Abstract: Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD Working Party evaluated standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a 2-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next-generation sequencing-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate end point for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular-MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.

Abstract: BACKGROUND. The detection of minimal residual disease (MRD) at the level of 0.01%/10-4 or above is a strong independent predictor of reduced progression-free (PFS) and overall survival (OS) in patients with CLL treated with chemoimmunotherapy. Although newer agents such as B-cell receptor pathway inhibitors can result in prolonged survival without achieving complete response, there remains a important role for MRD analysis in assessing therapeutic strategies aimed at disease eradication and cure. This is particularly important in front-line trials for fit patients which now require at least five years of follow-up if PFS is used as an endpoint. The feasibility of using MRD as a surrogate or intermediate endpoint for accelerated approval of new treatments is under review by regulatory agencies but further prospective validation is required. At the same time technology is rapidly evolving and high-throughput sequencing (HTS) technologies now detect MRD at the 0.0001%/10-6 level. It is therefore important to determine the most effective approaches for quantifying MRD that are compatible with previous studies but sufficiently sensitive for current treatments. AIMS. This collaborative project had two objectives. First, to identify the simplest and most flexible flow cytometry panel capable of detecting MRD at the 0.01%/10-4 or lower, that is compatible with published data and independent of instrument/reagent manufacturer. Second, to compare the flow cytometry approach with HTS analysis using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). METHODS AND RESULTS. A core panel of antibodies for MRD detection was identified by testing an 8-marker combination in 52 samples (27 post-treatment and 25 dilution study) and re-analysing data with serial exclusion of single markers to determine redundancy. A 1-tube core panel of CD19, CD20, CD5, CD43, CD79b, and CD81 was identified and validated against the previously published 2-tube 6-marker and 4-tube 4-marker ERIC panels in 76 samples (19 post-treatment and 57 dilution study). The results showed good concordance (for log-transformed data above the LoQ, linearity=0.977, Pearson correlation co-efficient=0.983, average difference=0.026 log, 95% limit of agreement 0.20log) and a limit of detection of 0.001%/10-5 for the 1-tube core panel. Inter-operator variation was similar to CML MRD monitoring with both experienced operators, or inexperienced cytometrists after ~1 hour of specific education, achieving a 95% limit of agreement less than 0.3log in samples with MRD levels ranging from 0.0001 – 100%. The flow cytometry approach was compared with the ClonoSEQ HTS assay in 109 samples (21 dilution study and 88 post-treatment samples, complete data currently available on 13/88). The assay was applicable to the vast majority CLL patients, often with two clonal markers. There was 94% concordance at the 0.01% (10-4) threshold (15 samples with ≥0.01% CLL by both methods, 14 samples with 〈 0.01% by both methods, 1 sample with 0.03% CLL by HTS and 〈 0.003% CLL by flow cytometry, and 1 sample with 0.005% CLL by HTS and 0.012% by flow cytometry. HTS detected CLL IGH sequences in 22% (7/31) samples with no detectable CLL cells by flow cytometry (i.e. CLL level 0.0001-0.001%, 3/13 patient samples and 4/18 dilution samples). HTS demonstrated a relatively high variability in quantification, as seen in previous studies, but with a clear superiority in the limit of detection and good linearity (linearity=0.905, Pearson correlation co-efficient=0.870, average difference=0.078 log, 95% limit of agreement 1.5 log). CONCLUSIONS. The 1-tube 6-marker flow cytometry core panel is compatible with published studies, manufacturer-independent and flexible, providing directly quantitative results to 0.001%/10-5 without requiring a pre-treatment sample. HTS requires further work to standardise the quantitative analysis and prospective validation but the ClonoSEQ assay is applicable to 〉 95% of CLL patients, does not require viable cells and is extremely sensitive, detecting residual disease in a significant proportion of cases with 〈 0.01% CLL. The results indicate that flow cytometry and HTS are complementary technologies with a combined approach offering the most reliable way of quantifying CLL at the 0.01%/10-4 threshold while allowing higher sensitivity in clinical trials aimed at disease eradication. Disclosures Rawstron: Roche: Honoraria; Biogen Idec: Consultancy; Gilead: Consultancy, Honoraria; Abbvie: Honoraria; BD Biosciences: Intrasure reagent Patents & Royalties; Celgene: Honoraria; GSK: Honoraria. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Sanders:Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Hallek:Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Gilead: Honoraria. Hillmen:Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria, Research Funding.

Abstract: Introduction Prednisolone has important potential side-effects, one of which is steroid-induced diabetes mellitus (DM). Due to the exposure to a high cumulative dosage of steroids during first-line treatment, patients with non-Hodgkin lymphoma (NHL) could face increased risk of new onset steroid-induced DM or dysregulation of a pre-existing DM. This nationwide observational cohort study evaluated the risk of new onset DM in lymphoma patients and the impact on pre-existing DM in lymphoma survivors following treatment with steroid-containing regimens. Methods Adult NHL patients (≥18 years) treated with ≥3 cycles of steroid-containing immunochemotherapy, such as R-CHOP(-like) and R-CVP, between 2002 and 2015 were identified in the Danish Lymphoma Register and matched to five random individuals from the general population on birth year, sex, Charlson Comorbidity Index score, baseline DM status (DM or not), and DM duration. NHL patients and matched comparators were followed from start of treatment for the patients until the event of interest (DM, insulin prescription), death, relapse, NHL diagnosis (for matched comparators), or censoring (emigration, missing, or end of study on 31 December 2018), whichever came first. DM was captured by either a diagnosis of any DM (ICD-10 codes: E10-E14) in the Danish National Patient Register or any redeemed anti-diabetic prescription registered in the National Prescription Register (insulin or oral anti-diabetic medicine; ATC A10A or A10B). In the analysis of insulin prescriptions following lymphoma treatment initiation, patients with any redeemed prescription of insulin prior to start of lymphoma treatment were excluded. Time-varying incidence rates (IRs) per 1,000 person years and incidence rate ratios (IRRs) with 95% confidence intervals were estimated using a spline-based Poisson regression approach with two-month time splits and five knots. The Aalen-Johansen estimator was used to compute the cumulative risk of an event treating death, relapse, and NHL diagnosis (in comparators) as competing events. Risk differences at specific time points were calculated using pseudo-observations. Crude and adjusted cause-specific hazard ratios (HR) were obtained using Cox regression. Results A total of 4,703 NHL patients were included in the present study. Median age was 66 years and median follow-up was 8.5 years. Among the NHL patients, 4,325 patients did not have pre-existing DM and were matched to 21,625 comparators without DM. The time-varying IR of DM among comparators was 8-10 cases/1000 person years. The IRR of DM for patients vs comparators was higher for patients in the first year following treatment initiation (maximum IRR: 2.40), lower from 1 to 5 years (minimum IRR: 0.52), and higher from 5 to 10 years (maximum IRR: 1.18) (Fig. 1). The cumulative incidence of DM was higher for NHL patients at six months (0.58 percentage units (%U), p & lt;0.01), but lower at 5 years (-1.17%U, p & lt;0.01) and 10 years (-2.09%U, p & lt;0.01) compared to the matched comparators (p & lt;0.01 for the whole period, Fig. 2). Among the NHL patients, 378 had pre-existing non-insulin dependent DM and were matched to 1,890 comparators. The cumulative incidence difference of any insulin use was higher for patients at 6 months (14.29%U, p & lt;0.01), 5 years (9.95%U, p & lt;0.01), and 10 years (4.61%U, p =0.15) (p & lt;0.01 for the whole period, Fig. 3). However, when events were limited ≥5 prescriptions of insulin, no difference was found (p =0.84 for the whole period). The crude HR for ≥5 prescriptions of insulin was 1.42 [1.10;183] for patients compared to the matched comparators and the HR adjusted for sex, age, and comorbidities was 1.39 [1.08;1.79] . Conclusion In conclusion, patients treated with steroid-containing immunochemotherapy did not experience a higher risk of diabetes mellitus compared to matched comparators beyond the first year. Matched comparators had a higher cumulative incidence of diabetes mellitus after 2 years, which was partly explained by the high competing risk of death in the patient group. NHL patients with pre-existing non-insulin dependent diabetes mellitus had an increased cumulative incidence of any insulin prescriptions; however, the difference was diminished when assessing the risk of at least five insulin prescriptions, suggesting that the impact of steroids on diabetes regulation is limited in time when taking competing risks into account. Figure 1 Figure 1. Disclosures Øvlisen: Abbvie: Other: Travel expenses. Frederiksen: Abbvie: Research Funding; Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding. Vestergaard: Novo Nordisk Foundation: Other: Head of Research at Steno Diabetes Center North Jutland funded by the Novo Nordisk Foundation, Research Funding. Jørgensen: Gilead: Consultancy; Novartis: Consultancy; Roche: Consultancy; Celgene: Consultancy. Clausen: Gilead: Consultancy, Other: Travel expences 15th ICML ; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expences ASH 2019; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Poulsen: Janssen: Consultancy; Abbvie: Consultancy. Ekstroem Smedby: Janssen Cilag: Research Funding; Takeda: Consultancy. Eloranta: Janssen Pharmaceutical NV: Other: NV. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee.

Abstract: Introduction: A cancer diagnosis is associated with profound psychological distress that potentially can lead to mental health problems such as depression and anxiety. Non-Hodgkin lymphomas (NHLs) are a heterogenous group of indolent and aggressive cancer diseases with high variability in treatment selections and patient outcomes. Some patients are chronically ill with recurrent need for mild chemotherapy whereas others face immediately life-threatening, yet curable disease. To gain valuable insights into the psychological distress associated with NHLs, the present study investigated the incident psychotropic drug (PD - antidepressants, anxiolytics, and antipsychotics) use, contact patterns to psychiatric departments, and intentional self-harm (including suicide) in Danish NHL patients relative to sex- and age matched individuals from the background population. Methods: The study was carried out as a nationwide population-based matched cohort study based on prospectively collected data from several Danish registries. All adult NHL patients (≥18 years) diagnosed between 2005 and 2015 were identified in the Danish Lymphoma Registry and included if they had not been treated with any kind of PD within the last 10 years prior to date of NHL diagnosis (index date). NHL patients were matched on age and sex with five random comparators from the Danish background population on the index date. Comparators had to be alive and without PD use 10 years prior to the index date. Incident PD use was defined as first redeemed prescription of PD after index date. Prescriptions were captured in the National Prescription Registry and described by cumulative incidences using the Aalen-Johansen estimator with death and NHL relapse as competing risk. Contacts with psychiatric departments and registration of intentional self-harm or completed suicide were captured in the Danish National Patient Registry. Patients were subcategorized according to type of lymphoma (Table 1). Results: In total, 7,201 NHL patients and 36,005 matched comparators were included (median follow-up 7.1 years). Follicular lymphoma (FL, 44.4%) and diffuse large B-cell lymphoma (DLBCL, 41.0%) were the most common subtypes (Table 2). Two-year cumulative incidence of PD use was higher in NHL patients overall (16.2%, 95%CI 15.4-17.0%) compared to matched comparators (5.7%, 95%CI 5.5-5.9%). Patients with aggressive NHL subtypes tended to have the highest incidence of PD use (Figure 1). Antidepressants (two-year cumulative incidence, 9.0%, 95%CI 8.4-9.6) and anxiolytics (8.2%, 95%CI 7.6-8.8) were the most used PDs in all NHL subtypes. The risk of PD use was higher in the first years following diagnosis, but except for patients with indolent NHL subtypes, the risk of PD use normalized over time to that of the background population. As for the risk of any psychiatric department contacts, there was no difference in two-year cumulative incidences between NHL patients (range 0.6-0.9%) and the matched comparators (range 0.6%-0.9%), whereas the two-year cumulative incidence of intentional self-harm and suicide was slightly higher for NHL patients (0.3%) compared to the matched comparators (0.2%, p=0.01). Conclusion: This study suggests that NHL patients have a significantly higher risk of mental health problems compared to the Danish background population, (when) using PD prescriptions as a proxy measure. The risk of intentional self-harm and completed suicide was also higher, but numerical differences were very small. Overall, the results emphasize the need for directing clinical attention on mental health in newly diagnosed NHL patients and screening for relevant symptoms during follow-up to provide best possible support to patients suffering from anxiety and depression. Figure 1 Figure 1. Disclosures Øvlisen: Abbvie: Other: Travel expenses. Kragholm: Novartis: Honoraria. Nielsen: Lundbeck: Honoraria, Other: Investigator, Research Funding; Otsuka Pharmaceuticals: Honoraria, Other: Prior Advisor, Research Funding; Bristol-Myers Squibb: Honoraria; Astra Zeneca: Honoraria, Other: Prior advisor; Janssen & Cilag: Honoraria, Other: Investigator; Servier: Honoraria; Teva A/S: Honoraria; Eli Lilly: Honoraria, Other: Prior Advisor; Takeda: Other: Prior advisor; Medivir: Other; Boehringer: Other: Investigator. Brown: BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartys: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Dahl-Soerensen: Takeda: Other: Travel grant. Frederiksen: Novartis: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding. Mannering: Novartis: Research Funding; Swedish Orphan Biovitrum (SOBI): Membership on an entity's Board of Directors or advisory committees. Jørgensen: Gilead: Consultancy; Roche: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Clausen: Janssen: 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, Other: Travel expences ASH 2019; Gilead: Consultancy, Other: Travel expences 15th ICML . El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee.

Abstract: Introduction: Patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) who are ineligible for intensive chemotherapy and autologous stem cell transplantation have limited therapeutic options and poor prognosis, and there is an unmet need for new therapeutic alternatives in this situation. Based on gene expression profiling, DLBCL can be divided into the germinal centre B-cell (GCB) and the activated B-cell (ABC) subtype. These subtypes are dependent on different oncogenic pathways and may differ in responsiveness to targeted therapies. Idelalisib is a small-molecule inhibitor of PI3Kδ, currently approved for treatment of follicular lymphoma and CLL. Based on the high response rate of idelalisib in heavily pretreated patients with indolent B-cell lymphomas, among whom many may have undetected transformed disease, we hypothesized that idelalisib may also be active in r/r DLBCL, particularly in the GCB subtype, due to frequent PTEN loss and unregulated activation of PI3K signaling in this subtype. Here, we evaluated the efficacy and safety of idelalisib as a single agent therapy in patients with r/r DLBCL in a multi-centre phase II non-randomized trial. To our knowledge, this is the first prospective study on the use of single agent idelalisib in patients with DLBCL. Methods: Eligibility criteria were: Patients with DLBCL, including transformed low-grade lymphoma, with r/r disease after at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and not candidate for autologous stem cell transplantation. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT for the GCB-DLBCL. Idelalisib 150 mg x 2 p o was given until progression or unacceptable toxicity. Results: In the period 2017-2020, 36 patients were included from six centers in Sweden and Denmark, 18 patients showed a GCB and 16 patients an ABC subtype, two patients could not be classified for subtype. The study was terminated prematurely due to futility in reaching the primary endpoint. The median age was 74 years. Patients had received a median of three previous regimens. In total, 34/36 patients have discontinued treatment (n=24 due to PD, n=7 due to an adverse advent (AE), n=2 due to death, n=1 due to other cause). Median duration of treatment was 8 weeks (range 2-92), see the swimmers plot. Treatment emergent-AEs of grade 3 or higher included elevated liver transaminases (n=6), hematological toxicity (n=4), colitis (n=2), CMV reactivation (n=1), and skin toxicity (n=1). No patient died due to possible treatment-related toxicity. With a median follow up time of 4.9 months, 22 patients were evaluable for efficacy after 8 weeks of treatment, as of May 31, 2020. Fourteen patients had progressive disease before that point of time. The ORR in all patients was 14 % with 3 patients achieving CR (8 %) and 2 patients PR (6 %). In GCB versus ABC subgroups, 2 patients (11 %) compared to 3 patients (19 %) patients reached CR/PR. Among the 9 patients with transformed lymphoma, 3 patients (33 %) reached CR/PR. Among the 5 patients with CR/PR, median duration of response was 67 weeks (95 % CI:19-not reached). Median OS in the GCB subgroup was 15 weeks (95 % CI: 11-56) compared to 23 weeks (95 % CI: 9-not reached) in the ABC subgroup. To date, 2 of the responding patients show ongoing response after 53 respectively 86 weeks of treatment. Conclusions: Single agent idelalisib demonstrated modest activity in patients with r/r DLBCL, but the primary endpoint with higher activity in the GCB subtype was not reached. Instead, a numerically higher response rate was observed in the ABC subgroup. In addition, we noticed a higher number of responding patients among patients with transformed lymphoma compared to patients with primary DLBCL. The results need to be interpreted with caution given the low number of patients. Idelalisib showed a manageable and expected safety profile. Considering the limited treatment options for patients with r/r DLBCL, there is an urgent need for novel therapeutic approaches, especially for patients who are ineligible for autologous stem cell transplantation and chimeric antigen receptor T-cells (CART) therapy. Further exploration of the potential benefit of PI3K inhibitors in selected subgroups of r/r DLBCL is motivated. Translational analyses to reveal potential biomarkers for efficacy of PI3K inhibition in DLBCL will now be performed, in tumor tissue and in circulating tumor DNA from plasma. Figure Disclosures Ekstroem Smedby: Celgene: Other: Advisory Board; Janssen Cilag: Research Funding; Takeda: Research Funding. Larsen:Roche: Other: Advisory Board; Gilead: Other: Advisory Board; Celgene/BMS: Other: Advisory Board; Novartis: Other: Travel grants, Advisory Board. Jørgensen:Gilead: Other: Advisory Board; Novartis: Other: Advisory Board; Roche: Other: Advisory Board. Brown:Gilead: Other: Advisory Board. Jerkeman:Celgene: Research Funding; Abbvie: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Roche: Research Funding. OffLabel Disclosure: Idelalisib is a small-molecule inhibitor of PI3KÃŽÃ'´ currently used for patients with CLL and follicular lymphoma. In this trial, based on the high response rate in heavily pretreated patients with indolent B-cell lymphomas, we hypothesize that this agent may also be active in relapsed/refractory DLBCL.

Abstract: Background: Disease progression (PD) after frontline IC therapy for DLBCL is a clinically significant event and only 20-40% of patients achieve durable remissions with salvage chemotherapy. Patients who experience early PD or have disease refractory to IC have especially poor outcomes. Chimeric antigen receptor T-cell therapy has emerged as a novel effective therapy for selected cases of relapsed or refractory (r/r) DLBCL, although its availability is limited by cost and logistic challenges. Simple, clinically applicable prognostic tools would be useful for selecting patients for consideration for novel therapies vs those who are more likely to be successfully managed by conventional therapies, but few have been developed for r/r DLBCL. Methods: Model building was performed in patients with PD after IC from 13 frontline, multicenter, randomized DLBCL clinical trials from the SEAL Consortium. All patients received rituximab and an anthracycline-based combination IC and were followed systematically; however therapy received, clinical, and laboratory data at progression were not available. OS was defined as time from first progression until death from any cause. Associations between variables and OS were evaluated using Cox models; splines were used to model functional forms. Validation was performed in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER) and Danish LYFO cohorts. Model performance was assessed using time-dependent concordance indices (c-stat), Brier scores, and calibration with metrics evaluated at two years from progression. Results: Model Development (SEAL): 1125 of 5112 patients had PD after IC. Median time to PD (TTP) was 11.8 months (IQR 6.6-23.5); median age at PD was 68 years (IQR 60-73). At a median follow-up of 21 months from PD (IQR 7-43), 732 patients (65%) had died and 24 month overall survival after PD (OS24) was 35% (95% CI: 32-38). TTP was strongly associated with post PD OS (spline p-value & lt;0.0001) with OS24 ranging from 18% in patients with TTP & lt;6 months compared to 69% in patients with TTP & gt; 36 months (Figure A). Additionally, age at PD (spline p-value & lt;0.0001) was associated with post PD OS. A model consisting of age at PD including patients 40-80 years and TTP ranging 0-60 months was created (n=1011, Figure B) due to sparse data outside these intervals. C-stat was 0.67, and the model was well calibrated (predicted OS24 = 34% vs. actual OS24 = 34%). External Validation (MER): The model was validated in 290 patients with DLBCL who initiated 2nd line therapy after PD to IC. Median age at PD was younger than the SEAL cohort at 62 years (IQR 57-70). Patients with biopsy proven indolent histology at relapse were excluded. Median TTP was 8.2 months (IQR 5.1-17.0). At a median follow-up of 87 months from PD, 201 patients (69%) had died. OS24 was 47% (95% CI: 41-53). The model showed similar concordance (c-stat=0.65), but underestimated OS24 (predicted =33% vs. 47% actual, Figure C). External Validation (LYFO): The model was validated in 599 patients with DLBCL and PD after frontline IC. Median age at PD was 67 years (IQR 60-73). Median TTP was 10.1 months (IQR 6.0-19.4). At a median follow-up of 82 months from PD, 435 patients (73%) had died. OS24 was 38% (95% CI: 34-42). The model showed similar concordance (c-stat=0.67) when applied to the LYFO cohort, but again underestimated OS24 (predicted =32% vs. 38% actual, Figure D). Case vignettes: A 74 year old patient who progressed 9 months after diagnosis would have a predicted OS24 of 20%. A 58 year old patient who progressed 32 months after diagnosis would have a predicted OS24 of 65% Conclusions: TTP to following IC is strongly associated with post-progression survival in DLBCL. We developed a model from the largest frontline clinical trial dataset in DLBCL and validated a simple to apply clinical prognostic tool in the r/r setting. The model allows better understanding of expected outcomes in r/r DLBCL and can aid design and interpretation of trial results in this setting. The model underestimated the actual survival probability when applied to non-trial validation cohorts. Recalibration of the model for transplant eligible patients and development of smartphone based point-of-care application of the model is ongoing. Figure Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Schmitz:Riemser: Consultancy, Honoraria; Celgene: Equity Ownership; Gilead: Honoraria; Novartis: Honoraria. Farooq:Kite Pharma: Research Funding; Celgene: Honoraria. Flowers:Optimum Rx: Consultancy; Burroughs Wellcome Fund: Research Funding; BeiGene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bayer: Consultancy; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Consultancy, Research Funding; National Cancer Institute: Research Funding; Denovo Biopharma: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Millenium/Takeda: Research Funding; AbbVie: Consultancy, Research Funding; V Foundation: Research Funding. Frederiksen:Alexion: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding. Cunningham:Eli Lilly: Research Funding; 4SC: Research Funding; Bayer: Research Funding; MedImmune: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding; Merrimack: Research Funding; Sanofi: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Merck: Research Funding; Clovis: Research Funding. Jørgensen:Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Poeschel:Amgen: Other: Travel, accommodations, expenses; Abbvie: Other: Travel, accomodations, expenses; Hexal: Speakers Bureau; Roche: Other: Travel, accomodations, expenses. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Seymour:Takeda: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta: Consultancy; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Merli:Takeda: Honoraria, Other: Travel Expenses; Gilead: Honoraria; Mundipharma: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Janssen: Honoraria. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Tilly:roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Celgene: Consultancy, Research Funding; Roche: Consultancy. Salles:Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

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.