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: This study aims to characterize the epidemiology of immunocompetent Primary central nervous system lymphoma ( PCNSL ) diagnosed 2000‐2013 in Sweden. Methods Cases were identified in the population‐based Swedish Lymphoma Register. Incidence per 100 000 person‐years and 95% confidence intervals ( CI ) were calculated, and PCNSL ‐specific survival was estimated using relative survival. Tests for temporal trends were performed using Poisson regression. Population incidence of all brain tumors was retrieved for comparison. Results With 359 identified PCNSL cases (median age 66 years), overall incidence was 0.26 (95% CI : 0.24‐0.29) and the average annual increase 4% ( P  = .002). The increasing trend was primarily observed among elderly individuals (70+ years). Similarly, an increase in incidence of all brain tumors was noted only among the elderly. There was no significant improvement in relative survival across the study period although, among fit patients (with Eastern Cooperative Oncology Group, EGOC 0), survival plateaued 6 years after diagnosis. Conclusion The increasing PCNSL incidence in the elderly was consistent with an increasing incidence of brain tumors of any type and may in part be attributable to improved diagnostics and reporting in this group. New treatment options have not yet translated into general survival improvements in a population‐based setting, although the presence of long‐term survivors among fit patients is encouraging.

Abstract: For indolent lymphoma, the optimal timing, sequence, and choice of therapeutic regimens remain a matter of debate. In two Nordic Lymphoma Group randomized trials, symptomatic or clearly progressing patients were treated first line with a rituximab-containing regimen without chemotherapy. The purpose of this study was to assess long-term survival, risk of transformation, and need of new therapies. Methods Data were collected at cross-sectional follow-up for 321 patients with indolent lymphoma (84% with follicular lymphomas [FL]) included in one of two Nordic Lymphoma Group trials (accrual 1998 to 1999 and 2002 to 2008). All patients received first-line therapy with one or two cycles of four weekly infusions of rituximab 375 mg/m 2 , and 148 were randomly allocated to the addition of interferon alfa-2a. Follow-up data were retrieved from initial trial databases and medical records on repeated clinical evaluations. Results At the end of follow-up, 73% of patients were alive, with a median follow-up after random assignment of 10.6 years. Among all, 36% (38% with FL) had never needed chemotherapy. For patients with FL who required new therapy within 24 months because of early disease progression, the 10-year survival rate was 59% versus 81% for those with longer remission. Interferon was not shown to improve long-term outcome. Transformation was diagnosed in 20% of all patients (2.4% per person-year) and in 18% with FL. An additional malignancy was found in 12%. Conclusion Approximately one third of patients with symptomatic indolent lymphoma (30% with FL, 23% without FL) did not need new therapy in the long term after first-line rituximab without chemotherapy. In the entire cohort, 10-year survival was excellent with no major safety issues, which suggests that chemotherapy can be delayed safely in the majority of patients.

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: Background Our knowledge of the outcome of patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in the rituximab era is mostly derived from randomised controlled trials or specialized center cohorts presenting selected patient materials. With new targeted therapies being evaluated in the relapsed/refractory setting such as CART therapy, there is a need for a better understanding of the expected survival in real-world cohorts of R/R DLBCL and the likelihood of patients being selected for established intensive treatment schedules and consolidation with autologous stem cell transplantation (ASCT). Here we investigated timing of relapse, treatment intensity and outcome among patients with R/R DLBCL in a nationwide population-based cohort. Methods Patients with R/R DLBCL (N=713) were identified among all patients with a first incident DLBCL diagnosed 2007-2014 recorded in the Swedish Lymphoma Register and treated with primary anthracycline-based immunochemotherapy (N=3528), with follow-up until December 31st 2018. The register holds information about clinical characteristics at diagnosis, primary treatment, treatment response and relapse. Data regarding treatment response and relapse was validated through medical chart review in the entire cohort and information about second-line treatment and ASCT was collected. Timing of progression/relapse was categorized by time interval in months from diagnosis (0-12, 12-24, 24+). Treatment intensity was categorized in four groups: intensive chemotherapy (e.g., DHAP, ICE, GDP) with intent of ASCT, remission-inducing chemotherapy (e.g., GemOx, IME, Benda), palliative therapy (oral chemotherapy, radiotherapy) and no active antitumoral treatment (e.g., steroids, best supportive care). Second-line treatments could have been given with or without immunotherapy. Overall survival probabilities were estimated in the entire cohort and by age 〉 /≤ 70 years using the Kaplan-Meier method. Results In the study population of 713 patients (59% men), median age at relapse was 71 years (range 18 to 95) and 61% had stage IV disease. Most patients relapsed within 12 months (N=428, 60%) whereas 135 patients (19%) relapsed 12-24 months from diagnosis and 148 patients (21%) after 24 months. In patients ≤70 years of age, intensive chemotherapy with intent of ASCT was started in 206 out of 354 patients (58%) and 124 (35%) subsequently received a consolidative ASCT. Remission-inducing chemotherapy was given to 95 patients (27%), 22 (6%) received palliative treatment directly and 31 (9%) were deemed unfit for any active treatment. Among patients 〉 70 years at relapse, 63 patients started intensive chemotherapy (18%) and 4 (1%) were eventually transplanted, whereas another 127 (35%) received remission-inducing chemotherapy, 92 (26%) palliative therapy directly and 77 (21%) no active therapy. Overall survival in the entire cohort was 26% at 2 years (Figure 1A). Timing of relapse strongly correlated with survival, primarily among patients 〈 70 years of age (2-year OS was 21% for 0- 〈 12, 38% for 12-24 and 77% for 24+) (Figure 1B). By treatment intensity, outcomes also varied more among young patients in favor of the intensive chemotherapy with intent of ASCT (with 39% 2-year OS). Among young patients, timing of relapse correlated with the possibility to give consolidative ASCT (23% in early relapse vs 〉 50% in relapse 12 months or after). Among patients 〉 70 years, outcomes were strikingly poor in all treatment intensity groups (2-year OS 23% or lower). Conclusion In the population-based setting, less than 60% of patients with R/R DLBCL ≤70 years at relapse could go on to receive curative intent second-line treatment and only about one third were consolidated with ASCT (even fewer among those with early relapse). Among patients 〉 70 years, outcomes were very poor and second-line treatment intensity seemed to have little impact on outcome, although there were a few longer-term survivors in all treatment groups. More efficient and less toxic therapies are urgently needed for R/R DLBCL at all ages. Figure 1 A-C Overall survival of patients with relapsed/refractory diffuse large B-cell lymphoma in Sweden 2007-2014 (N=713) in the entire cohort (1A), by age 〉 /≤ 70 years and timing of relapse (0- 〈 12, 12-24, 24+ months of diagnosis) (1B) and by age 〉 /≤ 70 years and treatment intensity categorized in 4 groups (1C). Disclosures Ekstroem Smedby: Janssen Cilag: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Takeda: Honoraria, Other: Grant funding, Research Funding. Ekberg:Swedish Cancer Society: Other: This project was partly funded by the Swedish Cancer Society; Janssen Pharmaceuticals: Other: This project was partly funded through a private-public collaboration between KI and Janssen pharmaceuticals.. Eloranta:Karolinska Institutet: Other: coordinator for a public-private real world evidence; Janssen Pharmaceuticals.: Other: project coordinator for a public-private real world evidence. Enblad:Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Jerkeman:Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Andersson:Gilead: Research Funding; Gilead, Janssen and Roche: Consultancy; Abbvie and Janssen: Membership on an entity's Board of Directors or advisory committees. Harrysson:Swedish Cancer Society: Other: This project was partly funded by the Swedish Cancer Society.; Janssen pharmaceuticals: Other: This project was partly funded through a private-public collaboration between KI and Janssen pharmaceuticals..

Abstract: Background: Non-endemic Burkitt lymphoma (BL) is a rare B-cell malignancy characterized by extreme tumor proliferation, frequent extranodal involvement, and the genetic hallmark of a MYC gene rearrangement. Despite an often dramatic initial presentation featuring tumor compression of vital organs and/or spontaneous tumor lysis syndrome, most patients who survive intensive immunochemotherapy induction are cured. Despite limited evidence of benefit, the current NCCN guidelines recommend that BL patients in CR are reviewed every 3 months for 2 years and every 6 months thereafter. Aims: To investigate outcomes, including relative survival and relapse risks conditional on event-free survival (EFS) milestones, in an international study of real-world BL patients treated with intensive immunochemotherapy. Patients and methods: This is a retrospective study of newly diagnosed BL patients identified from relevant population or hospital-based registers in Australia (Perth), Denmark (the Danish Lymphoma Registry), Sweden (the Swedish Lymphoma Registry) and Norway (Health Region South East). Patients who met the following criteria were included irrespective of HIV status: 1) age ≥18 years at diagnosis, 2) diagnosed during the period 2005-2017, 3) histology and immunohistochemistry consistent with BL, 4) MYC translocation detected by fluorescence in situ hybridization (FISH), and 5) intensive first line immunochemotherapy including rituximab (R-CHOEP or more intensive). Patient data were collected from registers and chart reviews. Overall survival (OS) was defined as time until death and EFS was defined as time to death, relapse/progression, or unplanned treatment, whichever came first. Prognostic features at baseline were evaluated using univariate Cox models with EFS as outcome. Standardized mortality ratios (SMRs), conditional relative survival estimates, and relapse risks were computed for the subset of patients achieving complete remission (CR or CRu), with follow-up measured from response evaluation and from different EFS milestones. Results: In total, 159 patients fulfilled the inclusion criteria of the study. The median age was 48 years (range 18-81) and the male:female ratio was 2.9. The baseline characteristics included stage III-IV (75%), elevated serum LDH (75%), extranodal involvement (83% - bone or bone marrow in 42% and CNS in 8%), B symptoms (60%), and ECOG performance score 〉 1 (30%). The chemotherapy protocols used were CHOEP (2%), DA-EPOCH (13%), HYPER-CVAD (26%), CODOX-M/IVAC (28%), BFM or GMALL (31%), and others (1%). Clinical tumor lysis syndrome defined by severe electrolyte derangement, renal impairment, and/or cardiac arrhythmia, was noted in 16% of the patients, but no fatal episodes occurred. The overall response rate to first-line treatment was 88% (87% in CR/CRu) with 67% assessed by PET technology. The five-year EFS and OS estimates for the total population were 75% (95% CI 68-82%) and 82% (95% CI 76-88%), respectively, and the EFS and OS of patients 〈 50 years of age were 81% (95% CI 71-90%) and 89% (95% CI 82-96%), respectively. In univariate analyses, age, advanced stage, and elevated LDH were associated with worse EFS. Among patients in CR/CRu (n=137), the 5-year EFS and OS from the time of response evaluation were 86% (95% CI 79-93%) and 91% (95% CI 86-96%), respectively. The 5-year cumulative incidence of relapse from the time of response assessment was 5% (95% CI 1-9%) in CR/CRu patients. The corresponding estimate was 3% (95% CI 0-6%) for patients alive after 6 months without events (EFS6), whereas no patients relapsed after 12 (EFS12, Figure 1). For CR/CRu patients, the 5-year relative survival after EFS6 and EFS12 was 97% (95% CI 93-102%) and 100% (95% CI 97-103%), respectively. In most subgroups, the SMRs gradually decreased with increased remission duration (Table 1). Conclusions: Outcomes of adult BL patients treated with intensive immunochemotherapy are excellent with no relapses occurring for patients reaching EFS12 and with a normalized relative survival after EFS6. For patients reaching EFS12, follow-up in late effects clinics, or discharging to primary care providers with a focus on survivorship issues rather than detection of recurrent lymphoma, should be considered. Updated analyses including patients from British Columbia (Canada) and the University of Iowa/Mayo Clinic SPORE MER register (USA) will be presented at the meeting. Disclosures Molin: Takeda Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Honoraria; Roche Holding AG: Honoraria; Merck & Co., Inc: Honoraria. Ekstroem Smedby:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals.