R and/or maintenance increased to 30% and 70% respectively in N=2937 patients treated in 2010-2018 (Era2) compared to &lt;1% and 40% respectively in N=3174 patients treated 2002-2009 (Era1). EFS was significantly higher for Era2 compared to Era1 (HR=0.77, 95% CI: 0.71-0.83), which remained significant after adjustment for FLIPI (EFS HR=0.82, 95% CI: 0.76-0.89). However, the association between treatment eras and overall survival was weaker (HR=0.89, 95% CI: 0.79-0.99) and not significant after adjusting for baseline FLIPI (OS HR=0.99, 95% CI: 0.88-1.10). Conclusion: EFS and OS from this large pooled analysis of observational cohorts is similar to long-term follow-up of randomized clinical trials in the IC era and support the use of these data for model development. Modeling efforts for early events should adjust for initial IC selection and use of maintenance therapy. Utilization of bendamustine and/or maintenance therapy increased over the study timeframe from 2002-2018, and Era2 was associated with improved EFS but not OS. This cohort provides comprehensive and robust observational data to define clinical predictors in IC treated patients. Figure 1 Figure 1. Disclosures Maurer: Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Flowers: Janssen: Research Funding; Takeda: Research Funding; National Cancer Institute: Research Funding; Biopharma: Consultancy; BeiGene: Consultancy; Amgen: Research Funding; Celgene: Consultancy, Research Funding; Xencor: Research Funding; Acerta: Research Funding; Bayer: Consultancy, Research Funding; Sanofi: Research Funding; 4D: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; EMD: Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Kite: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Denovo: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Epizyme, Inc.: Consultancy; Novartis: Research Funding; Nektar: Research Funding; Morphosys: Research Funding; Iovance: Research Funding; Spectrum: Consultancy; Pfizer: Research Funding; Ziopharm: Research Funding; Guardant: Research Funding; Eastern Cooperative Oncology Group: Research Funding; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics: Research Funding. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Weibull: Jansen-Cilag: Other: part of a research collaboration between Karolinska Institutet and Janssen Pharmaceutica NV for which Karolinska Institutet has received grant support. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Kridel: Gilead Sciences: Research Funding. Gandhi: Janssen: Research Funding; Novartis: Honoraria. Cheah: Celgene: Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; AstraZeneca: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Beigene: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Gilead: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding. Hawkes: Gilead: Membership on an entity's Board of Directors or advisory committees; Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees; Antigene: Membership on an entity's Board of Directors or advisory committees; Regeneron: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; Specialised Therapeutics: Consultancy; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Seymour: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Freeman: Amgen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Speakers Bureau; Incyte: Honoraria; Abbvie: Honoraria; Teva: Research Funding; Roche: Research Funding; Janssen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau. Clausen: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wahlin: Gilead Sciences: Research Funding; Roche: Consultancy, Research Funding. Link: Novartis, Jannsen: Research Funding; Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy. Ekstroem Smedby: Janssen Cilag: Research Funding; Takeda: Consultancy. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Trněný: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; NanoString: Research Funding.

Abstract Introduction: DNA mismatch repair (MMR) is a major mechanism cells use to repair erroneous insertion or deletion of bases during DNA replication. MMR deficiency (MMR-d), including rare germline mutations (Lynch syndrome) and somatic inactivation, has been extensively studied in solid tumors, such as colon, endometrial, pancreatic, and ovarian cancers. The prevalence of MMR-d in solid tumors ranges from 1% - 20% of somatic defects, and patients with MMR-d tumors have a longer overall survival. It is also well-known that MMR is an integral part of activation-induced cytidine deaminase (AID)-mediated somatic hypermutation and immunoglobulin class switch processes in normal mature B lymphocytes, while mice deficient in the MMR genes are prone to develop T and B cell lymphomas. It is also known that follicular lymphoma (FL) carries a high degree of somatic hypermutation with some heterogeneity induced by AID. Our understanding of MMR status in human blood cancers, especially in FL remains very limited. One could hypothesize that MMR-d status could permit cells to acquire and sustain high-degree of mutation rates, better sensitivity to DNA damaging chemotherapy while hindering rapid cell proliferation, which could manifest to a better prognosis in patients. Herein, we conducted an exploratory analysis to understand the frequency of MMR-d status and its prognostic significance in FL. Methods: Following approval of the Institution Review Board, we assessed the expression of MMR proteins; MLH1, PMS2 and MSH6 on formalin fixed paraffin embedded (FFPE) lymph node tissue obtained from patients with FL by immunohistochemistry (IHC) using standard methods on Ventana Benchmark XT automated stainers (Ventana Medical Systems, Tucson, AZ). Dako (clone ES05), Cell Marque (clone EPR3947) and Biocare (clone BC/44) antibodies were used to stain MLH1, PMS2 and MSH6, respectively. Fifty cases of FL with existing FFPE blocks were selected randomly. The expression of MLH1, PMS2 and MSH6 proteins in the tumor cells was scored as 0, +1 or +2, (Figure 1A). Cases with absence of the IHC signal (score of 0) in any one of the three proteins were classified as MMR-d. Progression free survival at 12 months (PFS12) or 24 months (PFS24) was defined as being free from disease progression or death at 12 or 24 months, respectively. All time-to-event analyses were done from the time of diagnosis. Results: Fifty patients with FL were included in the study. The median age at diagnosis was 65 years (range 34-85) and 58% were females. At initial diagnosis, 36 (72%) patients had advanced stage (stage 3, n=8, stage 4, n=28) disease. Of the 50 patients, 26 (52%) required treatment; chemotherapy (n=14), radiation treatment alone (n=9), surgery alone (n=3). Out of the 50 patients, 23 (46%) were classified as MMR-d due to lack of expression of one of the three assessed proteins: MLH1 (n=1, 2%), PMS2 (n=11, 22%) and MSH6 (n=19, 38%). The patient who had MLH1 loss had concomitant PMS2 loss. Stage IV disease was observed in 52% of the MMR-d patients and 59% in the MMR proficient (MMR-p) patients, p=0.77. Median age at diagnosis was 62 (range: 34-84) years and 67 (range: 34-85) years in MMR-d and MMR-p patients, respectively, p=0.1. FLIPI score was similar between the MMR-d [low n=10 (43%), intermediate n=9 (39%), high n=4 (18%)] and MMR-p [low n=5 (18%), intermediate n=14 (52%), high n=8 (30%)] patients, p=0.16. Fourteen (61%) of MMR-d patients required initiation of therapy upon diagnosis compared to 12 (44%) of MMR-p patients, p=0.27. The median follow-up for the entire cohort was 17 years [95% confidence interval (CI): 11.7-29.4]. The median overall survival (OS) of MMR-d patients was 10 years (95%CI: 7.8-20.7) compared to 6 years (95%CI: 4.5-NR) in MMR-p patients, p=0.036, Figure 1B. In patients with MMR-d and MMR-p, 83% and 55% achieved PFS12, p=0.04 and 65% and 41% achieved PFS24, p=0.08, respectively. After adjusting for FLIPI score, MMR status remained associated with OS (MMR-d HR: 0.51, 95%CI: 0.2-1.02, p=0.05). Discussion and Conclusion: In this pilot study, MMR-d in the FL tumors was common (46%) and, as predicted, was associated with a favorable OS. Association of MMR-d status with PFS in general and patients with early progression (short PFS12 and PFS24) and relationship of MMR-d with types of therapy need further study in large FL datasets. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. King: Celgene/BMS: Research Funding. Maurer: Celgene: Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding.

Abstract BACKGROUND: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with variable clinical outcomes. Commonly used risk stratification tools (Ki67 IHC, MIPI) in newly diagnosed MCL are not frequently used when selecting therapy, resulting in treatment choice being dictated by age and co-morbidities rather than disease biology. The MCL35 risk score was developed as a more reliable measure of proliferation and has been shown to be prognostic and can risk stratify younger transplant eligible MCL patients into three groups with significantly different overall survival (OS; Scott et al. 2017; Holte et al. 2018) but has not been evaluated in older transplant ineligible patients. We report results evaluating the prognostic value of the MCL35 assay in older MCL patients (≥65) treated with frontline bendamustine/rituximab (BR). METHODS: Archived tissue samples from 119 patients age ≥65 years treated with BR from collaborating Lymphoma/Leukemia Molecular Profiling Project (LLMPP) sites and the LEO/MER cohort were collected and analyzed using the MCL35 assay and stratified into three distinct risk groups (low, standard, and high risk). Association between MCL35 proliferation scores and OS were estimated by the Kaplan-Meier method and hazard ratios were calculated. Associations between Ki67, s-MIPI, p53 IHC status, morphology and OS were also evaluated. RESULTS: The MCL35 assay was run on tissue samples from 119 patients. Median patient age was 74 (range 65-93) and 69.5% were male. Ki67 was &lt;30% in 29 patients (24%) and ≥30% in 90 patients (76%). Simplified MIPI (s-MIPI) score was 0-3 in 21 patients (24%), 4-5 in 42 patients (48%) and ≥6 in 25 patients (28%). Thirty-one did not have sufficient data to calculate a s-MIPI score. MCL35 was low risk in 51 patients (43%), standard risk in 39 patients (33%) and high risk in 29 patients (24%). Eleven patients had blastic morphology, 7 had pleomorphic morphology and the remainder were classic morphology (n=56). Of 57 samples with p53 IHC staining 7 (12.3%) were positive. At a median follow up of 33.4 months, 82 patients were alive and 35 had died. Patients with high risk MCL35 score had inferior OS compared to low risk (HR 2.27, 95% CI: 1.03-5.00; p=0.042) while standard risk was not statistically significant compared to low risk (HR 0.87, 95% CI: 0.37-2.0; p=0.740)(Figure 1). Ki67 IHC using a cutoff of ≥ 30% and 10%-29% was not significantly associated with OS compared to Ki67 &lt;10% ( Ki67 ≥ 30% vs. Ki67 &lt; 10%, HR 0.87, 95% CI: 0.12-6.41; p=0.892, Ki67 ≥ 10%-29% vs. Ki67 &lt; 10%, HR 0.32, 95% CI: 0.04-2.83; p=0.303), however high s-MIPI score (≥6) (s-MIPI ≥6 vs. s-MIPI 0-3, HR 3.86, 95% CI 1.20-12.5; p=0.024) and positive p53 IHC (HR: 9.51, 3.26-27.7; p &lt;0.001) were both associated with poor OS. Eighteen cases were blastic/pleomorphic by morphology, 12 of which were in the high-risk group by MCL35, and this subset also had worse survival than classic MCL (p=0.0052). CONCLUSIONS: These results suggest high risk MCL35 score is a prognostic biomarker of poor OS in patients &gt;65 with MCL treated with BR. Conversely, Ki67 was not significantly associated with OS in these patients. Additional clinical validation using a larger sample size from the E1411 study is planned. If similar results are found, the MCL35 assay in combination with s-MIPI and p53 status may have utility in stratifying patients into risk adapted treatment arms in future prospective clinical trial designs. Figure 1 Figure 1. Disclosures Maurer: BMS: Research Funding; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Raess: Scopio Labs: Research Funding. Scott: Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Rich/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Incyte: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Rimsza: NanoString Technologies: Other: Fee-for-service contract.

Abstract Introduction: Brexucabtagene autoleucel (brexu-cel) was approved by US FDA for relapsed/refractory (R/R) mantle cell lymphoma (MCL) on July 24, 2020 based on results from the pivotal ZUMA-2 (NCT02601313) study, in which an objective response rate (ORR) of 93% and a complete response (CR) rate of 67% were achieved among the 60 treated patients with at least 7 months of follow-up. The study had stringent eligibility criteria, including prior treatment with a BTK inhibitor (BTKi), and only allowed BTKi and/or corticosteroid for bridging therapy. We report here the safety and efficacy of brexu-cel in standard of care practice among centers in the US Lymphoma CAR-T Consortium. Methods: Fourteen centers participated in this retrospective study. Patients who underwent leukapheresis by 6/15/2021 with an intent to manufacture brexu-cel were included. Baseline clinical characteristics, bridging therapy, adverse events after brexu-cel infusion, and post-infusion outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined based on characteristics at the time of leukapheresis. Duration of response (time from initial response to disease progression or death from any cause), progression-free survival (PFS; time from infusion to disease progression or death from any cause) and overall survival (OS; time from infusion to death from any cause) were analyzed using the Kaplan-Meier method. Results: At the data cut-off date of 7/9/2021, 107 patients underwent leukapheresis, among whom 93 (87%) completed brexu-cel infusion, 2 (2%) were waiting for infusion, and 12 (11%) did not receive infusion (manufacture failure n=6, organ dysfunction n=1, death n=5). Baseline clinical characteristics of the 93 infused patients are shown in Table 1. The median age was 67 years and 81% were male. 32% had high risk simplified MIPI, 77% had Ki-67≥30%, 45% had blastoid or pleomorphic variant, 46% had TP53 alteration, 29% had complex karyotype, and 7% had CNS involvement. The median number of prior lines of therapy was 3. Eighty-two percent had prior BTKi treatment, and 44% had refractory disease to the last line of therapy. Sixty-eight (73%) patients would not have met ZUMA-2 eligibility criteria. Reasons for ineligibility included ECOG PS ≥2 (n=8), CNS involvement by lymphoma (n=6), prior therapies (n=33), cytopenia (n=11), renal or hepatic dysfunction (n=13), other medical conditions (n=18), and active infection (n=2). Sixty (65%) of the 93 patients received bridging therapy, which included BTKi (n=27), venetoclax (n=14), chemotherapy (n=19), CD20 antibody (n=26), lenalidomide (n=3), corticosteroid (n=9), and radiotherapy (n=13). Only 13 (14%) patients received BTKi or corticosteroid alone as in ZUMA-2. Among 93 infused patients, cytokine release syndrome (CRS) rate was 88% (8% grade ≥3), and immune effector cell-associated neurotoxicity syndrome (ICANS) rate was 58% (33% grade ≥3). No grade 5 CRS or ICANS occurred. Medications used to manage CRS and ICANS were 71 (76%) for tocilizumab, 64 (69%) for steroid, and 16 (17%) for anakinra. Twenty-four (26%) patients required ICU admission, 9 patients required vasopressors, and 4 patients required mechanical ventilation. With a median follow-up of 3.0 months (range 0.1-9.6), day 30 response was evaluable in 81 patients, and the ORR was 86%, with 64% CR (Table 2). The ORR/CR rates were 94%/70% for blastoid or pleomorphic variants, 82%/50% for TP53 altered, 84%/61% for BTKi-exposed, 94%/76% for BTKi-naïve, and 88%/67% for those not meeting ZUMA-2 eligibility criteria. The ORR/CR rates were 87%/69% for patients who received bridging therapy and 85%/56% for those who did not. For patients who achieved a response at day 30, the rate of continued response at 3-month was 83.7% (95% CI 68.3%-92.0%). The 3-month PFS rate was 80.6% (95% CI 68.6%-88.4%), and the 6-month OS rate was 82.1% (95% CI 67.7%-90.5%). Conclusions: This multicenter retrospective study demonstrated encouraging safety and efficacy data of brexu-cel in R/R MCL in the real world practice. The CRS and ICANS incidences were comparable to those reported in ZUMA-2, but use of tocilizumab and steroid was more frequent than in ZUMA-2. Although 73% of the patients would have been ineligible for ZUMA-2, the ORR and CR rate were comparable to those reported in ZUMA-2. Longer follow-up is necessary to confirm long term safety and efficacy. YW, PJ and FLL are co-first authors, and YL, MW and MDJ are co-senior authors. Figure 1 Figure 1. Disclosures Wang: Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Jain: Kite: Consultancy; Lilly: Membership on an entity's Board of Directors or advisory committees. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Umoja: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Munoz: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Maurer: BMS: Research Funding; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Beitinjaneh: Kite/Gilead: Other: Ad Board Event Attendee. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Dahiya: Miltenyi Biotech: Research Funding; Kite, a Gilead Company: Consultancy; Jazz Pharmaceuticals: Research Funding; Atara Biotherapeutics: Consultancy; BMS: Consultancy. McGuirk: Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; EcoR1 Capital: Consultancy. Goy: Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Phamacyclics: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Incyte: Honoraria; Hoffman la Roche: Consultancy; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; OncLive Peer Exchange: Honoraria; Infinity/Verastem: Research Funding; Genentech/Hoffman la Roche: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; Xcenda: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; MorphoSys: Honoraria, Other; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Hill: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Shah: Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Servier Genetics: Other; Adaptive Biotechnologies: Consultancy. Paludo: Karyopharm: Research Funding. Miklos: Pharmacyclics: Patents & Royalties; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding. Lin: Legend: Consultancy; Novartis: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Wang: Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; InnoCare: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Newbridge Pharmaceuticals: Honoraria; Genentech: Consultancy; OMI: Honoraria; Physicians Education Resources (PER): Honoraria; Clinical Care Options: Honoraria; CAHON: Honoraria; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; CStone: Consultancy; Loxo Oncology: Consultancy, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; BGICS: Honoraria; Bayer Healthcare: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Molecular Templates: Research Funding; Imedex: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Lilly: Research Funding; Celgene: Research Funding; Anticancer Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy.

Abstract Introduction: Low-grade B-cell lymphomas (LGBCL), aside from follicular lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma, account for approximately 10% of B-cell non-Hodgkin lymphomas and consist of several subtypes. While a majority of LGBCL cases have an overall favorable prognosis, we have previously shown that cases who have an event (relapse or progression, transformation, or re-treatment) within 24 months of diagnosis (EFS24) have an inferior overall survival (OS) compared to those achieving EFS24 (Tracy et al., AJH 2019;94:658-66). However, the underlying biological characteristics associated with early failure and aggressive disease across LGBCL subtypes are unknown. In this study, we used matched transcriptomic, genomic, and immune profiling data from LGBCL cases, the largest cohort to date, and asked whether there were unique biological phenotypes across different LGBCL subtypes and whether we could identify signatures associated with aggressive LGBCL. Validation of the prognostic utility of this signature was performed on a previously published, independent cohort of 63 pre-treatment LGBCL cases. Methods: Tumors from 64 newly diagnosed LGBCL patients from the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence were included in this study (SMZL (n = 48), NMZL (n = 6), LPL (n = 5), B-NOS (n = 3), EMZL (n = 2)). RNA sequencing (RNAseq) data from 61 LGBCL tumors and 5 benign CD19+CD27+ memory B samples was subjected to NMF clustering to define groups. Differential expression and pathway analysis were used to identify biological characteristics of each cluster. CIBERSORT was used to identify immune cells in the tumor microenvironment. Whole exome sequencing (WES) was performed on 61 tumor-normal pairs. Singscore was used to assign a single score per patient representing gene expression of the survival-associated transcriptomic signature identified in this study. Results: NMF analysis of RNAseq data identified 5 clusters of patients, denoted LGBCL1-5 (Fig 1A). Patients from the same diagnostic subtype did not exclusively cluster together, with all LGBCL clusters comprised of patients from multiple subtypes (Fig 1B). Exploring the association between patient cluster and outcome, we observed significantly inferior event-free survival (EFS) (HR 2.24; 95% CI 1.01-4.98) and overall survival (OS) (HR 5.59; 95% CI 2.00-15.63) in LGBCL5 patients compared to LGBCL1-4 (Fig 1C). In addition, 80% of the transformation cases in our cohort were classified as LGBCL5 (Fig 1D). Differential expression and pathway analysis showed distinct processes significantly upregulated in each cluster (FDR &lt; 0.05), with LGBCL5 demonstrating enrichment of cell cycle and mitosis pathways. CIBERSORT identified increased immune cell content in LGBCL3 and LGBCL5 compared to other clusters, with high frequencies of mast cells in both (p = 0.0002), increased CD8 T cells in LGBCL3 (p &lt; 0.0001), and increased T follicular helper cells in LGBCL5 (p = 0.004). WES identified previously reported alterations in NOTCH, NFkB, and chromatin remodeling pathways and novel variants in LGBCL, including mutations in HNRNPK, CLTC, HLA-A, HLA-B and HLA-C. Assessment of alterations by cluster showed significant enrichment of TNFAIP3 (OR 5.54; 95% CI 1.20-28.14) and BCL2 alterations (OR 5.49; 95% CI 1.07-32.02) in LGBCL5 cluster. Finally, we identified a cell cycle-related transcriptomic signature of 108 genes upregulated in LGBCL5 and EFS24 failure cases. Cases with high expression of this signature showed significantly inferior EFS (HR 14.25; 95% CI 4.90-41.38) and OS (HR 7.82; 95% CI 2.40-25.44) compared to cases with low expression in our discovery cohort. This observation was reproduced in an independent validation cohort, where patients with high expression of this signature demonstrated significantly inferior EFS (HR 5.70; 95% CI 1.49-21.79) and OS (HR 10.07; 95% CI 2.00-50.61). Conclusions: In this study, we are the first to define mechanisms of pathogenesis in LGBCL with shared transcriptomic, genomic, and immune profiles present across LGBCL subtypes. We then further defined a gene expression signature associated with inferior patient outcome, with application of this signature to an independent validation cohort demonstrating proof of concept and utility of this signature as a prognostic marker in LGBCL patients. Figure 1 Figure 1. Disclosures Maurer: Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Nanostring: Research Funding. Paludo: Karyopharm: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Incyte: Other: Scientific Advisory Board; Seagen: Other: Data Monitoring Committee; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Link: MEI: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis, Jannsen: Research Funding. Rimsza: NanoString Technologies: Other: Fee-for-service contract. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Cerhan: Genentech: Research Funding; Regeneron Genetics Center: Other: Research Collaboration; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Novak: Celgene/BMS: Research Funding.

Abstract Introduction: Central nervous system (CNS) relapse is an uncommon but devastating complication occurring in about 2-10% of patients with diffuse large B-cell lymphoma (DLBCL). The CNS-IPI is a validated prognostic tool used to identify patients at high risk of CNS relapse. MYC and BCL2/BCL6 rearrangements (double-hit lymphoma- DHL) and non-GCB (NGCB) cell of origin may be at higher risk of CNS relapse. However, the ability of these molecular data to refine CNS-IPI risk prediction has not been assessed. In this study, we aimed to describe the impact of DHL and NGCB cell of origin in the incidence of CNS relapse in patients with newly diagnosed DLBCL. Methods: A retrospective review was conducted to identify patients with newly diagnosed DLBCL from 01/01/2002 - 06/30/2015 using the University of Iowa/Mayo Clinic Lymphoma Molecular Epidemiology Resource database. Patients with primary CNS lymphoma or with CNS involvement at diagnosis were excluded. All patients received chemoimmunotherapy. Clinical, biological, laboratory and radiological data were abstracted including the occurrence of CNS relapse. CNS IPI risk score categories were defined as low- (≤1) intermediate- (2-3) and high-risk (≥4) as originally described (Schmitz et al, JCO 2016). Cell of origin (COO) classification into GCB and non-GCB subtypes was performed using Hans algorithm and/or NanoString data. Characteristics between groups were compared using Kruskal-Wallis or Chi-squared test as appropriate. Survival analysis was performed using Cox proportional hazards model and the Kaplan Meier method. Statistical analysis was performed using SAS version 9.4M5 and R version 4.0.3. Results: We identified a total of 1,360 patients with newly diagnosed DLBCL. Patients had a median age of 62 years (range 18-93 years), were predominantly male (56%), had a performance status &lt;2 (84%), had stage III/IV disease (61%) and an elevated LDH (56%) at diagnosis. Fluorescent in situ hybridization data was present for 65% of patients. Among patients with available data, DHL and NGCG COO represented 2.8% and 36% of the cohort, respectively. CNS IPI high- and intermediate-risk categories were present in 12.4% and 52% of the patients, respectively. R-CHOP was the most common upfront chemotherapy (n=980, 72%). The median follow-up for the entire cohort was 84.9 months (IQR: 58.9-120.9). Overall, 50 patients (3.6%) had a CNS relapse during the study period. Lymphoma relapsed in the CNS in 3.0% (95% CI:2.1-4.4), 4.7% (95% CI: 3.4-6.3) and 4.9% (95% CI: 3.7-6.6)% of patients with CNS-IPI score of intermediate/high risk at 1, 3 and 5 years following the diagnosis of DLBCL. In patients with low risk CNS-IPI, 1.1% (95% CI: 0.4-2.5), 1.7% (95% CI: 0.9-3.4) and 1.7% (95% CI: 0.9-3.4) had a CNS relapse at 1, 3 and 5 years following DLBC diagnosis. Patients with CNS relapse were more likely to have elevated LDH (76% vs 56%, p=0.008), advanced stage (78% vs 61%, p=0.01), adrenal involvement (8% vs 2.4%, p=0.014) and have a CNS IPI intermediate risk (68% vs 51%), and high risk (16% vs 12.3%, p=0.014) at the time of initial diagnosis compared to patients without CNS relapse. Patients with CNS relapse had similar rates of DHL (4% vs 2.7%, p=0.17) and NGCB cell of origin (42% vs 36.2%, p=0.52) compared to patients without CNS relapse. In the multivariable analysis, the strongest predictors for CNS relapse were CNS IPI high risk (Hazard Ratio [HR]= 3.6, 95%CI= 1.4-9.7) and CNS IPI intermediate risk (HR= 3.15, 95%CI= 1.46-6.81). DHL and NGCB cell of origin were not associated with a significantly higher risk of CNS relapse (HR= 1.79, [95%CI=0.42-7.59] and HR= 1.26, [95%CI=0.62-2.57], respectively). Conclusion: CNS relapse was an uncommon occurrence in patients with DLBCL who were treated with chemoimmunotherapy. CNS IPI intermediate- and high-risk scores remain the strongest predictors of CNS relapse in patients with DLBCL after adjusting to biological high-risk variables including DHL and NGCB cell of origin. Larger studies are required to validate our findings due to the low incidence of CNS relapse in our cohort. Figure 1 Figure 1. Disclosures Farooq: Kite, a Gilead Company: Honoraria. Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Novak: Celgene/BMS: Research Funding.