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

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

AbstractBackgroundEpidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases.MethodsWe examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsHigher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1st-quartile = 1.13, 95% CI: 1.02–1.24, Ptrend = 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend = 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile = 1.22, 95% CI: 1.08–1.38, Ptrend = 1.36 × 10–5), which was driven by shared genetic susceptibility at the 6p25.3 locus.ConclusionThese findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.

AbstractMost patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

Abstract Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10−8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance–weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00–1.30) and MZL (OR = 1.09; 95% CI, 1.01–1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83–0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99–1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.

SummaryNon‐endemic Burkitt lymphoma (BL) is a rare germinal centre B‐cell‐derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic‐based and population‐based lymphoma registries from six countries were used to identify 264 real‐world patients. The median age was 47 years and the majority had advanced‐stage disease and elevated LDH. Treatment protocols were R‐CODOX‐M/IVAC (47%), R‐hyper‐CVAD (16%), DA‐EPOCH‐R (11%), R‐BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two‐year overall survival and event‐free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two‐year relapse risk was 6% but diminished to 0·6% for patients reaching 12 months of post‐remission event‐free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0·4 (95% CI: −0·7 to 2) months. In conclusion, real‐world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow‐up strategies with increased focus on survivorship and less focus on routine disease surveillance.

Abstract The IGHV4-34 gene is very frequent (~10%) in the B cell receptor immunoglobulin (BcR IG) gene repertoire of chronic lymphocytic leukemia (CLL). Over 30% of IGHV4-34 CLL cases can be assigned to different subsets with stereotyped BcR IG. The largest is subset #4 which represents ~1% of all CLL and ~10% of IGHV4-34 CLL and is considered a prototype for indolent disease. The BcR IG of a great majority (~85%) of IGHV4-34 CLL cases carry a significant load of somatic hypermutation (SHM), often with distinctive SHM patterns. This holds especially true for stereotyped subsets and is suggestive of particular modes of interactions with the selecting antigen(s). In detail, subsets #4 and #16, both involving IgG-switched cases (IgG-CLL), exhibit the greatest sequence similarity in SHM profiles, whereas they differ in this respect from IgM/D subsets #29 and #201. Prompted by these observations, here we explored the extent that these subset-biased SHM profiles in different IGHV4-34 stereotyped subsets were reflected in distinct demographics, clinical presentation, genomic aberrations and outcomes. Within a multi-institutional series of 20,331 CLL patients, 1790 (8.8%) expressed IGHV4-34 BcR IG. Following established bioinformatics approaches for the identification of BcR IG stereotypy, 573/1790 IGHV4-34 CLL cases (32%) were assigned to stereotyped subsets; of these, 340 cases (19% of all IGHV4-34 CLL and 60% of stereotyped IGHV4-34 cases) belonged to subsets #4, #16, #29 and #201, all concerning IGHV-mutated CLL (M-CLL). Clinicobiological information was available for 275/340 patients: #4, n=150; #16, n=44; #29, n=39; and #201, n=42. Comparisons between subsets revealed no differences in gender and age distribution. Interestingly, however, 36-43% of each subset cases were young for CLL (defined as patients aged ≤55 years), which is higher compared to general CLL cohorts, where young patients generally account for ~25% of cases. In contrast, significant differences were identified between subsets regarding: (i) disease stage at diagnosis, with >90% of IgG subsets #4 and #16 diagnosed at Binet stage A versus 83% in subset #201 and 74% in subset #29 (p=0.029); (ii) CD38 expression, ranging from 1% in subset #4 to 10% in subset #201 (p=0.013); (iii) the distribution of del(13q), peaking at a remarkable 92% in subset #29 versus only 37% in subset #16 (p<0.0001). Regarding other genomic aberrations, they were either absent (NOTCH1 mutations) or rare (SF3B1 mutations, trisomy 12, del(11q), TP53 aberrations due to either del(17p) and/or TP53 mutations). The sole exception concerned a high frequency (14%) of TP53 aberrations in subset #29 (p<0.05 compared with the other subsets), which is notable for M-CLL cases in general. Time to first treatment (TTFT) could be analyzed in 228 cases. IgG subsets #4 and #16 had significantly (p=0.036) longer TTFT (median TTFT: not yet reached) compared to the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). In conclusion, we have identified distinct clinicobiological profiles for different stereotyped IGHV4-34 M-CLL subsets, highlighting subsets #4 and #16 as particularly indolent, which is important for both medical and social reasons, especially considering that a significant proportion of patients in these subsets are diagnosed at younger ages. Our findings support the notion that BcR IG stereotypy refines prognostication in CLL, superseding the crude immunogenetic distinction based on SHM load only. Additionally, the observed heterogeneity suggests that not all M-CLL are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Disclosures Tausch: Gilead: Other: Travel support. Shanafelt:Glaxo-Smith_Kline: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Polyphenon E Int'l: Research Funding; Hospira: Research Funding; Janssen: Research Funding; Pharmactckucs: Research Funding; Cephalon: Research Funding. Niemann:Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy; Novartis: Other: Travel grant. Langerak:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics.; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam). Hallek:Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Ghia:Janssen Pharmaceuticals: Research Funding.

Abstract Background Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified several associations at both HLA and non-HLA loci. However, much of HL heritability remains unexplained. Methods To identify novel risk loci, we performed a meta-analysis of 3 HL GWAS including a total of 1,810 cases and 7,879 controls. Results were replicated in an independent set of 1,163 cases and 2,580 controls, for a total of 3,097 and 11,097 cases and controls combined, respectively. participants in discovery and replication stages were of European descent. quality control and imputation we conducted a meta-analysis addressing 1,004,829 variants (λ= 1.10, λ1000= 1.03). Associations between SNP genotypes and HL risk were evaluated under a log-additive model of inheritance adjusting for sex, study center and significant principal components to control for population stratification. We performed an analysis with all HL cases and then conducted stratified analyses by histological subtype (classical, nodular sclerosis and mixed cellularity), age at diagnosis (nodular sclerosis among those diagnosed at 15- 35 years in all studies, and those diagnosed at 35 and older years in the European Study only) and EBV tumor status (negative and positive). We then used a bioinformatic approach (FunciSNP) to identify potential functional variants associated with HD risk correlated with risk loci of interest. We extracted publically available ENCODE data on biofeatures to identify potential functional motifs associated with the index SNP or correlated SNPs. Finally, we measured expression levels of the two alternative mRNA transcripts in lymphoblastoid cell lines (LCLs) from 49 post-therapy HL patients and 25 unaffected controls. RT-PCR was carried out in triplicate. Relative expression levels were calculated relative to TBP as housekeeping gene. Linear models were used to assess correlation between genotype and TCF3expression levels. Results The meta-analysis identified a novel susceptibility variant at chromosome 19p13.3 (rs1860661) associated with HL risk (Odds Ratio [OR]= 0.78, P=2.0*10-8, I2=0%). variant is located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment. was also significantly associated with HL (OR= 0.85, P=0.002) in the replication series of 1,281 cases and 3,218 controls. the combined analysis consisting of the discovery and replication sets, rs1860661was strongly associated with HL (OR=0.81,=3.5*10-10), with no evidence of heterogeneity between contributing studies (Phom=0.41, I2=0%). The number of G alleles defined by rs1860661 was significantly associated with a reduced risk of each HL subtype except EBV positive HL. rs1860661 and two correlated SNPs, rs10413888 (r2=0.90) and rs8103453 (r2=0.89) identified by FunciSNP analysis map in or near marks of open chromatin and in DNAse hypersensitivity sites in TCF3 in CD20+ B cell lines., the protective minor alleles of these SNPs as defined by the G-G-G haplotype map to the binding sites for ZBTB7a (rs10413888 and rs1860661) and (rs8103453) transcription factors, likely improving the binding efficiency to the sites which may result in increased transcription rates of TCF3. TCF3 is encoded by two alternative transcripts (E12 and E47). Higher expression levels of TCF3-E47, whose transcription start site is located close to rs1860661, was associated with the rs1860661-G allele in controls (P=0.02), but not in HL patients (P=0.22). Conclusion/Discussion TCF3 is essential for the commitment of lymphoid progenitors to both B-cell and T-cell lineage development. A molecular and phenotypic hallmark of classical HL is the loss of the B-cell phenotype in HRS cells, including lack of demonstrable B-cell receptor and most B-cell specific markers such as CD19 or CD20. HRS cells have a low level of TCF3, particularly homodimers of the isoform E47, due to expression of the ABF-1 and ID2 inhibitors that bind to TCF3. Thus, higher TCF3 levels in HRS precursor cells may lead to enhanced retention of the B cell phenotype, thereby conferring a protective effect. These data suggest a link between the 19p13.3 locus including TCF3 and HL risk, indicating that TCF3 could be relevant to HL etiology and pathogenesis. Disclosures: Link: Genentech: Consultancy; Millenium: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy.

Introduction: Non-endemic Burkitt lymphoma (BL) is a rare and highly aggressive B-cell malignancy, of whom a substantial number are adolescents and young adults (AYAs). In this particular group of patients, the balance between efficacy and long-term toxicities is of major concern, due to the long expected remaining lifetime. In this study, we investigated the outcomes for AYA patients treated with intensive immunochemotherapy. Patients and methods: Patients were identified through queries to clinic based and population-based lymphoma registries from six countries (Australia, Canada, Denmark, Norway, Sweden, and USA). All diagnoses were confirmed by local investigators; patients with classical BL histology plus detectable MYC translocation, were included. Patients between 18 and 39 years of age at diagnosis treated with intensive immunochemotherapy (DA-EPOCH-R or more intensively) were evaluated in pre-specified age groups. All treatment protocols included rituximab. Overall survival (OS) was defined as the time from diagnosis until death from any cause or censoring, while event-free survival (EFS) was defined as the time from diagnosis until unplanned re-treatment, progression/relapse, death, or censoring, whichever came first. Response evaluation was assessed using established response criteria based on CT and/or PET/CT imaging. Survival curves were computed using the Kaplan-Meier estimator. The cumulative incidence of relapse in patients reaching complete remission (CR) or CR unconfirmed (CRu) was computed by Aalen-Johansen estimator. The 5-year restricted loss of lifetime (RLOL) was defined as the area between the patient and general population survival curves until 5-years. The general population survival was retrieved from publicly available lifetables stratified on age, sex, calendar year, and country. Results: In total, 108 AYA BL patients were included. The median age was 30 years, ranging between 18 and 39 and 82% were male. The majority had advanced stage disease (Ann Arbor stage III-IV, 76%), extranodal involvement (87%), and elevated LDH (67%). Seven patients (6%) had CNS involvement at the time of diagnosis. The chemotherapy regimens used were CODOX-M/IVAC (51%), BFM/GMALL (34%), hyper-CVAD (7%), DA-EPOCH (5%), and others (3%). Among 74 patients for whom data on tumor lysis were available, 10 (14%) developed clinical tumor lysis upon start of chemotherapy, all presenting with advanced stage and extranodal disease. The response rate was 91% (89 in CR/CRu and 2% in partial remission). At a median follow-up of 53 months, 15 had an event and 10 died. The 2-year OS and EFS for the total population was 92% (87-97%, Figure 1) and 88% (82-94%), respectively. For 13 patients aged 18-21 2-year OS and EFS were both 100%, while 2-year OS and EFS for 43 patients aged 22-30 were 98% (93-100%) and 93% (85-100%), respectively. The 2-year OS and EFS for patients aged 31-39 were 86% (76-96%) and 80% (69-91%), respectively. For patients in CR/CRu and available date of response evaluation, the 2-year post-remission OS was 99% (97-100%) and the 2-year relapse risk was 2% (0-5%), with no relapses after 6 months. Compared to the general population, the RLOL was 0.8 months (-0.5-2.2 months). Nine patients did not respond to primary treatment (SD or PD), all which belonged to the age group 31-40 years (P<0.001 versus age group 18-30 years). The oldest age group had an inferior OS compared to younger patients (P=0.008), largely due to non-responders having poor subsequent survival with a 1-year OS of 33%. Conclusion: The outcomes of AYA BL patients following intensive immunochemotherapy are excellent with high remission rates and low risk of relapse in general. However, even among young patients age remained prognostic, with patients 31 years or older having inferior OS and lower response rate to first-line treatment. In patients achieving CR, survival was similar to that of the general population over the median follow-up of 4.5 years, illustrating the need to focus on survivorship issues in these individuals. Figure 1: Overall survival for BL patients following intensive immunochemotherapy for all patients and for age groups (18-21, 22-30, and 31-39 years). Figure 1 Disclosures 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. Holte:Novartis: Honoraria, Other: Advisory board. Molin:Roche Holding AG: Honoraria; Merck & Co., Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria. Ekstroem Smedby:Takeda: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Janssen Cilag: Honoraria, Other: Grant funding, Research Funding. Song:Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria. Cheah:Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel expenses; Celgene, Roche, Abbvie: Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

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.