Citations

Introduction: The long term effectiveness of preventive intracranial treatment of unruptured aneurysms for hemorrhage and aneurysm-related morbidity and mortality has been hypothesized. No randomized trial has been done. Propensity adjusted comparison within The International Study of Unruptured Intracranial Aneurysms was undertaken to compare long-term effectiveness. Hypothesis: The purpose of this analysis was to compare the long-term outcome in the treatment cohorts (surgery and endovascular) with those of the untreated subgroup. Methods: Patients were subdivided into the initial treatment and untreated cohorts based upon observation or treatment practices in 61 centers from 1991-1998. 1691 patients were in the observational cohort, 471 were in the endovascular cohort and 1917 patients were in the surgical cohort. The cohorts were followed for a median follow-up of 9.2 years. Outcomes were determined prospectively and with central review. The data were grouped together and analyzed to determine treatment decisions. Comparison of outcomes was done using covariate adjustment and using propensity analysis where equivalent probability groups were constructed. Similar main predictors of treatment and outcome were observed. Analysis of hemorrhage, mortality and short-term and long-term morbidity and mortality were assessed. Risk-benefit ratios were also calculated. Results: Significant differences in baseline variables between treatment and observed patients were aneurysm size, symptoms, age, prior SAH or not group, geographical region, family history, hypertension and myocardial infarction history. The results show comparability of groups using the patient propensity-based score subset. Using the propensity score method, the results showed a benefit in prevention of hemorrhage by surgery and endovascular treatment versus observation (p<.01). No difference was found between endovascular versus surgery. However when procedure-related outcomes are included, no significant difference at 1 year, 5 years or 10 years in the combined aneurysm or procedure related endpoint was evident between cohorts. Conclusions: Propensity score matching to achieve comparability resulted in balanced groups. Comparison of long-term results showed that intervention demonstrated a benefit in reducing hemorrhage risk. However, peri-procedural risk negates any short-term benefit for 10 years.

Introduction: Mortality in patients with unruptured intracranial aneurysm (UIA) is significantly higher than the general population. However a minority of the deaths are due to subarachnoid hemorrhage. Hypothesis: There are differential characteristics of patients that might predict specific causes of death that would be informative in counseling patients about aneurysm risk. Methods: 4059 patients with UIA who were enrolled prospectively between 1991 and 1998 were followed by 61 medical centers in North America, Canada, and Europe. Patients have at least one UIA, which may or may not be symptomatic. Patients were Rankin grade 1 or 2 at enrollment. Patients were followed annually from enrollment to 2007. For patients who died a death certificate search was done and information was requested from local physicians and other contacts. A National Death Index search in 2008 determined cases who died and cause of death. Foreign centers also did a national search where possible. Patients who died before 30 days post treatment or lost to follow up before 30 days post enrollment were excluded. Results: Twenty-five percent of patients died during follow-up. The life expectancy was significantly less than age-, sex-, and country-matched expected estimates. Among the total of 4004 patients with UIA who survived 30 days after enrollment, 2331 were treated and 1673 were not. There were 965 deaths after 30 days after treatment, of which 320 died from vascular disease (252 died from non-SAH vascular disease), 114 died from respiratory tract disease, 255 died from cancer, and the rest died of other or unknown reasons. Predictors of SAH death were aneurysm size, site, age and convulsive disorders at enrollment. Factors related to vascular death were UIA treatment, age, gender, race, hypertension, Rankin at discharge and diminishing influence of aneurysm characteristics over time. Respiratory deaths were related to treatment, race, smoking, age, initial Rankin and presentation with convulsive disorder. Cancer deaths were related to gender, race, smoking and age. Conclusions: In patients with UIA, an assessment of risk for death underscores the importance of age, race and gender and several modifiable risk factors. Patient management should include not only aneurysm rupture prevention but also modification of smoking and hypertension.

Introduction: Quality of life changes can occur following procedural interventions and subarachnoid hemorrhage in unruptured intracranial aneurysms (UIA). The International Study of Unruptured Intracranial Aneurysms conducted quality of life assessment using the Mini-Mental State Exam, Rankin Score, and Barthel Index at baseline and the Telephone Interview Cognitive Status Exam (TICS), Rankin Score, and Barthel Index at follow-up. Hypothesis: The purpose of this analysis was to compare the 1 year and 5 year outcome in the treatment cohorts (surgery and endovascular) with those of the untreated subgroup. Methods: Patients were subdivided into the initial treated and untreated cohorts based upon observation or treatment practices in 61 centers from 1991-1998. 1691 patients were in the observational cohort and 2388 in the treated cohort. The cohorts were followed annually with measures of neurological status, Rankin Scale, Barthel Index and cognition (TICS). Outcomes were determined prospectively. Comparison of outcomes was done using continuous and categorical data. Covariate adjustment was done using general linear models. Stratified analysis was done by Rankin Score at the time of follow-up. Results: The percent of patients with a Barthel Index score of less than 60 at 1 year in the cohort was 9.4% (treated patients, 9.7%; untreated patients, 9.2%). The percent of patients at year 1 with a score of greater than 90 was 87.6%, 87.4% for treated patients and 87.8% for untreated patients. The percent of patients with a Barthel Index score of less than 60 at 5 years in the cohort was 41.4% (treated patients, 41.4%; untreated patients, 41.4%). The percent of patients at year 5 with a score of greater than 90 was 56.3%, 56.1% for treated patients and 56.5% for untreated patients. TICS and Barthel Index scores were significantly associated with each other for patients with Rankin Scores 0-2 (P<0.0001). This was seen at both year 1 and year 5 follow-up, but not for patients with Rankin Score 3-5. At both 1 year and 5 year follow-up, after controlling for Rankin Score, the distribution of Barthel Index scores of untreated patients and treated patients did not significantly differ. At both the 1 year follow-up, baseline Rankin Score, TICS and follow-up Rankin Score were significant predictors of Barthel Score (P<0.0001). At 5 years, only the follow-up Rankin Score was associated with Barthel Score (P<0.0001). Conclusions: Barthel Index Score decreased over time, but does not differ with treatment. The Rankin Score was the main predictor at follow-up of Barthel Index Score distribution.

AbstractModern fluoroscopes used for image guidance have become quite complex. Adding to this complexity are the many regulatory and accreditation requirements that must be fulfilled during acceptance testing of a new unit. Further, some of these acceptance tests have pass/fail criteria, whereas others do not, making acceptance testing a subjective and time‐consuming task. The AAPM Task Group 272 Report spells out the details of tests that are required and gives visibility to some of the tests that while not yet required are recommended as good practice. The organization of the report begins with the most complicated fluoroscopes used in interventional radiology or cardiology and continues with general fluoroscopy and mobile C‐arms. Finally, the appendices of the report provide useful information, an example report form and topics that needed their own section due to the level of detail.

Abstract Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

Abstract Leukemia relapse and treatment related mortality (TRM) remain major obstacles for successful allogeneic hematopoietic cell transplantation (allo-HCT). The number of induction cycles using intensive chemotherapy at AML diagnosis to achieve complete remission (CR) and the number of consolidation cycles and disease status at the time of allo-HCT for patients with acute myeloid leukemia (AML) may each affect TRM and relapse rates. We investigated the impact of the number of induction/consolidation cycles and disease status on the success of allo-HCT in 3113 AML patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2019). They received allo-HCT in first CR or with persistent leukemia (primary induction failure-PIF) receiving myeloablative (MA) or reduced-intensity (RIC) conditioning. 1473 AML patients (median age, 47 years) in CR received MAC; 862 (58%) achieved CR after 1 cycle of intensive induction chemotherapy and 74% of these had no evidence of measurable residual disease (MRD). 454 (31%) patients required 2 cycles to CR (72 % MRD negative) and 157 (11%) patients (69% MRD negative) after ≥ 3 cycles. The overall survival (OS), relapse and TRM by induction cycle number is shown in Table 1. Multivariate analysis demonstrated that CR after 1 cycle led to higher OS vs. 2 cycles (HR 1.32 95%CI 1.11-1.56, p&lt; 0.01) or ≥ 3 cycles (HR 1.47 95%CI 1.16-1.87, p&lt; 0.01), while OS after 2 cycles or ≥ 3 cycles were similar (HR 1.2 95%CI 0.87-1.4, p=0.38). Higher TRM was observed in patients receiving 2 or ≥ 3 cycles vs. only 1 induction cycles (HR 1.34 95%CI 1.05-1.72, p&lt; 0.02). Relapse risk was greater in those needing ≥ 3 cycles to achieve CR. Consolidation therapy after CR was associated with improved OS vs. no consolidation therapy (HR 1.57 95%CI 1.24-1.99, p&lt; 0.01). The need for ≥2 induction cycles plus consolidation therapy was associated with higher TRM (HR 1.34 95%CI 1.05-1.72, p&lt; 0.02). 1162 AML patients (median age, 63 years) in CR received allo-HCT after RIC; 714 (61%) achieved CR after 1 cycle of induction chemotherapy (72% MRD negative); 310 (27%) patients after 2 cycles (67% MRD negative) and 138 (12%) patients (58% MRD negative) after ≥ 3 cycles (Table 1). Multivariate analysis demonstrated that the number of induction cycles did not affect the OS or TRM. Relapse risk was greater in patients requiring ≥2 cycles to achieve CR. The use of consolidation therapy did not affect OS or TRM. MRD status at the time of allo-HCT did not have a significant impact on OS, TRM and relapse rates after either MA or RIC conditioning. 478 AML patients received allo-HCT after PIF (328 patients with MAC [median age, 51 years], 150 patients RIC [median age, 61 years], Table 1). After MAC, OS and relapse were significantly worse in PIF patients compared to any CR patients (p&lt;0.01). After RIC, relapse was significantly more frequent in PIF patients vs. CR patients after 1 or more induction cycles (p&lt;0.01). TRM was similar for PIF vs CR patients after MAC or RIC allo-HCT. These data demonstrate that among patients eligible for allo-HCT, the need for only one induction cycle to achieve CR, particularly when combined with consolidation therapy is associated with better outcomes after MA conditioning. Achieving CR prior to allo-HCT needing one or more induction cycles is associated with lower relapse rates and improved OS compared to patients with PIF that receive allo-HCT. Figure 1 Figure 1. Disclosures de Lima: BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hourigan: Govt. COI: Other. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Saber: Govt. COI: Other. Weisdorf: Incyte: Research Funding; Fate Therapeutics: Research Funding.

Abstract Background: In the ELARA (E2202) trial (NCT03568461), tisagenlecleucel (tisa-cel) demonstrated high response rates in patients with relapsed/refractory follicular lymphoma (r/r FL), including those with high-risk disease, with an overall response rate (ORR) of 86% and complete response rate (CRR) of 66%. As ELARA did not include a comparator arm, an adjusted indirect treatment comparison (ITC) using patient-level data from a global retrospective cohort study was conducted. This study aimed to provide comparative, contextual evidence to the efficacy outcomes of tisa-cel from ELARA relative to standard of care (SOC) in routine practice. Methods: ELARA is an ongoing, single-arm, global, multicenter, phase II trial which evaluates the efficacy and safety of tisa-cel in adult patients with r/r FL. As of March 29, 2021, 98 patients were enrolled with a median follow-up of 15 months. SOC data were obtained from ReCORD-FL, a global retrospective cohort study of clinical outcomes in patients with r/r FL meeting the ELARA eligibility criteria who were treated per routine practice at 10 academic centers across North America and Europe; 7 ReCORD-FL sites are also participating in ELARA, but no patients are enrolled in both studies. In ReCORD-FL, with a data cutoff date of December 31, 2020, a total of 187 patients with ≥2 lines of previous treatment were identified for inclusion, with a median follow-up from third-line of 57 months. A complete-case comparison analysis was performed for 97 ELARA apheresed patients and 143 ReCORD-FL patients with complete data on all baseline variables and prognostic factors used for adjustment. For the comparative analysis, one line of therapy (LoT) per patient was selected using a propensity score model to identify the LoT which had the highest chance of being enrolled in ELARA conditional on baseline characteristics and prognostic factors available at the start of the LoT (i.e., the selected LoT was the one with the highest propensity score to be in ELARA). After selection of LoT, an adjusted ITC was performed to assess the effect of tisa-cel versus SOC by measuring CRR, ORR, progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT). A subgroup analysis of SOC patients with ≥1 eligible LoT initiated from 2014 on (coinciding with the introduction of the Lugano response criteria as well as regulatory approval of idelalisib) was performed for all endpoints. Results: Baseline characteristics for the tisa-cel and SOC cohorts are described in Table 1; after weighting, baseline variables, including number of previous lines of systemic therapy (median: 4 lines) were well balanced between the tisa-cel and SOC cohorts. Treatment regimens observed for ReCORD-FL patients at LoT selection were: anti-CD20 antibody plus alkylator (31.5% of patients), anti-CD20 antibody without alkylator (25.9%), alkylator without anti-CD20 antibody (17.5%), and regimens other than anti-CD20 antibody and alkylator (25.2%). After LoT selection and adjusting for differences in baseline variables, tisa-cel was associated with improvement over SOC in CRR (69.1% vs. 37.3%), ORR (85.6% vs. 63.6%), as well as PFS, TTNT and OS (Table 2, Figures 1-2), with a numerically higher 6-month PFS rate vs. SOC (85.3% vs. 66.5%), as well as higher 24-month OS rate (87.8% vs. 64.8%). Further, there was an estimated 80% reduction in death risk in favor of tisa-cel over SOC, a 40% reduction in risk of progression in favor of tisa-cel over SOC and a 69% reduction in risk of death or requiring a new anticancer therapy (Table 1). In the sub-analysis of SOC patients with lines of therapy initiated in or after 2014, the superiority of tisa-cel over SOC was confirmed in all the efficacy outcomes (CRR: 69.1% vs. 30.5%; ORR: 85.6% vs. 58.8%; hazard ratios substantially &lt; 1 for OS, PFS, TTNT). Conclusion: The ITC results suggest that tisa-cel has superior efficacy over SOC in r/r FL for all evaluated endpoints. A key limitation of this study is that response assessment criteria and schedule was more heterogeneous in ReCORD-FL than in ELARA. However, the sub-analysis on SOC patients assessed with a LoT selected in 2014 or later (when more patients could have been assessed using the Lugano response criteria) showed similar favorability for tisa-cel over SOC in all the efficacy outcomes. Moreover, outcome parameters independent of response criteria, namely OS and TTNT, were also significantly better for tisa-cel vs. SOC. Figure 1 Figure 1. Disclosures Salles: Abbvie, Epizyme, Morphosys, Regeneron: Consultancy, Honoraria; Bayer: Honoraria; Beigene, BMS/Celgene, Debiopharm, Genentech/Roche, Genmab, Incyte, Ipsen, anssen, Novartis. Kite/Gilead, Loxo, Miltneiy, Rapt, TAKEDA, Velosbio, Allogene: Consultancy. Schuster: Acerta Pharma/AstraZeneca: Consultancy; Alimera Sciences: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Tessa Theraputics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Dreyling: BeiGene: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau. Kuruvilla: AbbVie: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria, Research Funding; Antengene: Honoraria; Roche: Honoraria, Research Funding; Incyte: Honoraria; BMS: Honoraria; Merck: Honoraria; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Novartis: Honoraria; Medison Ventures: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Seattle Genetics: Honoraria; TG Therapeutics: Honoraria. Patten: ROCHE: Research Funding; GILEAD SCIENCES: Honoraria, Research Funding; ABBVIE: Honoraria; NOVARTIS: Honoraria; ASTRA ZENECA: Honoraria; JANSSEN: Honoraria. Von Tresckow: AbbVie: Other: Congress and travel support; Amgen: Consultancy, Honoraria; AstraZeneca: Honoraria, Other: Congress and travel support; BMS-Celgene: Consultancy, Honoraria, Other: Congress and travel support; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Smith: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Celgene, Genetech, AbbVie: Consultancy. Davis: Novartis, Vertex Pharmaceuticals, Pfizer, Eisai, Eli Lilly, AstraZeneca: Research Funding. Anjos: Novartis: Current Employment. Chu: Novartis: Current Employment, Current equity holder in publicly-traded company. Zhang: Novartis: Current Employment, Current equity holder in publicly-traded company. Lobetti Bodoni: Spouse: Harlcok Healthcare: Current holder of individual stocks in a privately-held company; Spouse: Takeda: Consultancy, Honoraria, Speakers Bureau; Spouse: Celgene: Honoraria; Spouse: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Spouse: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spouse: NHS: Ended employment in the past 24 months; Spouse: F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Gilead: Other: Travel sponsorship in June 2019; Novartis: Current Employment, Current equity holder in publicly-traded company. Thieblemont: Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Takeda: 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, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dickinson: Janssen: Consultancy, Honoraria; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria; Celgene: Research Funding; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Martinez-Lopez: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Wang: Eli Lilly: 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; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Link: Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy; Novartis, Jannsen: Research Funding.

Abstract Background: Novel therapies for multiply relapsed follicular lymphoma (FL) are often evaluated in single arm trials with no comparative data on patients receiving usual care. This study (ReCORD-FL) therefore sought to construct a historical control cohort to augment current and future single arm trials in relapsed/refractory (r/r) FL. The analytic aims were to document patient characteristics, treatment patterns and clinical outcomes in a r/r FL population treated with standard therapies in routine practice. Methods: This was a retrospective cohort study via medical record review in 10 oncology centers across North America and Europe. Adult patients were required to meet several criteria defining multiply r/r FL (i.e., r/r after ≥2 lines of therapy, or relapsed during or within 6 months after completion of anti-CD20 antibody maintenance, or relapsed after autologous HSCT). Patients were also required to have ≥1 line of systemic therapy (i.e., first qualifying salvage therapy) after first meeting the r/r FL criteria; the date of first qualifying salvage therapy defined the study index date. At index, patients were required to have grade 1-3A FL, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and no evidence of prior histological transformation. Outcomes were observed from the index date and from the start of each therapy line until the earliest of death, last follow-up, or December 31, 2020 (data cutoff). Endpoints were complete response (CR) rate, overall response rate (ORR), time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). In a subgroup analysis, endpoints were examined by double refractoriness (r/r to both an anti-CD20 mAb and an alkylator) and POD24 status at index (best response of stable/progressive disease or relapsed within 24 months of front-line anti-CD20 mAb-containing therapy). Time to event outcomes were analyzed using the Kaplan-Meier method. Results: A total of 187 patients were identified for inclusion (Table 1). Most patients' (80.2%) first qualifying salvage (index) therapy occurred in third line (3L) (range: 3L - 6L). Anti-CD20 mAb plus chemotherapy (including alkylating and/or non-alkylating agents) was the most common index regimen (64.2% of patients); 8% received anti-CD20 mAb monotherapy, 11.2% received alkylator-based chemotherapy alone (i.e., an alkylator-containing regimen without anti-CD20 mAb), and 16.6% received other therapies (i.e., other regimens containing neither anti-CD20 mAb nor alkylator). Median follow-up from FL diagnosis was 9 years (range: 1 - 21 years), over which a median of 5 (range: 3 - 11) lines of therapy were observed per patient. CR rate and ORR to the index treatment were 39.0% and 70.6%, respectively (Table 2). Median (95% confidence interval [CI]) TTNT and PFS from index were 14.4 (11.8 - 18.6) and 14.6 (11.0 - 18.0) months, respectively; median OS from index was 128 months (10.6 years). Compared with non-double refractory, those with double refractory disease at index had numerically lower CR (34.3% vs. 45.1%) and ORR (67.6% vs. 74.4%) and substantially shorter median (95% CI) TTNT (11.8 [9.0 - 15.2] vs. 20.9 [14.4 - 26.2] months), PFS (10.7 [7.7 - 14.5] vs. 20.1 [14.4 - 25.4] months), and OS (78.1 [45.8 - 146.7] vs. [Not Reached] months). Outcomes were similarly less favorable for patients who were POD24 at index. All outcomes steadily worsened across successive treatment lines (Table 2, Figures 1a-c). ORR, for example, decreased from 69.5% in 3L (n = 187) to 45.8% in 5L (n = 96) and 41.2% in ≥8L (n = 51), while median (95% CI) PFS decreased from 11.8 (10.1 - 16.6) months in 3L to 9.4 (6.8 - 13.1) months in 5L and 4.4 (1.7 - 5.9) months in ≥8L; median (95% CI) OS had a similar trend: 133.7 (78.1 - 232.4), 46.3 (31.7 - 76.5), and 11.4 (5.9 - 21.2) months in 3L, 5L, and ≥8L, respectively. Conclusions: Our findings further demonstrate the poor outcomes and limited survival in FL patients with multiply r/r, double refractory, or POD24 disease. In assessing response rates and PFS, it is important to consider that response assessment criteria and schedules were more heterogenous in the routine practice settings of ReCORD-FL than in clinical trials. Based on comparability of results with another similar study (SCHOLAR-5), the robustness of data collected, and continued low likelihood of randomized trials in this area, ReCORD-FL provides valuable historical control data for new r/r FL therapies in development. Figure 1 Figure 1. Disclosures Salles: Beigene, BMS/Celgene, Debiopharm, Genentech/Roche, Genmab, Incyte, Ipsen, anssen, Novartis. Kite/Gilead, Loxo, Miltneiy, Rapt, TAKEDA, Velosbio, Allogene: Consultancy; Abbvie, Epizyme, Morphosys, Regeneron: Consultancy, Honoraria; Bayer: Honoraria. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma/AstraZeneca: Consultancy; Alimera Sciences: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Tessa Theraputics: Consultancy; Genentech/Roche: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Nordic Nanovector: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Kuruvilla: Seattle Genetics: Honoraria; Merck: Honoraria; Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria; Antengene: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Karyopharm: Honoraria, Other: Data and Safety Monitoring Board; Janssen: Honoraria, Research Funding; Incyte: Honoraria; Medison Ventures: Honoraria; Roche: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pfizer: Honoraria; TG Therapeutics: Honoraria. Patten: GILEAD SCIENCES: Honoraria, Research Funding; ROCHE: Research Funding; ASTRA ZENECA: Honoraria; NOVARTIS: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria. von Tresckow: Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding; Pentixafarm: Consultancy, Honoraria; AbbVie: Other: congress and travel support; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; AstraZeneca: Honoraria, Other: congress and travel support; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding. Smith: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Celgene, Genetech, AbbVie: Consultancy. Davis: Novartis, Vertex Pharmaceuticals, Pfizer, Eisai, Eli Lilly, AstraZeneca: Research Funding. Nagar: Novartis, AstraZeneca, Eisai: Research Funding. Zhang: Novartis: Current Employment, Current equity holder in publicly-traded company. Bollu: Novartis: Current Employment, Current equity holder in publicly-traded company. Jousseaume: Novartis: Current Employment, Current equity holder in publicly-traded company. Ramos: Novartis: Current Employment, Current equity holder in publicly-traded company. Wang: Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Link: Genentech/Roche: Consultancy, Research Funding; MEI: Consultancy; Novartis, Jannsen: Research Funding.

Small-molecule recruitment of an endogenous nuclease rescues pathologies associated with c9ALS/FTD in vivo by targeting an RNA repeat expansion.