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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<0.0001). There were significant differences in EFS and OS by IC type (both p<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<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 <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 Central nervous system relapse (secondary central nervous system lymphoma -SCNS) is an uncommon but devastating complication of aggressive B-cell lymphoma. Patients (Pts) with CNS-IPI 4-6 are at greatest risk (10.2% at 2 years). Intravenous high-dose methotrexate (HD-MTX) is widely used to mitigate SCNS risk but data supporting this practice are limited. Methods We performed a multicentre, retrospective study at 21 sites in Australia, Asia, North America and Europe. Chart or registry review was performed for consecutively diagnosed pts with diffuse large B-cell lymphoma (DLBCL) and CNS-IPI 4-6, high grade B-cell lymphoma (HGBL) with rearrangements of MYC+BCL2 and/or BCL6 and primary breast/testicular DLBCL irrespective of CNS-IPI. Pts were diagnosed between 2000-2020, 18-80 years at diagnosis, and treated with curative intent anti-CD20 based chemo-immunotherapy. Pts with CNS involvement at diagnosis were excluded. HD-MTX was defined as at least one cycle of intravenous MTX at any dose. Time to SCNS was calculated from date of diagnosis (all-pts), and from the end of frontline systemic lymphoma therapy, defined as 6x21 days from diagnosis (complete response (CR-pts)), until SCNS, systemic relapse, death, or censoring, whichever came first. Cumulative risk of SCNS was computed using the Aalen-Johansen estimator treating death and systemic relapses as competing events. Adjusted cumulative risks were obtained by using an inverse probability of treatment weighting approach. The average treatment effect was computed as the difference in adjusted 5-year risk of SCNS. Results - 2300 and 1455 pts were included in the all-pts and CR-pts analyses, respectively. Baseline demographics and details of therapy are summarised in Table 1. Except for a predominance of males, pts ≤60 years and pts with ECOG 0-1 in the HD-MTX vs no HD-MTX groups, the demographics and treatments were well balanced. At a median follow up of 5.9 years (range 0.0-19.1) and 5.5 years from diagnosis (range 0.0-18.7), 201/2300 and 84/1455 pts experienced CNS events in the all-pts and CR-pts analyses respectively. For all-pts(n=2300), CNS-IPI was 4-6 in 2052(89.2%), with R-CHOP-like therapy given to 93.8%. 410 pts (17.8%) received HD-MTX (265 HD-MTX alone, 145 in combination with intrathecal methotrexate (IT-MTX);435 received IT-MTX alone;1455 received neither. There were 32/410 and 169/1890 SCNS events, with median time from diagnosis to SCNS of 8.8 and 6.7 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 70% (95% CI, 65-76%) and 55% (95% CI 53-57%) in HD-MTX and no HD-MTX groups respectively. There was no difference in the adjusted 5-year risk of SCNS between the HD-MTX and no HD-MTX groups (8.4% vs 9.1%, adjusted hazard ratio [HR] 0.71, p=0.100) (Figure 1). For CR-pts(n=1455), CNS-IPI was 4-6 in 1267(87.0%), with R-CHOP-like therapy given to 93.3%. 284 pts (19.5%) received HD-MTX (170 HD-MTX alone, 114 with IT-MTX);298 received IT-MTX alone;873 received neither. There were 16/284 and 68/1171 SCNS events, with median time from diagnosis to SCNS of 11.0 and 10.3 months in the HD-MTX and no HD-MTX groups respectively. 5-year OS was 74%(95% CI 67-81%) and 75%(95% CI 72-78%) in the HD-MTX groups and no HD-MTX groups respectively (adjusted HR 1.08, p=0.622). There was no difference in the 5-year risk of CNS relapse between the HD-MTX and no HD-MTX groups 5.0% vs 6.0% (adjusted HR 1.03, p=0.903) (Figure 2). Exploratory analysis of the impact of HD-MTX among the highest risk groups CNS IPI 5 (n=368), CNS-IPI 6 (n=59) and CNS-IPI 6 plus all pts with testicular, renal or adrenal involvement (n=349) did not reveal differences in SCNS rates in HD-MTX treated pts. Additional subgroup analyses will be presented at the meeting. Conclusions To our knowledge, this is the largest study of the efficacy of HD-MTX in reducing SCNS events focusing exclusively on high-risk pts. The overall incidence of CNS relapse observed was consistent with previous reports in similar patient cohorts at 9%. The use of HD-MTX did not lower SCNS rates overall or when analysis was confined to CR pts at completion of curative intent therapy to compensate for potential immortal bias associated with HD-MTX therapy. Despite the limitations of the non-randomized and retrospective design, it appears unlikely that HD-MTX is associated with a clinically meaningful reduction in SCNS rates in pts with high risk for SCNS. Figure 1 Figure 1. Disclosures Lewis: AstraZeneca: Consultancy, Honoraria; Novartis: Patents & Royalties: Conference attendance; Janssen: Honoraria, Patents & Royalties: Conference attendance; Roche: Consultancy, Honoraria. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. Bobillo: F. Hoffmann-La Roche Ltd: Consultancy, Speakers Bureau; Gilead: Speakers Bureau. Ekstroem Smedby: Takeda: Consultancy; Janssen Cilag: Research Funding. Savage: Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Eyre: Beigene: Honoraria, Research Funding; Incyte: Consultancy; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria. Cwynarski: Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. Stewart: Teva: Honoraria; Sandoz: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Bishton: Gilead: Honoraria, Other: Travel grants; AbbVie: Honoraria, Other: Travel grants; Celgene/BMS: Honoraria, Other: travel grants; Celltrion: Honoraria, Other: Travel grants; Takeda.: Honoraria, Other: Travel grants . Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. Sehn: Genmab: Consultancy; Novartis: Consultancy; Debiopharm: Consultancy. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hawkes: Specialised Therapeutics: Consultancy; 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; Novartis: 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; Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck KgA: Research Funding; 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. Minson: Novartis: Research Funding; Hoffman La Roche: Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Takeda: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Øvlisen: Abbvie: Other: Travel expenses. Gregory: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Talaulikar: Roche: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Maurer: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months. Cheah: Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory; Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory.

Abstract Background: Generalizability of results from clinical trials with narrow in-/exclusion criteria are a concern as significant deviations in efficacy or toxicity may occur when treatments are used in populations of elderly and more comorbid patients. The cost-effectiveness of novel therapies may also be less favorable if real-world treatment effects are inferior to clinical trial results. In diffuse large B-cell lymphoma (DLBCL), a recent US study showed that baseline organ function-based eligibility criteria had substantial impact on survival with ineligible patients being at higher risk of dying from progressive lymphoma (1). Aims: The present study explored the impact of commonly used in-/exclusion criteria in key completed and ongoing first line DLBCL trials on survival in a Danish population-based study of patients with de novo DLBCL. Patients and methods: DLBCL patients enrolled in the Danish Lymphoma Registry (LYFO) and treated with R-CHOP in the period 2008-19 were screened for completeness of data to match trial eligibility criteria. The key organ/hematology eligibility criteria of completed or ongoing all-comers DLBCL studies (REMoDL-B, Goya, Polarix and Hovon84) were collected (bilirubin, ALAT, creatinine, eGFR, leucocytes, neutrophils, thrombocytes and ECOG). First, high-level trial matching on disease risk group (Ann Arbor, bulky disease, international prognostic index (IPI)) and age-groups were performed so that patients assessed for trial eligibility had a relevant risk profile. Subsequently, patients were divided into eligible or ineligible based on selected in/exclusion criteria. For each trial, overall survival (OS) from treatment start were compared for eligible and ineligible patients using inverse probability of treatment weighted Kaplan-Meier and log-rank tests. Crude OS and OS adjusted for residual imbalances in IPI and age were estimated. When possible, the OS curves from standard arms of the original trials were superimposed on OS plots. For each trial, the Shapley value of each criterion was calculated, using the HRs as well as the 5y restricted loss of lifetimes (RLOLs). The Shapley value measures the average influence of each eligibility criterion on the estimated IPI- and age-adjusted HR/5y RLOL. Results: A total of 3,150 R-CHOP treated DLBCL patients without discordant low-grade lymphoma were identified in the surveyed period. A total of 1,666 patients (52.89% of surveyed population) were available for the REMoDL-B trial, 1,431 (45.43%) for Goya, 1,125 (35.71%) for Polarix, and 1,432 (45.46%) for Hovon84. The variations of numbers for each trial evaluation were explained by trial inclusion criteria and missing data in LYFO. Crude OS estimates for patients with and without all necessary information were similar (data not shown). OS curves for eligible and ineligible patients are shown in Figure 1 and, when possible, with superimposed trial results (Goya, REMoDL-B, Hovon84). Survival differences between trial eligible and ineligible patients were robust to further adjustment of imbalances in age and IPI. Associated crude and adjusted 2 and 5-year OS rates for trial eligible and ineligible are shown in Table 1. The largest numerical difference in 2-year crude OS between eligible and ineligible was observed in the REMoDL-B trial (ineligible had 26% lower 2-year OS rate). The largest numerical difference in 2-year OS adjusted for IPI and age between eligible and ineligible was observed for the Polarix trial (ineligible had 17% lower 2-year OS rate). The strongest drivers of OS differences between trial eligible and ineligible patients in terms of the tested eligibility criteria were thrombocyte count (HR-contribution calculated from Shapley values -0.11; -0.14) and ECOG (HR-contribution -0.09; -0.21). Liver function parameters (bilirubin and ALAT) had low impact on OS (HR-contribution 0.00; -0.05 and 0.00; 0.07). Conclusions: The present population-based study confirms that trial ineligible patients have worse survival even after adjustments in imbalances in age and disease risk category. Thus, trial eligibility criteria have substantial impact on generalizability of results to a wider unselected population. Interestingly, the trial eligible patients identified in the present study had very similar outcomes to R-CHOP treated patients in the original trials supporting the possible use of RWD as synthetic control arms. Figure 1 Figure 1. Disclosures 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; Nanostring: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jørgensen: Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Celgene: Consultancy. Larsen: BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Odense University Hospital, Denmark: Current Employment; Gilead: Consultancy. 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. Poulsen: Abbvie: Consultancy; Janssen: Consultancy. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months.

Abstract BACKGROUND Validation of the 2016 LANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. The objective of this joint EORTC Brain Tumor Group and RANO effort was to validate the feasibility of the revised MRI scorecard for assessing response in leptomeningeal metastasis. METHODS Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The kappa coefficient (K) was used to evaluate inter-observer pairwise agreement. Statistical analyses were performed using SAS V9.4 software (Cary, NC). The sponsor of the study was the University Hospital Zurich (2018-00192). RESULTS Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons and 2 medical oncologists. Among leptomeningeal metastases-related items at baseline, the best median concordance was noted for hydrocephalus (K=0.63), and the worst median for spinal linear enhancing disease (K=0.46). The median concordance for overall response was moderate (K=0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was minimal (K=0.29). Significant differences were observed when considering the specialty of the raters. Only 394 of 700 ratings (56%) were fully completed. Among 394 fully completed ratings, perfect concordance was noted in 293 ratings (74%) when comparing the overall response according to the guidelines provided in the scorecard and the overall response provided by the raters. The main discordances were noted for partial response according to the rater versus stable disease according to the guidelines (n=44), followed by progression according to the raters versus stable disease according to the guidelines (n=23). CONCLUSION Electronic case report forms with "blocking solutions" are probably required to enforce completeness and quality of scoring. These results confirm the necessity of central review and the need for training of MRI assessment in clinical trials.

Abstract Context Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism. Objective This work aimed to investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism. Methods This phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension enrolled 59 individuals with hypoparathyroidism. Interventions included TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by a 22-week extension during which TransCon PTH dose was titrated (6-60 µg PTH[1-34]/day). Results By Week 26, 91% of participants treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 μg/day and calcium [Ca] ≤ 500 mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while normal serum Ca (sCa) was maintained and serum phosphate and serum calcium-phosphate product fell within the normal range. By Week 26, mean scores on the generic 36-Item Short Form Health Survey domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale symptom and impact scores improved through 26 weeks. TransCon PTH was well tolerated with no treatment-related serious or severe adverse events. Conclusion TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500 mg/day) for most participants, achieving normal sCa, serum phosphate, uCa, serum calcium-phosphate product, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

Background: Tissue reperfusion is a critical determinant of outcomes after intra-arterial therapy (IAT). However, there is no standardized method for grading angiographic reperfusion. We sought to compare the two most commonly used reperfusion scales, TIMI and modified TICI (m-TICI), for predicting good long-term outcome following IAT. Methods: From a multicenter database, we evaluated acute stroke patients presenting with middle cerebral artery (MCA) M1 occlusions who underwent IAT. Clinical and angiographic data were collected. Reperfusion for each case was graded using the TIMI and m-TICI scales. The primary distinction between these scales is that partial reperfusion (TIMI 2) is sub-divided into minor (m-TICI 2A: <50%) and major (m-TICI 2B: 50-99%) grades in the m-TICI system. The performance of these scales for predicting a good 90-day outcome (mRS 0-2) was evaluated using the c-statistic. Results: There were 313 acute stroke patients with MCA M1 segment occlusions who underwent IAT at 6 academic centers; 171 (54.6%) were female. Mean age was 65.3±16.5 years. There were 157 (50.2%) right-sided strokes. Median baseline NIHSS score was 17 (IQR 15-20). Good outcome at 90 days was achieved in 32.5%. For predicting good outcome, the c-statistic was significantly higher for m-TICI (0.74 vs. 0.68; p<0.0001). The threshold that maximized predictive accuracy was m-TICI ≥2B (sensitivity 78%, specificity 65%; figure). Conclusions: The modified TICI scale is superior to the TIMI scale for predicting clinical outcome after IAT, and should be the standard tool for grading angiographic reperfusion. An m-TICI score ≥2B (≥50% reperfusion) is the optimal biomarker for successful reperfusion.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Abstract Background Pineoblastoma (PB) is a rare embryonal brain tumour most often diagnosed in young children. To date, no clinical trials have been conducted specific to pediatric PB. Collaborative studies performed over the past 30 years have included PB in studies accruing for other embryonal tumours, primarily medulloblastoma (MB), but also including the entity formerly known as CNS-PNET and atypical teratoid rhabdoid tumors. Each of these studies have included only a small number of children with PB, making clinical features difficult to interpret and determinants of outcome difficult to ascertain. Patients and Methods Published centrally reviewed series with sufficient treatment and outcome data from North American and Australian cases were pooled. To investigate associations between variables, Fisher’s exact and Wilcoxon-Mann-Whitney tests, and Spearman correlations were used as appropriate. Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used in survival analysis. Results We describe a 30-year review of the reported clinical features of PB and a pooled centrally reviewed, cohort analysis of cases (n=178) from the Children’s Oncology Group (COG) (n=82) groups and several published, centrally reviewed institutional series (n=96). We find young children &lt;3 years of age have a dramatically poorer outlook compared to older children (5-year OS 16.2% +/- 5.3% vs 67.3% +/- 5%) confirming new and novel approaches are needed in future clinical trials for this at risk group. Interestingly, male gender was predictive of worse outcome possibly suggestive of gender specific subgroup risks that needs validation in future studies. Assessment of radiation therapy is not possible as the vast majority of children under age three did not receive any form of radiation therapy. Conclusion Given the relative scarcity of this tumor and the emerging data on subgroups of pineoblastoma, prospective, collaborative international studies will be vital to improving the long-term survival of these patients.