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Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell–like (ABC) to germinal center B-cell–like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC–DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC–DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of

Follicular lymphoma (FL) is morphologically and clinically diverse, with mutations in epigenetic regulators alongside t(14;18) identified as disease-initiating events. Identification of additional mutational entities confirms this cancer’s heterogeneity, but whether mutational data can be resolved into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n = 548) with full clinical follow-up (n = 538), which included 96 diffuse large B-cell lymphoma (DLBCL) transformations. We investigated whether molecular subclusters of FL can be identified and whether mutational data provide predictive information relating to transformation. DNA extracted from FL samples was sequenced with a 293-gene panel representing genes frequently mutated in DLBCL and FL. Three clusters were resolved using mutational data alone, independent of translocation status: FL_aSHM, with high burden of aberrant somatic hypermutation (aSHM) targets; FL_STAT6, with high STAT6 & CREBBP mutation and low aSHM; and FL_Com, with the absence of features of other subtypes and enriched KMT2D mutation. Analysis of mutation signatures demonstrated differential enrichment of predicted mutation signatures between subgroups and a dominant preference in the FL_aSHM subgroup for G(C>T)T and G(C>T)C transitions consistent with previously defined aSHM-like patterns. Of transformed cases with paired samples, 17 of 26 had evidence of branching evolution. Poorer overall survival (OS) in the aSHM group (P = .04) was associated with older age; however, overall tumor genetics provided limited information to predict individual patient risk. Our approach identifies 3 molecular subclusters of FL linked to differences in underlying mechanistic pathways. These clusters, which may be further resolved by the inclusion of translocation status and wider mutation profiles, have implications for understanding pathogenesis as well as improving treatment strategies in the future.

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.

Objectives Relapse occurs in ~20% of patients with classical Hodgkin lymphoma (cHL) despite treatment adaption based on 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography response. The objective was to evaluate pre-treatment FDG PET/CT–derived machine learning (ML) models for predicting outcome in patients with cHL. Methods All cHL patients undergoing pre-treatment PET/CT at our institution between 2008 and 2018 were retrospectively identified. A 1.5 × mean liver standardised uptake value (SUV) and a fixed 4.0 SUV threshold were used to segment PET/CT data. Feature extraction was performed using PyRadiomics with ComBat harmonisation. Training (80%) and test (20%) cohorts stratified around 2-year event-free survival (EFS), age, sex, ethnicity and disease stage were defined. Seven ML models were trained and hyperparameters tuned using stratified 5-fold cross-validation. Area under the curve (AUC) from receiver operator characteristic analysis was used to assess performance. Results A total of 289 patients (153 males), median age 36 (range 16–88 years), were included. There was no significant difference between training (n = 231) and test cohorts (n = 58) (p value > 0.05). A ridge regression model using a 1.5 × mean liver SUV segmentation had the highest performance, with mean training, validation and test AUCs of 0.82 ± 0.002, 0.79 ± 0.01 and 0.81 ± 0.12. However, there was no significant difference between a logistic model derived from metabolic tumour volume and clinical features or the highest performing radiomic model. Conclusions Outcome prediction using pre-treatment FDG PET/CT–derived ML models is feasible in cHL patients. Further work is needed to determine optimum predictive thresholds for clinical use. Key points • A fixed threshold segmentation method led to more robust radiomic features. • A radiomic-based model for predicting 2-year event-free survival in classical Hodgkin lymphoma patients is feasible. • A predictive model based on ridge regression was the best performing model on our dataset.

Introduction Brentuximab vedotin (BV)-CHP is the new standard regimen for first-line treatment of systemic anaplastic large cell lymphoma (sALCL). We undertook a retrospective analysis of consecutive patients diagnosed with sALCL, treated in routine practice, to serve as a benchmark analysis for comparison BV-CHP efficacy in routine practice. Methods Patients aged 16 years or older with sALCL treated in seven UK and Australian centres and from 14 additional centres from the UK Haematological Malignancy Research Network database (n = 214). Treatment allocation was clinician choice and included best supportive care (BSC). Main outcomes were time to treatment failure (TTF) and overall survival (OS). Multivariable analysis for predictors of both TTF and OS was also undertaken. Results The median age 52 years (range 16–93), 18% ECOG ≥ 3 and 40% of cases were ALK positive. CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) was employed in 152 (71%) of patients and CHOEP (CHOP + etoposide) in 4% of patients. For CHOP-treated patients overall response rate (ORR) was 65% and complete response (CR) 47%. Only 9% of patients underwent autologous stem cell transplant (ASCT). With 57 months median follow-up, 4-year TTF and OS were 41.2% (95% CI 33.1–49.1) and 58.9% (95% CI 50.3–66.5) respectively. Multivariable analysis showed ALK+ status was independently associated with superior TTF (HR 0.36, 95% CI 0.21–0.63) but not OS (0.44, 95% CI 0.18–1.07). Discussion We present a retrospective analysis with mature follow-up of one of the largest multicentre populations of sALCL available, comparable to similar large retrospective studies. ALK status remains a strong predictor of outcomes. Conclusion These data serve as a robust benchmark for BV-CHP as the new standard of care for sALCL. Similar real-world evidence with BV-CHP will be desirable to confirm the findings of ECHELON-2. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01764-0.

Diffuse large B-cell lymphoma (DLBCL) is characterised by pronounced genetic and biological heterogeneity. Several partially overlapping classification systems exist – developed from mutation, rearrangement or gene expression data from single studies. We apply a customised network analysis to nearly five thousand DLBCL cases to identify and quantify modules of tumour biology. Shared patterns of activity in these tumour biology modules identify biologically similar DLBCL, which resolve into communities of related cases. These lymphoma communities correlate with genetic mutation and rearrangement status, supporting and extending existing concepts of disease biology and delivering insight into relationships between differentiation state, genetic subtypes and rearrangement status. A notable example are communities linked to distinct germinal centre states that separate DLBCL respectively associated withMYC/BCL2andMYC/BCL6double hit rearrangement. By exploiting network analysis across a large number of well characterised cases, this study provides the first birds eye view of DLBCL tumour biology.

An implementation of the windows based DLBCL automatic classification (DAC) algorithm for determining cell of origin (COO) written in the R language and designed for use with the HTG EdgeSeq Reveal Software package is described. Classifications using the new implementation (DAC-R) were compared to the those using the original version (DAC-Win), the HTG DLBCL COO classifier, the HTG EdgeSeq Reveal DLBCL algorithm. Classifications made using HTG data were tested for concordance with those made using WG-DASL data for the same samples. To analyse small numbers of samples a background dataset was developed to allow for the reliable classification of individual cases. Classification accuracy was assessed using percentage of agreement of discrete classification groups and Pearson correlation of probability scores where appropriate. In the data tested it was seen that the correlation of probability scores for DAC-R and DAC-Win was 0.9985 or higher. Agreement with the HTG DLBCL COO classifier was 85.1% and agreement with the HTG EdgeSeq Reveal DLBCL algorithm was also high (Pearson correlation of GCB probabilities = 0.91). Agreement between classifications made using HTG and WG-DASL data was also high (83.7%). In summary, the R based algorithm of DAC successfully replicates the functionality of the original routine and produces comparable COO calls in data produced from the HTG Pan B-Cell Lymphoma Panel to the other methods listed.

Background: Over 13,000 new cases of non-Hodgkin’s lymphoma (NHL) are diagnosed in the UK, with approximately 4,900 attributable deaths each year. Diffuse Large B-cell Lymphoma (DLBCL) is the most common NHL comprising one third of adult NHL cases. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) is accepted as the international standard first-line regimen, but improvement in first line treatment is needed. Dysregulated B-cell receptor (BCR) signalling has been identified as a feature of DLBCL. Inhibition of Bruton’s tyrosine kinase (Btk), downstream of the BCR has proven efficacious in other B-cell malignancies and in combination with R-CHOP. The second generation Btk inhibitor, acalabrutinib, may have improved target potency and specificity, and therefore better efficacy and tolerability. Methods: ACCEPT is an open-label non-randomised Phase Ib/II trial testing the addition of acalabrutinib to conventional R-CHOP therapy. ACCEPT incorporates an initial 6+6 modified Phase I design of up to 24 participants followed by 15 participant single arm Phase II expansion cohort in treatment naive patients with histologically confirmed DLBCL expressing CD20. Participants are recruited from UK secondary care sites. Phase I will establish the recommended Phase II dose (RP2D, primary endpoint) of acalabrutinib in combination with R-CHOP. Phase II will gain additional information on safety and efficacy on the RP2D. The primary endpoints of Phase II are overall response rate and toxicity profile. Secondary endpoints include duration of response (progression-free survival and overall survival OS) in relation to cell of origin. Analyses are not powered for formal statistical comparisons; descriptive statistics will describe rates of toxicity, efficacy and translational endpoints. Discussion: ACCEPT will provide evidence for whether acalabrutinib in combination with R-CHOP is safe and biologically effective prior to future Phase II/III trials in patients with previously untreated CD20 positive DLBCL. Trial registration: EudraCT Number: 2015-003213-18 (issued 16 July 2015); ISRCTN13626902 (registered 07 March 2017).

We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Español de Linfomas/Transplante de Médula Ósea (GELTAMO)-IPI, where baseline β2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.

Highlights • First report in literature of curative management with radiotherapy for histiocytic sarcoma. • Radiotherapy to localised base of tongue histiocytic sarcoma was well tolerated. • No evidence of relapse following 5 years follow up., Histiocytic sarcoma (HS) is an exceedingly rare and aggressive neoplasm of lymphoid and haematopoietic tissues and expresses histological and phenotypical characteristics of mature histiocytes. There have only been a few cases of documented HS in the head and neck region. Whilst patients with HS often have nodal or disseminated disease, patients can present with localised disease. There are currently no established treatment guidelines, and reported cases of localised disease have been managed with primary surgery and adjuvant radiotherapy and/or chemotherapy. Here we present, the case of a 49 year old man with a HS of the base of tongue treated with radical radiotherapy to a dose of 60 Gy in 30 fractions, achieving disease free survival of greater than 5 years with minimal toxicity. To our knowledge, this is the first reported case of HS treated with radical radiotherapy, and suggests that when the potential morbidity of surgery for localised disease is significant, radiotherapy may represent an alternative treatment.

We report a case of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) occurring in a 53-year-old female with Li Fraumeni syndrome (LFS) with a prior history of breast cancer. We present the clinical features, investigation, and management of this patient and potential mechanisms that could explain the increasing association of BIA-ALCL and LFS.

We recently published results of targeted sequencing applied to 928 unselected cases of DLBCL registered in the Haematological Malignancy Research Network (HMRN) registry (1). Clustering allowed us to resolve five genomic subtypes. These subtypes shared considerable overlap with those proposed in two independent genomic studies(2, 3), suggesting the potential to use genetics to stratify patients by both risk and biology. In the original studies, clustering techniques were applied to sample cohorts to reveal molecular substructure, but left open the challenge of how to classify an individual patient. This was addressed by the LymphGen classification tool (4). LymphGen assigns an individual case to one of six molecular subtypes. The tool accommodates data from exome or targeted sequencing, either with or without copy number variant (CNV) data. Separate gene expression data allows classification of a seventh, MYC-driven subtype defined by a double hit (DHL) or molecular high-grade (MHG) gene expression signature(5-7).

Summary Breast implant‐associated anaplastic large cell lymphoma (BIA‐ALCL) is an uncommon T‐cell non‐Hodgkin Lymphoma (NHL) associated with breast implants. Raising awareness of the possibility of BIA‐ALCL in anyone with breast implants and new breast symptoms is crucial to early diagnosis. The tumour begins on the inner aspect of the peri‐implant capsule causing an effusion, or less commonly a tissue mass to form within the capsule, which may spread locally or to more distant sites in the body. Diagnosis is usually made by cytological, immunohistochemical and immunophenotypic evaluation of the aspirated peri‐implant fluid: pleomorphic lymphocytes are characteristically anaplastic lymphoma kinase (ALK)‐negative and strongly positive for CD30. BIA‐ALCL is indolent in most patients but can progress rapidly. Surgical removal of the implant with the intact surrounding capsule (total en‐bloc capsulectomy) is usually curative. Late diagnosis may require more radical surgery and systemic therapies and although these are usually successful, poor outcomes and deaths have been reported. By adopting a structured approach, as suggested in these guidelines, early diagnosis and successful treatment will minimise the need for systemic treatments, reduce morbidity and the risk of poor outcomes.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon T cell Non-Hodgkin Lymphoma (NHL) associated with breast implants. Raising awareness of the possibility of BIA-ALCL in anyone with breast implants and new breast symptoms is crucial to early diagnosis. The tumour begins on the inner aspect of the peri-implant capsule causing an effusion, or less commonly a tissue mass to form within the capsule, which may spread locally or to more distant sites in the body. Diagnosis is usually made by cytological, immunohistochemical and immunophenotypic evaluation of the peri-implant fluid: pleomorphic lymphocytes are characteristically anaplastic lymphoma kinase (ALK) negative and strongly positive for CD30. BIA-ALCL is indolent in most patients but can progress rapidly. Surgical removal of the implant with the intact surrounding capsule (total en-bloc capsulectomy) is usually curative. Late diagnosis may require more radical surgery and systemic therapies and although these are usually successful, poor outcomes and deaths have been reported. By adopting a structured approach, as suggested in these guidelines, early diagnosis and successful treatment will minimize the need for systemic treatments, reduce morbidity and the risk of poor outcomes. These guidelines provide an evidence-based and systematic framework for the assessment and treatment of patients with suspected or proven BIA-ALCL and are aimed at all clinicians involved in the care of people with breast implants.

Background Outcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen. Patients and methods Eligible patients were aged 18–65 years with stage II–IV untreated DLBCL and an International Prognostic Index (IPI) score of 3–5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS). Results A total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9–74.6] and 2-year overall survival was 76.0% (90% CI 68.5–82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9–58.0). Conclusions This trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care. Trial Registration ClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19)., Highlights • R-CODOX-M/R-IVAC is an effective regimen for treatment of high-risk DLBCL and high-grade B-cell lymphoma (IPI score 3–5). • Treatment was well tolerated in patients aged

Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of ∼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also commonly found in MYC-translocated diffuse large B cell lymphoma and reveal functional co-operation between mutant DDX3X and MYC. DDX3X promotes translation of mRNAs encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells subsequently restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y-chromosome homologue that is normally expressed exclusively in testis. These findings show that DDX3X loss-of-function can buffer MYC-driven proteotoxic stress, and highlight the capacity of male B cell lymphomas to later compensate for this loss by ectopic DDX3Y expression.

AVENuE - Avelumab in the frontline treatment of advanced classic Hodgkin lymphoma - a window study Background Response adapted ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) has become a standard of care in many countries for advanced stage classic Hodgkin Lymphoma (cHL), as investigated in the RATHL study: following 2 cycles of ABVD patients with negative (Deauville 1-3) interim PET (iPET2) proceeded to 4 cycles of AVD; those with positive (Deauville 4-5) iPET2 intensified therapy to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone (escBEACOPP) or BEACOPP every 14 days. Overall this strategy was associated with a 3-year progression free survival (PFS) of 82.6%, and outcomes for patients with positive iPET2 were disappointing with 3y progression-free survival (PFS) of 67.5%. More intensive treatment such as upfront use of escBEACOPP has been reported to produce higher PFS (89% at 5 years), but it is unclear whether overall survival (OS) is improved. More intensive treatment is, however, associated with higher risk of toxicity. Inhibitors of programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have established efficacy in relapsed / refractory cHL with response rates of 55-87%. In the front line setting PD-1 inhibitors have a reported complete metabolic response (CMR) rate of 18-37%. Response to PD-L1 inhibitors in the frontline setting has not been explored. Serial serum TARC (thymus and activation-regulated chemokine) is reported to be prognostic in the frontline treatment of cHL and may aid response assessment because PET interpretation with checkpoint inhibitors is often complex. In the context of PD-1 inhibition, PD-1 expression by immunohistochemistry (IHC) and 9p24.1 copy gain by fluorescence in situ hybridisation (FISH) are reported to correlate with response. Methods AVENuE is a Phase II single-arm multicentre study with sites in the UK and Australia assessing the safety and efficacy of 2 cycles (4 doses) of the PD-L1 inhibitor avelumab for untreated high-risk stage II-IV cHL prior to the iPET2 response adapted approach described above. Eligible patients must be 16-60 years, ECOG 0-1, and have adequate organ function. Patients with; compressive symptoms from lymphoma, autoimmune disorders or immunosuppressive treatment within 2 months are excluded. The primary endpoint is the centrally reviewed PET CMR rate to avelumab. Secondary endpoints are: the safety and tolerability of sequential avelumab and combination chemotherapy as assessed by CTCAE v 5.0; the iPET2 CMR rate after avelumab and 2 cycles of ABVD; PFS and OS at one year. Using a single stage A'hern design, target recruitment is 47 patients to give 90% power at a 0.05% one sided alpha to exclude an overall response rate (ORR) to 2 cycles of avelumab of < 20%; an ORR of 40% would be considered worthy of further study. Recruitment has continued during the COVID-19 pandemic. 29 patients have been enrolled. Exploratory endpoints include correlating disease response with baseline PD-1 copy number by FISH and PD-1 expression by IHC. Serial serum TARC is being explored as an aid to response assessment and changes in peripheral blood immune cell subset are being investigated as possible biomarkers of response. Trial funder: Pfizer Ltd in alliance with Merck KGaA Pfizer Ltd is providing funding as part of an Alliance between Pfizer and Merck KGaA Clinical trials.gov NCT03617666 EUDRACT No.: 2018-002227-42 Disclosures Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau; Regeneron: Speakers Bureau; Merck KgA: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; 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; Gilead: Membership on an entity's Board of Directors or advisory committees; Antigene: 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; Specialised Therapeutics: Consultancy. Barrington: Bristol Myers Squibb international corporation: Research Funding; Pfizer Inc: Research Funding; Amgen Ltd: Research Funding; Takeda Speakers Bureau: Honoraria. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Iyengar: Janssen: Other: conference support, Speakers Bureau; Abbvie: Other: conference support; Beigene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau. Radford: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Current holder of individual stocks in a privately-held company; ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau; BMS: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Clifton-Hadley: Bristol-Myers Squibb Pharmaceuticals Ltd..: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Amgen: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Celgene: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Merck Sharp and Dohme: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Janssen-Cilag: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Pfizer: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.; Millennium pharmaceutics inc.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.. Collins: Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Research Funding; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. OffLabel Disclosure: Avelumab prior to frontline chemotherapy in advanced stage classic Hodgkin lymphoma.

Summary DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression.

Rates of cancer survival have increased in recent decades due to earlier diagnosis and improved therapies, but a longer life span does not necessarily equate to a healthier life. Chronic illness as a consequence of cancer and its treatment is reported in a significant proportion of survivors. An increased risk of cardiovascular diseases, such as myocardial infarction, stroke and heart failure. Is one of the side effects of some cancer therapies. Nurses in oncology and primary care can minimise cardiovascular risks by improving people’s awareness of symptoms, conducting health assessment and appropriate referrals. Secondary prevention through lifestyle advice, smoking cessation and obesity reduction is also essential. This should be in combination with more detailed cardiac assessment for those high-risk groups at all stages of the patient pathway. Appropriate risk management and early detection of heart problems can prevent long term illness and reduce multimorbidity for people living with and beyond cancer.

Introduction: R-CHOP remains the standard of care for DLBCL yet many patients (pts.) either fail to respond or relapse after having achieved an initial remission. Dysregulation of B Cell receptor (BCR) signalling is well recognised in some sub-types of DLBCL. In the phase III PHOENIX study (NCT01855750), the addition of the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib (I) to R-CHOP (R-CHOP-I) did not improve the outcome of the study population with non-germinal centre like DLBCL. However, R-CHOP-I treated pts. who were aged less than 60 years had a significantly improved progression free survival (PFS) and overall survival (OS) compared to those receiving R-CHOP alone. In pts. aged over 60 years, the addition of I increased toxicity and compromised the delivery of R-CHOP. Acalabrutinib (A) is a second generation BTKi, with enhanced kinase selectivity and potential for better efficacy and tolerability over first-generation inhibitors. There is a strong rationale to combine A with R-CHOP in untreated de novo DLBCL to understand its safety profile and efficacy. Methods: Eligible pts. were treatment naive with histologically confirmed DLBCL. All pts. received 6 cycles of R-CHOP therapy on a standard 21-day schedule, with the addition of A in cycles 2-6. A continuation phase of A only, for 2 cycles of 28 days was administered after R-CHOP. The primary objective of the phase Ib was to establish a recommended phase II dose (RP2D) of A in combination with R-CHOP (modified classical 6+6 design). Phase II assessed the overall response rate (ORR) of the combination and ascertained additional safety information. Secondary endpoints included metabolic complete response rates (mCR), PFS and OS and their relation to the COO, pharmacokinetics and pharmacodynamics. Cell of origin (COO) was determined by HTG EdgeSeq. Recruitment of pts. over the age of 65 was suspended as an urgent safety measure (USM) following the abstract release of data from PHOENIX (Nov 2018). ACCEPT reopened to all ages after a comprehensive safety review by the Independent Data Monitoring Committee (Sep 2019). The trial was endorsed by CRUK (CRUKDE/16/006). Results: From May 2017 to Jan 2020, 38 pts. were enrolled (safety population: Pts. in receipt of any component of therapy). The median age was 64 years (range 24-80, 39% >65 years old); 74% stage III/IV; 66%; raised LDH; 29% B symptoms; 32% bulk; 26% high IPI; 29% high-intermediate IPI; 16% High NCCN-IPI. Seven of the enrolled pts. were found to be ineligible (insufficient material for translational work, 2pts.; taking a proton pump inhibitor during therapy, 2 pts.; follicular histology, 1pt.; abnormal LFTs at baseline, 1pt.; age >65 at time of USM, 1 pts). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The RP2D was chosen as 100mg bd acalabrutinib. The most common >grade3 adverse events were neutropenia (26% of pts.), febrile neutropenia (13%) and diarrhoea (11%). The most frequently reported serious adverse event was febrile neutropenia (13% of pts.). Age did not compromise the delivery of full dose R-CHOP in combination with A. One patient in the first cohort (A 100mg od) progressed on therapy. Of the 24 eligible patients who received the RP2D (A 100mg bd) in either dose escalation or expansion, 22 responses have been reported (1 awaiting response assessment and 1 not assessed). Four pts. withdrew early from treatment (2 pts. subject withdrawal, 1 pt. investigator withdrawal and 1pt. due to toxicity) and are included in the efficacy analysis. The ORR was 95% with 82% of pts. achieving a mCR (3 pts. partial response (PR), 1pts. stable disease). One pt. with MYC/BCL2/BCL6 rearrangements and one pt. with MYC/BCL2 rearrangement achieved a mCR; neither have progressed. Ten of twelve ABC pts. (83%), 7/8 GCB pts (88%) and 1/2 unclassified pts. (50%) achieved a mCR. With a median follow-up of 15 months, the primary progressive patient from cohort 1 has died. PFS and OS at 12 months for those eligible pts. in receipt of the RP2D is 100%. Two of the RP2D pts. not achieving mCR have however received additional therapy (1 radiotherapy, 1 chemotherapy) prior to progression. R-CHOP did not affect the pharmacokinetics of A. Additional translational data will be presented. Conclusions: Acalabrutinib is well tolerated when given in combination with R-CHOP chemotherapy and may be associated with improved efficacy that should be explored in future randomised trials. Disclosures Davies: Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Acerta Pharma: Consultancy, Research Funding; Karyopharma: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; AstraZeneca: Research Funding; Gilead: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Honoraria, Research Funding. Collins:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; BeiGene: Consultancy; Amgen: Research Funding; MSD: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Celleron: Consultancy, Honoraria, Research Funding. Schuh:Illumina: Other: Consulting fees; Roche: Other: Consulting fees; Gilead: Other: Consulting fees; Abbvie: Other: Consulting fees. Ardeshna:University College London (UCL)/UCL Hospitals (UCLH) Biomedical Research Unit: Other: Supported by this organisation; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi, Genzyme, AstraZeneca: Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. McMillan:F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel expenses, Speakers Bureau; Pfizer: Research Funding; Celgene: Honoraria, Other: Travel expenses, Speakers Bureau. Radford:Pfizer: Research Funding; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau. Burton:Leeds Teaching Hospitals NHS Trust: Current Employment; Takeda: Honoraria, Other: Travel Support; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Other: Travel Support. Johnson:Janssen: Consultancy; Oncimmune: Consultancy; Janssen: Consultancy; Takeda: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Kymera: Honoraria; Kite Pharma: Honoraria; Incyte: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Bristol-Myers: Honoraria; Epizyme: Consultancy, Research Funding; Epizyme: Consultancy, Research Funding; Oncimmune: Consultancy; Boehringer Ingelheim: Consultancy. OffLabel Disclosure: Acalabrutinib, a second generation Bruton's tyrosine kinase inhibitor is being used in combination with R-CHOP chemotherapy

Introduction: Interim PET identifies patients with early stage classical HL (cHL) suitable for risk-adapted treatment escalation or de-escalation, but relapse-free survival remains inferior for patients with a negative interim PET who omit radiotherapy. Genetic risk predictors have demonstrated potential to enhance the negative predictive value of interim PET. In the BioPET study reported here, we evaluated the association between a priori selected candidate genes with interim PET and cHL-specific event free survival (cHL-EFS) for patients enrolled on the UK NCRI RAPID trial (NCT00943423). Methods: Patients with stage 1A or 2A cHL treated with 3 cycles of ABVD followed by interim PET assessment using a 5-point scale, full clinical data and available diagnostic biopsy material were included. Patients with a score of 1-2 (PET 'negative') were randomised (1:1) to involved field radiotherapy (IFRT) or no further treatment (NFT); those with a score of 3-5 (PET 'positive') received a further cycle of ABVD plus IFRT. Pre-treatment diagnostic FFPE material was obtained for 227 patients (21 with cHL events). Tissue homogenates were prepared and analysed using Quantigene 2.0 (QG_2.0) Plex for expression of 57 candidate genes known to be associated with treatment response and survival in cHL. QG_2.0 data were generated for experimental samples (n=227), RNA controls (n=15) and FFPE controls (n=12). Data were capped at both upper and lower limits of detection. Four housekeeper genes with the lowest variance (GUSB, TBP, HMBS, ABL1) were used for normalisation using the geometric mean. Candidate genes were ranked according to variability of expression. The association between gene expression, PET outcomes and cHL-EFS (disease progression or death) in the three treatment groups was evaluated in a series of regression analyses (Cox and binary logistic), both in univariable and multivariable settings using stepwise procedures, taking baseline EORTC and GHSG risk stratification into account. Analyses were run on the full dataset as there were insufficient cases for a training:validation split. Results: In total, cHL events were observed in 10/121 (8.3%) PET score 1, 4/53 (7.5%) PET score 2, 2/33 (6.1%) PET score 3, 1/10 (10.0%) PET score 4 and 4/10 (40.0%) PET score 5 respectively. Several genes were found to be associated with PET response after ABVD, and two genes remained in the multivariable model: PRF1 increased the risk of PET score 3-5 (OR=1.49, 95% CI: 1.05-2.13, p=0.03); BCL2L1 decreased risk (OR=0.65, 95% CI: 0.44-0.96, p=0.03). BCL2L1 was also strongly associated with a lower PET score (OR=0.62, 95% CI: 0.46-0.83, p Conclusions: A combined multivariable model using interim PET and selected pre-treatment genes shows promising utility for enhanced prediction of cHL-EFS in early stage cHL that is independent of EORTC and GHSG pre-treatment clinical risk scores. These findings warrant further evaluation in an independent cohort with a view to more precisely individualising treatment, improving disease control and minimising late toxicity for patients with early stage cHL. Figure 1. Kaplan-Meier survival plot of cHL-EFS based on expression of CD22, BID and IL15RA Figure Disclosures Linton: Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel, accommodations, expenses ; Celgene: Other: Travel, accommodations, expenses; Beigene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Burton:Leeds Teaching Hospitals NHS Trust: Current Employment; Takeda: Honoraria, Other: Travel Support; BMS: Honoraria; Celgene: Honoraria; Roche: Honoraria, Other: Travel Support. Illidge:Takeda: Honoraria; Merck: Research Funding; Roche: Consultancy; Takeda: Consultancy; Roche: Speakers Bureau; Takeda: Speakers Bureau; Roche: Honoraria. Radford:Pfizer: Research Funding; AstraZeneca: Current equity holder in publicly-traded company, Other: Spouse; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Speakers Bureau; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Current equity holder in publicly-traded company, Other: Spouse.

Introduction Plasmablastic lymphoma (PBL) is a rare, aggressive large cell lymphoma, first described in 1997. PBL is strongly associated with immunodeficient states, such as HIV infection and solid organ transplantation, but up to one third of cases are reported to occur in immunocompetent patients. The pathogenesis of PBL is incompletely understood, though the oncogenic impact of EBV, in particular in the context of dysregulated immune surveillance, together with acquired abnormalities in the MYC pathway appear to play key roles in many cases. Plasma cell markers such as CD138 and CD38 are typically positive, as well as CD30 in a significant subset. Classical B cell markers such as CD20, CD19 and PAX5 are typically absent. The literature on clinical outcomes in PBL is generally limited to small, single-centre case series. Reports describe an aggressive disease of poor prognosis, with median survival of 8 to 15 months, with one series reporting a longer median survival of 32 months. Methods We retrospectively identified patients diagnosed with PBL between 1999 and 2019 from 16 sites across Australia, the United Kingdom and Canada. Patients aged ≥18 years with confirmed tissue diagnosis of PBL at their local treating centre were included. Factors associated with overall survival (OS) were analysed using Cox regression, stratified by site to account for heterogeneity across sites. Risk time for mortality began on the date of diagnosis and ended on the date of death. Patients who were alive, lost to follow-up or transferred to another centre for care, were censored on the date of last follow-up. Risk factors analysed included age, year of diagnosis, HIV status, MYC rearrangement status, CD30 status, lactate dehydrogenase level, disease stage by Lugano consensus criteria, and bone marrow involvement. Results We identified 197 patients with PBL (Table 1). The median age at diagnosis was 55 years (range 18-95) and there was a male predominance (69%). 37% of patients were HIV positive, 56% were HIV negative and 7% were either not tested or had missing results. Other immunosuppressive risk factors included solid organ transplant, allogeneic stem cell transplant (SCT), and immunosuppressive medication. No immunodeficient state was detected in 44%. Fifty per cent of patients were stage IV at diagnosis. Fifty-four per cent were staged using PET/CT. The median follow-up time from diagnosis was 1.36 years, with the longest follow up out to 18.4 years. There were 87 deaths (44%). For patients receiving first-line treatment with curative intent, the rate of complete remission was 57% (103 of 181 patients). Most patients (53%) received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy as first line, and 27% treatment of higher intensity than CHOP. Rituximab was administered to 20% and 10% were exposed to proteasome inhibitors as part of first line therapy. Five percent of patients underwent autologous SCT in first remission, and a further 5% after first relapse or later. The median survival time was 4.8 years, with a 5-year OS of 49% and 10-year OS of 45% (figure 1). In multivariate analysis the only adverse factors associated with OS were bone marrow involvement and stage IV disease. Patients without bone marrow involvement at diagnosis had improved OS, compared to those who did (hazard ratio (HR) 0.36, 95%CI 0.18-0.72, p=0.004) (figure 2). There was an increasing trend for mortality with higher disease stages (p-trend=0.002). The median survival was 14.1 years for stage I, 10.7 years for stage II, 5.1 years for stage III and 1.2 years for stage IV. However, only stage IV disease was independently associated with inferior OS in multivariate analysis (HR 2.93, 95%CI 1.43-6.00, p=0.003) (figure 3). OS did not change depending upon year of diagnosis. Conclusion We report a multinational retrospective cohort of patients diagnosed with PBL and to our knowledge the largest single series of PBL to date. OS was longer than previously published data, particularly in patients with early-stage disease. However, patients with stage IV disease and baseline bone marrow involvement had inferior OS. HIV infection did not affect outcome. These findings suggest that baseline bone marrow biopsy and PET staging are useful prognostic tools. There is also an ongoing need for the evaluation of the predictive value of PET imaging and novel agents in PBL, especially in higher-risk disease. Disclosures Di Ciaccio: Jansen: Honoraria, Other: travel and accomodation grant. Cwynarski:Takeda: Consultancy, Other: Conference/travel support; Roche: Consultancy, Other: Conference/travel support. Burton:Celgene: Honoraria; Leeds Teaching Hospitals NHS Trust: Current Employment; Takeda: Honoraria, Other: Travel Support; BMS: Honoraria; Roche: Honoraria, Other: Travel Support. Kuruvilla:Antengene: Honoraria; Janssen: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding; Merck: Consultancy, Honoraria; Celgene Corporation: Honoraria; Amgen: Honoraria; TG Therapeutics: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb Company: Consultancy. McKay:Greater Glasgow and Clyde Health Board: Current Employment; Roche, Gilead, Takeda, Janssen: Other: For lectures etc; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Linton:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Conference/travel support; Roche: Consultancy, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Patents & Royalties; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Hartley-Taylor: Honoraria; The Christie NHS Foundation Trust and The University of Manchester: Current Employment. Manos:Bristol-Myers Squibb: Other: Conference sponsorship. Hamad:Abbvie: Honoraria; Novartis: Honoraria.

While conventional therapy is curative for most patients with high grade lymphomas, there is considerable heterogeneity in this diagnosis, with scope to refine treatment according to the precise molecular phenotype. This is increasingly used to guide specific therapy and to predict outcomes. The

Background: older women are at high risk of presenting with breast cancer when it has reached a late stage, which may be partly because of poor breast cancer awareness. Aim: the aim of this project was to implement and evaluate a new way of delivering the Promoting Early Presentation (PEP) Intervention during flu vaccination appointments in primary care. The PEP Intervention is a 1–minute intervention, accompanied by a booklet and delivered by primary care health professionals to provide older women with the knowledge, confidence and skills to present promptly on discovering symptoms of breast cancer. Method: health professionals delivered the PEP Intervention to older women at six general practices in south London. The authors measured changes in breast cancer awareness after the intervention and interviewed practice staff about their experiences of using it. Findings: knowledge of breast symptoms and breast checking was greater in women aged 70 years and above after the implementation than before. Health professionals' found it acceptable and feasible to implement. Conclusion: this intervention is a novel way of increasing breast cancer awareness in older women, which could contribute to earlier presentation and diagnosis of breast cancer in the UK.

Background Diffuse large B-cell lymphoma (DLBCL) is the commonest non-Hodgkin lymphoma. Previous studies examining the cost of treating DLBCL have generally focused on a specific first-line therapy alone; meaning that their findings can neither be extrapolated to the general patient population nor to other points along the treatment pathway. Based on empirical data from a representative population-based patient cohort, the objective of this study was to develop a simulation model that could predict costs and life expectancy of treating DLBCL. Methods All patients newly diagnosed with DLBCL in the UK’s population-based Haematological Malignancy Research Network (www.hmrn.org) in 2007 were followed until 2013 (n = 271). Mapped treatment pathways, alongside cost information derived from the National Tariff 2013/14, were incorporated into a patient-level simulation model in order to reflect the heterogeneities of patient characteristics and treatment options. The NHS and social services perspective was adopted, and all outcomes were discounted at 3.5 % per annum. Results Overall, the expected total medical costs were £22,122 for those treated with curative intent, and £2930 for those managed palliatively. For curative chemotherapy, the predicted medical costs were £14,966, £23,449 and £7376 for first-, second- and third-line treatments, respectively. The estimated annual cost for treating DLBCL across the UK was around £88–92 million. Conclusions This is the first cost modelling study using empirical data to provide ‘real world’ evidence throughout the DLBCL treatment pathway. Future application of the model could include evaluation of new technologies/treatments to support healthcare decision makers, especially in the era of personalised medicine. Electronic supplementary material The online version of this article (doi:10.1007/s10198-016-0775-4) contains supplementary material, which is available to authorized users.

Background: The anti-CD20 monoclonal antibody (mAb), obinutuzumab (G), has shown improved outcomes versus rituximab (R) in indolent lymphomas; however, no improvement was seen in diffuse large B-cell lymphoma (DLBCL), and the molecular basis is unclear. The inhibitory Fc gamma receptor IIB (Fc γRIIB), expressed on lymphoma cells, can impair the effects of direct targeting mAbs, such as R, by binding and internalizing them, reducing opsonization and limiting FcγR-mediated killing. We hypothesized that FcγRIIB expression on cellular effectors and/or the lymphoma confers treatment resistance in some patients (pts) and evaluated if outcomes differ for therapies involving a non-internalized mAb (G). Methods: We evaluated correlates between FCGR2B mRNA and/or FcγRIIB protein expression and pt outcomes in two discovery cohorts of de novo DLBCL treated with R-CHOP (Arthur et al. 2018, n=372; Schmitz et al. 2018, n=234), and the phase III GOYA trial (NCT01287741; n=552), which compared R-CHOP with G-CHOP in pts with previously untreated DLBCL. FCGR2B mRNA expression was assessed by RNA-Seq, and protein expression was assessed in evaluable cohorts by immunohistochemistry, using tissue microarrays with macrophages identified by CD68. FCGR2B expression was also measured by a NanoString assay (Arthur cohort). Cox regression analyzed the impact of FcγRIIB/FCGR2B expression on progression-free survival (PFS), with univariate and multivariate models adjusted for International Prognostic Index (IPI), cell of origin (COO), and BCL2 protein expression. Results: In the discovery cohorts, a higher FCGR2B expression was significantly associated with shorter PFS (Arthur: HR 1.09 [95% CI: 1.01–1.19], P=0.036; Schmitz: HR 1.13 [95% CI: 1.02–1.26], P=0.0243). Expression by NanoString strongly correlated with RNA-Seq, confirming the association with shorter PFS (HR 1.13 [95% CI: 1.04–1.23], P=0.0048). In GOYA, a significant association between PFS and FCGR2B was observed in the R arm (HR 1.26 [95% CI: 1.00–1.58], P=0.0455), with no prognostic effect observed for G (HR 0.91 [95% CI: 0.69–1.20], P=0.5). Pts with high FCGR2B expression appeared to benefit more from G than R (HR 0.67 [95% CI: 0.44–1.02], P=0.0622), in contrast to pts with low FCGR2B expression (HR 1.58 [95% CI: 1.00–2.50], P=0.0503). In both Arthur and GOYA cohorts, FCGR2B expression by RNA-Seq was associated with FcγRIIB on the tumor, which correlated with a shorter PFS for R (HR 2.17 [95% CI: 1.04–4.50], P=0.03), but not G (HR 1.37 [95% CI: 0.66–2.87], P=0.4). This prognostic effect on PFS was independent of established prognostic biomarkers, IPI, COO and BCL2. Conclusion: High FcγRIIB/FCGR2B expression in pts with DLBCL has prognostic value in those treated with R and may confer differential responsiveness to R or G. Citation Format: Laura K. Hilton, Malgorzata Nowicka, Margaret Ashton-Key, Chantal E. Hargreaves, Chern Lee, Russell Foxall, Matthew J. Carter, Stephen A. Beers, Kathleen N. Potter, Christopher R. Bolen, Christian Klein, Andrea Knapp, Farheen Mir, Matthew Rose-Zerilli, Cathy Burton, Wolfram Klapper, David W. Scott, Laurie H. Sehn, Umberto Vitolo, Maurizio Martelli, Marek Trneny, Graham W. Slack, Pedro Farinha, Jonathan C. Strefford, Mikkel Z. Oestergaard, Ryan D. Morin, Mark S. Cragg. Prognostic significance of Fc gamma receptor IIB expression in the response of previously untreated diffuse large B-cell lymphomas to anti-CD20 monoclonal antibodies: Differing impact of rituximab and obinutuzumab [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-26.

DNA samples from formalin-fixed paraffin-embedded tissues are highly degraded with variable quality, and this imposes a big challenge for targeted sequencing due to false positives, largely caused by PCR errors and cytosine deamination. To eliminate false positives, a common practice is to validate the detected variants by Sanger sequencing or perform targeted sequencing in duplicate. Technically, PCR errors could be removed by molecular barcoding of template DNA prior to amplification as in the HaloPlexHS design. Nonetheless, it is uncertain to what extent variants detected using this approach should be further validated. Here, we addressed this question by correlating variant reproducibility with DNA quality using HaloPlexHS target enrichment and Illumina HiSeq4000, together with an in-house validated variant calling algorithm. The overall sequencing coverage, as shown by analyses of 70 genes in 266 cases of large B-cell lymphoma, was excellent (98%) in DNA samples amenable for PCR of ≥400 bp, but suboptimal (92%) and poor (80%) in those amenable for PCR of 300 bp and 200 bp respectively. By mutation analysis in duplicate in 93 cases, we demonstrated that 20 alternative allele depth (AAD) was an optimal cut-off value for separating reproducible from non-reproducible variants in DNA samples amenable for PCR of ≥300 bp, with 97% sensitivity and 100% specificity. By cross validation with a previously established targeted sequencing protocol by Fluidigm-PCR and Illumina MiSeq, the HaloPlexHS protocol was shown to be highly sensitive and specific in mutation screening. To conclude, we proposed a stratified approach for mutation screening by HaloplexHS and Illumina HiSeq4000 according to DNA quality. DNA samples with good quality (≥400 bp) are amenable for mutation analysis with a single replicate, with only variants at 15–20 AAD requiring for further validation, while those with suboptimal quality (300 bp) are better analysed in duplicate with reproducible variants at >15 AAD regarded as true genetic changes. HaloPlexHS target enrichment incorporates molecular barcodes in hybridization probes in order to detect data resulting from PCR errors. The authors combined HaloPlexHS technology with Illumina HiSeq sequencing and developed a new validated variant-calling algorithm. Thus, they were able to establish a targeted sequencing protocol that allows reliable mutation detection with a single replicate using DNA samples from formalin-fixed paraffin-embedded tissues.

Relapsed or refractory classical Hodgkin lymphoma (cHL) is associated with a poor outcome when standard chemotherapy fails. Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate licensed for use at relapse after autologous stem cell transplant (ASCT) or following two prior therapies in those unsuitable for ASCT. There are limited data assessing the ability of BV to enable curative SCT. We performed a UK-wide retrospective study of 99 SCT-naïve relapsed/refractory cHL. All had received 2 prior lines and were deemed fit for transplant but had an insufficient remission to proceed. The median age was 32 years. Most had nodular sclerosis subtype, Eastern Cooperative Oncology Group performance status 0-1 and advanced stage disease. The median progression-free survival (PFS) was 5·6 months and median overall survival (OS) was 37·2 months. The overall response rate was 56% (29% complete response; 27% partial response). 61% reached SCT: 34% immediately post-BV and 27% following an inadequate BV response but were salvaged and underwent deferred SCT. Patients consolidated with SCT had a superior PFS and OS to those not receiving SCT (P < 0·001). BV is an effective, non-toxic bridge to immediate SCT in 34% and deferred SCT in 27%. 39% never reached SCT with a PFS of 3·0 months, demonstrating the unmet need to improve outcomes in those unsuitable for SCT post-BV.

BackgroundHodgkin lymphoma is usually detected in primary care with early signs and symptoms, and is highly treatable with standardised chemotherapy. However, late presentation is associated with poorer outcomes.AimTo investigate the relationship between markers of advanced disease, emergency admission, and survival following a diagnosis of classical Hodgkin lymphoma (CHL).Design & settingThe study was set within a sociodemographically representative UK population-based patient cohort of ~4 million, within which all patients were tracked through their care pathways, and linked to national data obtained from Hospital Episode Statistics (HES) and deaths.MethodAll 971 patients with CHL newly diagnosed between 1 September 2004–31 August 2015 were followed until 18th December 2018.ResultsThe median diagnostic age was 41.5 years (range 0–96 years), 55.2% of the patients were male, 31.2% had stage IV disease, 43.0% had a moderate–high or high risk prognostic score, and 18.7% were admitted via the emergency route prior to diagnosis. The relationship between age and emergency admission was U-shaped: more likely in patients aged PConclusionThese findings suggest that CHL survival as a whole could be increased by around 4% if the cancer in patients who presented as an emergency had been detected at the same point as in other patients.

Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.

Background: Although diffuse large B cell lymphoma (DLBCL) can be cured using immuno-chemotherapy, 40% of patients experience relapse or refractory disease. Large-scale profiling studies have mainly focused on DLBCL at diagnosis, resolving different outcome groups based on gene expression (e.g. cell-of-origin (COO) or molecular high grade), MYC/BCL2 translocations (double-hit lymphoma) or gene mutations and copy number aberrations (Schmitz et al, NEJM 2018; Chapuy et al, NatureMedicine 2018). In comparison, longitudinal studies have been hindered by the limited availability of sequential biopsy samples. To date, the relapse-specific gene mutations identified are limited and inconsistent across studies. In our study, we have focussed attention on the changes in gene expression profile (GEP) accompanying DLBCL relapse. Methods: We retrospectively collected archival paired diagnostic/relapse formalin fixed paraffin embedded tumor biopsies from 38 de novo DLBCL patients collected from multiple UK sites treated with rituximab-based immuno-chemotherapy, where partial or complete remission was reported following treatment. COO classification was performed by the Lymph2Cx assay on NanoString to distinguish activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes. The Ion AmpliSeq™ Transcriptome Human Gene Expression Kit was used to measure the expression levels of > 20,000 genes on the paired samples. Results: COO remained stable from diagnosis to relapse in 17 ABC-ABC pairs, 11 GCB-GCB pairs and 4 unclassified (UNC)-UNC pairs. Frank COO switching was observed in 6 cases (1 ABC-GCB, 2 ABC-UNC, 2 GCB-UNC, 1 UNC-ABC). Pairs with stable COO were taken forward for further analysis. Gene expression analysis using the limma R package identified 163 and 136 genes as differentially expressed (DE) (p 1) between the diagnostic and relapse biopsies in ABC and GCB tumors respectively, with only a one gene overlap. Gene Set Enrichment Analysis further suggested that ABC and GCB relapses are mediated via different mechanisms, with tumor growth and proliferation signatures enriched in ABC relapses, whilst adaptive immunity-related signatures accompanied GCB relapses. Next, we aimed to utilise our relapse-specific genes to identify outcome predictors at diagnosis using publicly available GEP datasets. In order to increase our discovery power and accuracy, a larger set of DE genes from the paired differential analysis (796 genes in ABC pairs and 387 from GCB pairs) were selected (p The prognostic significance of this 30-gene discriminator was successfully validated using a linear predictor in two independent GEP datasets: 1) a population-based cohort (Lenz et al, NEJM 2008) with 93 R-CHOP-treated ABC cases identifying 47 low and 46 high-risk cases (HR=1.92, p=0.046, C-index=0.77; Fig1.C) and 2) a clinical trial dataset (REMoDL-B, Davies et al, Lancet Oncol 2019) with 255 ABC cases identifying 110 low and 145 high-risk ABC cases (HR=1.95, p=0.0051, C-index=0.70; Fig1.D). Conclusions: Here we describe a 30-gene discriminator in ABC-DLBCL, derived from genes differentially expressed between diagnosis and relapse, that allowed the definition of clinically distinct high and low risk subgroups in ABC-DLBCLs at diagnosis. The clinical translation of such a tool may be useful to guide therapy for this unfavourable subgroup of ABC-DLBCLs. Validation of this signature is currently underway in additional datasets and further study is required to understand the contribution of these genes in DLBCL pathology. Disclosures Korfi: Roche: Consultancy. Burton:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rule:TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Crosbie:Janssen: Honoraria. Scott:Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding; Roche/Genentech: Research Funding. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Davies:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Acerta Pharma: Honoraria, Research Funding; ADCT Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gribben:Abbvie: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Okosun:Gilead Sciences: Honoraria, Research Funding. Johnson:Epizyme: Honoraria, Research Funding; Novartis: Honoraria; Kite: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Boehringer Ingelheim: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Celgene: Honoraria; Incyte: Honoraria. Fitzgibbon:Epizyme: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Speakers Bureau.

Introduction Anaplastic large-cell lymphoma (ALCL) is a rare subtype of T-cell non-Hodgkin lymphoma, characterized by uniformly strong CD30 expression and further delineated by expression of the Alk protein. Standard first-line (1L) therapy is CHOP-based chemotherapy, with or without consolidative autologous stem cell transplant (ASCT) (Schmitz, Blood, 2010). Despite intensive chemotherapy approaches, 40-65% of patients experience relapsed/refractory disease, for which brentuximab vedotin (BV) as monotherapy has established efficacy (Pro, Blood, 2017) Recent results from ECHELON-2 (E2), led to FDA approval of BV in combination with CHP (CHP+A) as first-line treatment for CD30+ PTCL, based on a 34% reduction in risk of death compared to CHOP, an effect only demonstrable in ALCL (70% of the E2 cohort) (Horwitz, Lancet, 2019). Given this renewed treatment landscape, we investigated outcomes of unselected patients with ALCL treated in routine clinical practice. Methods/Study Population Consecutively diagnosed patients with systemic ALCL from 6 UK and Australian centres (n=166) were studied (Dec 2004-Dec 2018). Patients ≥16 years with ALCL were included irrespective of Alk status. Treatment allocation was clinician choice and included best supportive care (BSC). Post-mortem diagnosis and 10 patients treated on E2 were excluded. Principal outcomes were PFS and OS following 1L treatment. Additional outcome measures included frequency of ASCT and use of BV for r/r ALCL. Data were retrospectively collected following GDPR guidelines and in accordance with the declaration of Helsinki. Results Median age at diagnosis was 57.5 years (range 16-93), 62% were male, 19% had ECOG ≥3 and 53 (35%) patients were ALK positive. Median lines of therapy was 1 (range 0-6). Baseline patient characteristics are shown in table 1. The most frequent 1L treatment regimen was CHOP in 104 pts (67%), 26 (18%) received intensified regimens (CHOEP, CHOP/IVE/MTX, CODOX-M, ALCL99), 4 received other regimens (2.6%) and 14 had best supportive care (9%). Treatment-related mortality was 5.6% (8/142). 12 (8%) patients underwent ASCT in first response, of whom 10 had received intensified induction regimens. Of 141 evaluable pts, ORR was 71% and CR rate was 52%. Median follow up of all patients was 40 months, 3-year PFS and OS for 1L of treatment were 46% and 58% respectively. For the CHOP-treated cohort (n=104), 3-year PFS and OS were 47% and 57%. Outcomes for ALK-negative patients treated with CHOP (n=78) were inferior to ALK-positive; 3-year PFS, OS of 35% and 44% vs 66% and 82% respectively (p=0.003 for both, figure 1). BV was given to 24 pts (15%), mostly for second (16/24) line of therapy. Median doses received were 5 (range 1-14). ORR to BV was 11/24 (45%) and CR rate was 7/24 (30%). Median follow up after BV was 18 months, at which point the PFS and OS rates were 33% and 35% respectively (Figure 1). Bridging to ASCT or alloSCT occurred in 3 and 4 pts respectively, of whom 6 remain alive at data cutoff. 41 patients were staged with both CT and PET-CT, with concordant staging in 63%. 9/41 patients were upstaged by PET, 3 of which resulted in upgraded IPI score (extranodal sites not found on CT). 52 patients had PET-CT after first-line therapy. At data cutoff, 26/35 patients did not progress after PET-defined CR (74%), whereas 6/12 patients progressed after PET-defined PR (50%). Conclusions This study describes a large unselected cohort of ALCL treated in routine clinical practice prior to publication of the E2 study, observing a comparable baseline Alk pos/neg distribution. Notably, survival outcomes of our CHOP-treated cohort are similar to those in the E2 control arm, notwithstanding 28% of our patients with ECOG ≥3 (an E2 exclusion criterion) and also comparable to data from the prospective international T-cell lymphoma project (Shustov, Haematol Oncol, 2019). A minority of pts received intensified regimens and only 8% underwent ASCT consolidation. Achievement of CMR by PET-CT was still associated with a significant proportion of relapses. Outcomes of r/r ALCL treated with single-agent BV were inferior in our cohort as compared to the pivotal Phase 2 data (Pro, Blood, 2017). Our data represent an important benchmark as an unselected ALCL population treated with conventional chemotherapy in routine clinical practice; future studies of CHP+A in the real-world setting will be crucial in assessing the wider impact of the E2 study. Disclosures Martinez-Calle: ABBVIE: Other: Travel support. Manos:Janssen: Honoraria; Novo Nordisk Pharmaceuticals: Other: Travel. Bishton:Takeda: Other: Travel support, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; AbbVie: Research Funding; Celltrion: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Roche: Other: Travel support, Research Funding. Hawkes:Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundi pharma: Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau; Roche: Research Funding; Astra Zeneca: Research Funding; Merck KgA: Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Speakers Bureau. Osborne:Gilead: Consultancy; Pfizer: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Novartis: Other: Travel; Servier: Consultancy; MSD: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau. Collins:Gilead: Consultancy, Honoraria. Burton:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fox:AbbVie: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support.