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BackgroundAnthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy.MethodsIn a multicenter prospective randomized open label blinded endpoint trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk non-randomized patients with cardiac troponin I concentrations in the lower two tertiles, we hypothesised the absence of a 6-month change in left ventricular ejection fraction (±2%).ResultsBetween October 2017 and June 2021, 175 patients (mean age 53 years; 87% female; 71% breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy respectively. After adjusting for age, pre-treatment left ventricular ejection fraction and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between cardioprotection and standard care groups was -0.37% (95% confidence interval, -3.59 to 2.85%; P=0.82). In low-risk non-randomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3% respectively: estimated mean difference, 2.87% (95% confidence interval, 1.63 to 4.10%; P=0.92, not equivalent)ConclusionsCombination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk non-randomized patients had similar declines in left ventricular ejection fraction questioning the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy needs to be better defined in patients receiving high-dose anthracycline regimes.REGISTRATIONEudraCT 2017-000896-99, ISRCTN24439460Clinical PerspectiveWhat is new?In this randomized controlled trial of patients at high risk of anthracycline cardiotoxicity, combined candesartan and carvedilol therapy did not protect against decline in 6-month left ventricular ejection fraction after completion of chemotherapy.Overall decline in 6-month left ventricular ejection fraction occurred irrespective of changes in cardiac troponin concentration during chemotherapy.What are the clinical implications?The Cardiac CARE trial findings do not support recent guideline recommendations advocating the use of cardiac troponin monitoring and early preventive neurohormonal blockade in patients at risk of anthracycline cardiotoxicity.Future studies should focus on factors determining transition to subsequent development of heart failure from initial mild and asymptomatic changes in cardiac function following anthracycline chemotherapy.

Background: Anthracyclines are effective cytotoxic drugs used in the treatment of breast cancer and lymphoma but are associated with myocardial injury, left ventricular dysfunction, and heart failure. Anthracycline-induced cardiotoxicity is highly variable in severity and without a proven therapeutic intervention. β-Adrenergic receptor blockers and renin-angiotensin-system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients. Methods: The Cardiac CARE trial is a multicentre prospective randomized open-label blinded end point trial of combination β-adrenergic receptor blocker and renin-angiotensin-system inhibitor therapy in patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy that is associated with myocardial injury. Patients at higher risk of cardiotoxicity with plasma high-sensitivity cTnI (cardiac troponin I) concentrations in the upper tertile at the end of chemotherapy are randomized to standard of care plus combination candesartan and carvedilol therapy or standard of care alone. All patients undergo cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. The primary end point is the change in left ventricular ejection fraction at 6 months after chemotherapy. In low-risk nonrandomized patients, left ventricular ejection fraction before and 6 months after anthracycline will be compared with define the specificity of the high-sensitivity cTnI assay for identifying low-risk participants who do not develop left ventricular systolic dysfunction. Discussion: Cardiac CARE will examine whether cardiac biomarker monitoring identifies patients at risk of left ventricular dysfunction following anthracycline chemotherapy and whether troponin-guided treatment with combination candesartan and carvedilol therapy prevents the development of left ventricular dysfunction in these high-risk patients.

A consensus statement for the management for patients of all ages with all stages of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) - All StAGEs - is proposed by representatives of the UK National Cancer Research Institute (NCRI) Hodgkin lymphoma study group and the Children's CancerLeukaemia Group. Based on current practices and published evidence, a consensus has been reached regarding diagnosis, staging and risk-ik7 stratified management which includes active surveillance, low- and standard-dose immunochemotherapy and radiotherapy.

Background: Tazemetostat, a first-in-class, oral, enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. Progression of disease within 24 months (POD24), exposure to multiple lines of prior therapy, and refractoriness to rituximab therapy have been shown to adversely affect the prognosis of patients receiving second- or third-line regimens for R/R FL, including chemoimmunotherapy. We performed a post hoc exploratory analysis to better understand how these factors impact the outcomes in patients receiving tazemetostat. Methods: This open-label, multicenter study (NCT01897571) evaluated tazemetostat 800 mg administered orally twice daily in patients with MT or WT EZH2 R/R FL. The primary endpoint was objective response rate (ORR; complete response + partial response) as assessed by an independent review committee (IRC); secondary efficacy endpoints included duration of response (DOR) by IRC, progression-free survival (PFS) by IRC, and overall survival (OS) by investigator assessment. Predictive modeling using baseline demographic and disease characteristic variables combined from patients with MT or WT EZH2 R/R FL was performed to identify variables predictive of response (ORR, DOR, PFS, and OS). Models were fitted for variables that were categorical and had no missing observations; they also were fitted with/without Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria and with the number of prior lines of therapy (1, 2, or >2, and 1 or 2 vs >2). Due to incomplete data collection, GELF criteria were analyzed with missing observations (n=28) set to "no." Stepwise logistic and Cox regression was used to determine possible predictors; inclusion at a specified step was based on P≤0.40. Final model inclusion was based on P≤0.20. A final model was run using the possible predictors identified from the previous stepwise regressions. Contingency tables and Kaplan-Meier plots were used to examine significant variables (P≤0.05). Results: In the phase 2 study, the efficacy outcomes by IRC in combined WT and MT EZH2 populations (N=99) were: ORR, 51% (n=50); median DOR, 11 months (95% CI: 7, 19); and median PFS, 12 months (95% CI: 8, 15). Median OS was not reached (95% CI: 38.2, not estimable). Predictive modeling using 17 baseline variables identified possible predictors of efficacy outcome. For ORR, the number (1 or 2 vs >2) of prior lines of therapy was identified as possibly predictive (Table). Patients with 1 line of prior therapy had an ORR of 66% (n=27) vs 40% (n=23) in patients with 2 prior lines of therapy. Disease refractory to rituximab and number (1, 2, or >2) of prior lines of therapy (Table) were identified as possible predictors for DOR. Disease refractory to rituximab, GELF criteria, disease refractory to any treatment, and sex (Table) were possibly predictive for PFS. However, the percentage of subjects that met GELF criteria may be underestimated due to retrospective collection of qualifying data points; therefore, the translation of GELF criteria as a predictive factor for PFS should be interpreted with caution. Other baseline demographic and disease characteristics, including patient age (≤65 y, >65 y), double refractory disease, ECOG performance status, myelosuppression, POD24, disease refractory to last therapy, prior stem cell transplant, and time since last therapy, were not found to be predictive of response, as measured by ORR, DOR, PFS, and OS. Conclusions: In this post hoc exploratory analysis of patients with R/R FL (WT and MT EZH2 cohorts combined), variables associated with heavily pretreated patients (ie, refractory to rituximab, treatment-refractory disease, and number of prior treatments) were identified as possible predictors of response. However, in these analyses other high-risk disease characteristics, such as POD24, were not predictive, although the results may be confounded by the small number of patients in some of the groups. In addition to reinforcing the efficacy of tazemetostat in heavily pretreated patients, these data also suggest that ORR is greater in patient populations who receive treatment as an earlier line of therapy. Prospective confirmatory studies are warranted to confirm these post hoc observations. Disclosures Salles: Kite: Consultancy, Honoraria, Other; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Bristol Myers Squibb: Consultancy, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Genmab: Consultancy; Epizyme: Consultancy; Debiopharm: Consultancy; MorphoSys: Consultancy, Honoraria, Other; Karyopharm: Consultancy; Novartis: Consultancy, Honoraria, Other. Tilly:BMS: Honoraria. McKay:Greater Glasgow and Clyde Health Board: Current Employment; Roche, Gilead, Takeda, Janssen: Other: For lectures etc; 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; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Phillips:Beigene: Consultancy; Karyopharm: Consultancy; AstraZeneca: Consultancy; Incyte: Consultancy, Other: travel expenses; Seattle Genetics: Consultancy; BMS: Consultancy; Bayer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Cardinal Health: Consultancy. Assouline:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Batlevi:Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding; Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Ribrag:BAY1000394 studies on MCL: Patents & Royalties; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; argenX: Current equity holder in publicly-traded company, Research Funding; Institut Gustave Roussy: Current Employment; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; arGEN-X-BVBA: Research Funding; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; Servier: Consultancy, Honoraria; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AZD: Honoraria, Other; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Damaj:Roche, Takeda, Accord: Honoraria; Roche, Takeda, Iqone, Accord: Consultancy; Abbevie, Pfizer, Takeda, Roche: Other: Travel. Dickinson:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jurczak:BeiGene: Consultancy, Research Funding; Celgene: Research Funding; Epizyme: Consultancy; Gilead Sciences: Research Funding; MorphoSys: Research Funding; Nordic Nanovector: Research Funding; Servier: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Sandoz-Novartis: Consultancy; European Medicines Agency,: Consultancy; AstraZeneca: Consultancy; Takeda: Research Funding; Roche: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Afimed: Research Funding; Janssen China R&D: Consultancy, Research Funding; MEI Pharma: Research Funding; Acerta: Consultancy, Research Funding; Bayer: Research Funding; TG Therapeutics, Inc.: Research Funding. Kaźmierczak:Department of Hematology and Bone Marrow Transplantation Poznan University of Medical Sciences: Current Employment. Opat:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZenca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Epizyme: Research Funding; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Research Funding. Radford: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; ADCT: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: 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. Schmitt:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche, Janssen: Honoraria. Whalen:TESARO (ended employment Nov 2018): Ended employment in the past 24 months; Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Hamlett:Epizyme, Inc.: Current Employment, Research Funding; Sanofi: Ended employment in the past 24 months. Kamp:Karyopharm: Consultancy; Epizyme, Inc.: Current Employment, Current equity holder in publicly-traded company. Adib:Epizyme, Inc.: Consultancy; Alacrita: Current Employment. Morschhauser:Janssen: Honoraria; Genentech, Inc.: Consultancy; F. Hoffmann-La Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; Servier: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

Funder: Janssen Pharmaceuticals; Id: http://dx.doi.org/10.13039/100008897, Ibrutinib is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL) and clinical trial data supports use at second line compared to later relapse. We aimed to investigate outcomes and tolerability for ibrutinib when given second line in a real-world setting. Our multicentre retrospective analysis included 211 R/R MCL patients, median age 73 years, receiving ibrutinib second-line within the United Kingdom's National Health Service. Overall response to ibrutinib was 69% (complete response 27%). The median progression-free survival (PFS) was 17·8 months (95% CI 13·1-22·2) and median overall survival (OS) 23·9 months (95% CI 15·0-32·8). Drug-related adverse event led to dose reduction in 10% of patients and discontinuation in 5%. In patients with progressive disease, accounting for 100 of 152 patients stopping ibrutinib, 43% received further systemic therapy. Post-ibrutinib rituximab, bendamustine and cytarabine (R-BAC) showed a trend toward improved survival compared to alternative systemic treatments (post-ibrutinib median OS 14·0 months, 95% CI 8·1-19·8, vs. 3·6 months, 95% CI 2·6-4·5, P = 0·06). Our study confirms the clinical benefit and good tolerability of ibrutinib at first relapse in a real-world population. Patients progressing on ibrutinib had limited survival but outcomes with R-BAC in select patients were promising.

Background: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. Methods: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18–70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500–1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine–thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1–2 h infusion, day −6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days −5 and −4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55–61). 49 patients (65%; 95% CI 54–76) had an objective response after MATRix–RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51–71) had an objective response, with a median duration of objective response of 26 months (IQR 16–37). At a median follow-up of 29 months (IQR 20–40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39–53). Grade 3–4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07–9·93). Interpretation: MATRix–RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. Funding: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.

BACKGROUND Peripheral T-cell lymphomas (PTCL) are a diverse group of diseases, of which the majority of histological types respond poorly to first line treatments. While there are licensed treatments for refractory and relapsed PTCL responses are only observed in 25 to 35% of patients and these are rarely sustained. Programmed Death 1 (PD1) and its ligand (PDL1) are expressed on the malignant lymphocytes of some PTCL with PDL1 also being variably expressed on the stroma. Animal experiments suggest that PD1-PDL1 interactions contribute to the regulation of normal T-cell regulation. We tested the hypothesis that perturbation of PD1-PDL1 could be a generally useful strategy in PTCL and while other groups have used anti-PD1 antibodies in this setting (Barta SK, Zain J, MacFarlane AW, et al. Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2019;19(6):356-364.e3) we used avelumab, a depleting anti-PDL1 antibody. METHODS AVAIL-T is a multicentre, single arm, open-label, phase 2a trial to determine best overall response to avelumab (10 mg/kg by IV infusion once every 2 weeks for 8 cycles (28 day cycles)) using contrast-enhanced CT scans and the Revised Response Criteria for Malignant Lymphoma in patients with refractory and relapsed PTCL (RR PTCL). Antihistamine and paracetamol premedication was given. Sample size was determined by Bayesian probability methodology such that if 30 patients were recruited and 11 responses were observed there would be a 60% chance that the true response rate is greater than 35%. RESULTS 34 patients were recruited from Jun 2017 to Nov 2019 at 14 UK centres. Median age was 63.5 (range 36.6 to 84.5), 28/34 (82.4%) were male and 6 (17.6%) were female (Table 1). Histologies were angioimmunoblastic T-cell lymphoma (AITL) 11/34 (32.4%), PTCL-not otherwise specified (PTCL-NOS) 17/34 (50%), extranodal NK/T-cell lymphoma 4/34 (11.8%) and 1/34 (2.9%) anaplastic large cell lymphoma and transformed mycosis fungoides. The patients were heavily pre-treated with a median of 3 previous therapy lines (range 1 to 7). 18/34 (53%) of patients did not achieve a first assessment (Cycle 3, post day 15) either due to progressive disease 12/18, death 4/18 or withdrawal of consent 2/18. Of the remaining 16/34 (47%) patients who were evaluable there was a median reduction in tumour size during the first 8 cycles of treatment of 14.9% (range -94.2% to 61.1%) but only 6/34 (17.6%) achieved a PR while 7 (20.6%) showed progressive disease (PD) and 3 had stable disease (SD) (Figure 1). Currently the longest duration of response is 9.6 months with on-going responses in 4 PR patients. These patients did not differ from those patients with PD or SD by age, gender, baseline performance status, number of previous treatments, diagnosis or PDL1 expression (assessed by immunohistochemistry). Median overall survival was 8.9 months (95% CI 5.1 to 11.2) and median progression free survival was 2.9 months (95% CI 1.7 to 5.0). During the course of the trial there were 27 serious adverse events with 12/28 of the SAEs treatment-related (8 SARs and 4 SUSARs). The SUSARs included one patient who died of fulminant hepatic failure associated with unsuspected liver involvement by T-cell lymphoma (grade 5, treatment-related) and another who died due to the effects of gastric perforation (grade 4, possibly treatment-related). There was one serious infusion-related reaction (treatment-related) and one immune-mediated colitis (grade 3 treatment-related). CONCLUSIONS Over 50% of this patient cohort did not reach the first evaluation point although there was no definite evidence for hyperprogression, which has been previously reported in some cases of PTCL treated with check-point inhibitors (Bennani NN, Pederson LD, Atherton P, et al. A Phase II Study of Nivolumab in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma. Blood (2019) 134 (Supplement_1): 467). Therefore, as a single agent, avelumab did not have significant rapid activity against RR PTCL with diverse diagnoses. Of the evaluable patients there were only overall modest reductions in tumour size. Therefore, interruption of PD1-PDL1 signalling by means of a therapeutic anti-PDL1 antibody does not appear effective in the setting of RR PTCL, in line with reported results of anti-PD1 antibodies, although a clinical effect in subgroups cannot be completely excluded. Disclosures Fox: Gilead: Honoraria, Research Funding; Adienne: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Atarabio: Research Funding; Sunesis: Research Funding; Takeda: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding. Collins:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Consultancy; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodations, expenses , Speakers Bureau; Taekda: Consultancy, Honoraria, Other: travel, accommodations, expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Pfizer: Honoraria; Amgen: Research Funding; Celleron: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria. Davies:Pfizer: Honoraria, Research Funding; 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. Cwynarski:Atara: 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, 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. McKay: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; Greater Glasgow and Clyde Health Board: Current Employment; BeiGene: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Roche, Gilead, Takeda, Janssen: Other: For lectures etc. OffLabel Disclosure: Avelumab is an anti-PD-L1 antibody which blocke the protein PD-L1 on tumour cells, and the AVAIL-T trial is a phase 2a trial to look at the responses to this drug in patients with refractory and relapsed PTCL.

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.

Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/mBetween Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Introduction: Approximately 20% of patients with Hodgkin lymphoma (HL) are aged 60 years or older. There is no standard of care for such patients, who have a markedly inferior prognosis compared with younger patients and are significantly underrepresented in clinical trials. Escalated BEACOPP chemotherapy has been demonstrated to be highly effective in frontline HL management, but when used in older patients (even at non-escalated doses) there is an unacceptable rate of toxicity-related death. We proposed that a modification of the BEACOPP regime by removing bleomycin and etoposide and dose reduction of cyclophosphamide ('ACOPP') would potentially be a well-tolerated and effective regimen for older HL patients. Methods: This is a single centre pilot study investigating the feasibility of ACOPP chemotherapy for frontline management of older patients with HL who were deemed unfit for more intensive management approaches. Patients received intravenous (IV) Doxorubicin (35mg/m2) and Cyclophosphamide (650mg/m2) on day 1 along with oral Procarbazine (100mg/m2) for 7 days and oral Prednisolone (40mg/m2) for 14 days. IV Vincristine (1.4mg/m2, max 2mg) was given on day 8 and subcutaneous granulocyte colony stimulating factor given on days 9-13. Treatment was delivered as an outpatient every 21 days to a maximum of 6 cycles. Interim PET/CT assessment was performed after 2 cycles of treatment. Results: Seven patients with a median age of 81 years (range 58-92) were treated between March 2018 - March 2019. All patients had histologically confirmed classical Hodgkin lymphoma. 6/7 patients had advanced stage disease with median IPS 3. One patient had unfavourable stage 2 disease by EORTC criteria. Median Charlson Comorbidity Index (CCI) score was 6 with further details outlined in Table 1. All 7 patients completed at least 2 cycles of therapy and all had a complete metabolic response on interim PET with ongoing response confirmed on end of treatment CT. Four patients completed 6 cycles of therapy, with the other 3 patients completing 2, 4 and 5 cycles respectively. Reasons for completing less than 6 cycles of therapy were physician concerns over increased frailty in patient 5, concurrent diagnosis of Parkinsons disease with resultant physical deconditioning in patient 3 and postural hypotension (possibly secondary to vincristine) in patient 7. Grade 3/4 neutropenia was seen in 5/7 patients but only 1 patient had an episode of febrile neutropenia. Thrombocytopenia (2 patients, both grade 3, none requiring platelet transfusion) and anaemia (5 patients, all grade 3 and required red cell transfusion) were also seen. Peripheral neuropathy occurred in 2 patients (grade 1, grade 2). 6/7 patients required admission to hospital during therapy - primary reasons for admission were infection (n=2), constipation (n=2), anaemia (n=1) and autonomic neuropathy (n=1). All 7 patients remain alive and in remission at time of analysis (median FU 9 months). Conclusion: We have demonstrated the feasibility of ACOPP as a chemotherapy regimen which can be delivered in an outpatient setting to elderly patients with HL. We would highlight the median age of 81 years and significant co-morbidity burden of the patients in this pilot study. All patients achieved a negative interim PET and remain in remission at the time of analysis. Toxicity was mainly haematological but was manageable with only 1 episode of febrile neutropenia and no platelet transfusion required. The majority had hospital admissions during therapy, with only 4/7 managing to complete six cycles of treatment. Definitive conclusions regarding efficacy and safety cannot be drawn from this small number of patients but the high rates of metabolic response are encouraging and we feel the regimen merits further, prospective assessment in a large clinical trial. Disclosures Travers: Celgene: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees. McKay:Janssen: Honoraria, Speakers Bureau; Epizyme: 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, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Leach:Abbvie: Honoraria; Janssen: Consultancy, Honoraria; Roche: Honoraria.

Introduction: Secondary CNS dissemination (SCNSL) is a rare but lethal event in pts with diffuse large B-cell lymphoma (DLBCL). It can occur both at presentation, in pts with systemic disease, or at relapse, during or after primary therapy. Following the experience from primary CNS lymphoma, pts with SCNSL are currently treated with high-dose-methotrexate-based chemo and autologous transplant (ASCT). However, this strategy is associated with poor control of extra-CNS disease, and only 1/3 of pts proceed to ASCT and recover from this event. Thus, we designed a multicenter phase II trial addressing an intensified chemoimmunotherapy consolidated by ASCT in HIV-neg pts with SCNSL (NCT02329080). Methods: Inclusion criteria were: histologically confirmed DLBCL; CNS involvement at presentation (concomitant to systemic disease) or relapse (isolated or concomitant to systemic lymphoma); age 18-70 ys; ECOG-PS ≤3; no prior treatment with high-dose methotrexate. Registered pts received 3 courses of MATRIX followed by 3 courses of RICE combined with intrathecal chemo and consolidated by BCNU-thiotepa/ASCT. The primary endpoint was 1-yr PFS. The Fleming design was used; to detect a difference in 1-yr PFS from 50% (P0) to 65% (P1), 69 pts were required (one-sided, type I error 5%, power 80%), with a dropout of 10%, 76 pts were needed. If ≥41 pts were progression-free at 1 yr, the strategy would be considered effective. Results: Between 3/2015 and 8/2018, 79 pts were enrolled at 24 centers in 4 countries; 75 pts (median age 58, range 23-70; 38 males) were assessable. CNS involvement was recorded at presentation in 32 (43%) pts and at relapse in 43 (isolated site in 15, concomitant to systemic relapse in 28). CNS sites were brain parenchyma in 34 (45%) pts, brain + eyes in 10 (13%), brain + CSF in 13 (17%), brain + CSF + eyes in 6 (8%), CSF/meninges in 8 (11%), spinal cord in 2 (3%), and eyes in 2 (3%). Median time to CNS involvement was 5 months (range 1-61) in the 43 pts registered at relapse; 20 (47%) of them had refractory disease. 320 (71%) of the 450 planned chemo courses were delivered; 64 (85%) pts received intrathecal chemo. 78 SAEs were recorded in 42 pts, mostly due to FN and infections (64) or bleeding (5); 74 (95%) SAEs were followed by recovery. The 4 lethal SAEs (TRM= 5%) and the 5 transient interruptions occurred during MATRIX. Dose reductions were indicated in 33 (10%) courses. Most common g4 toxicities were thrombocytopenia in 118 (37%) courses, neutropenia in 113 (35%) and infections in 9 (3%). Stem cells collection was successful (median of 6.75M/kg; range: 2.4 - 45) in 42 (88%) of the 48 pts referred for leukapheresis. 55 (73%; 95%CI 63-83%) pts achieved a response after 2 courses of MATRIX; 19 (95%) of the 20 pts who had a CR after 2 MATRIX maintained the response after RICE; 9 (26%) of the 35 pts who had a PR after 2 MATRIX achieved a CR after RICE. Conversely, only 3 of 16 pts with PD/SD after 2 MATRIX achieved a response from RICE. 49 pts (65%; 95%CI 54-76%) achieved a response after MATRIX-RICE induction, and 36 responders received ASCT; 13 responders did not receive ASCT due to insufficient mobilization (n=4), PD due to treatment delay (5), frailty (2), neurological decline (1), and consent withdrawal (1). 45 pts (60%; 95%CI 50-70%) had responsive disease after the whole treatment. At 1 year from registration, 41 pts were progression free (efficacy threshold ≥41). At a median follow-up of 25 (12-47) months, 31 pts are progression free, with a 2-yr PFS of 42 ± 6% for the whole series and 75 ± 7% for the 36 transplanted pts (Fig. A & B). Sites of relapse/progression were CNS in 10 pts, extra-CNS organs in 9 and both in 18. Overall, 33 pts are alive, with a 2-yr OS of 42 ± 6% for the whole series and 82 ± 7% for transplanted pts. Causes of death were lymphoma (35) and toxicity (4); 3 pts died without evidence of disease due to neurological decline, PTE and sudden death. Pts with CNS disease at presentation had the best outcome (Fig. C), whereas CSF/meningeal disease (Fig. D) and age >60 ys were independently associated with poor outcome. Conclusions: MATRIX-RICE followed by ASCT achieved the primary endpoint in this very-poor-prognosis population, without major safety concerns. Survival figures of transplanted pts seem a little better than reported in prior trials, whereas pts with MATRIX-refractory disease had no benefit from crossing to RICE. The best survival figures were recorded in chemo-naïve pts treated at presentation and in pts without CSF/meningeal disease. Figure Disclosures Ferreri: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Doorduijn:Roche: Honoraria, Research Funding. Nassi:Merck: Consultancy; Takeda: Consultancy; Janssen: Consultancy. McKay:Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: 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, Speakers Bureau. Davies:ADCT Therapeutics: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Janssen: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Research Funding. Fox:Celgene: Consultancy; Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Osborne:Gilead: Membership on an entity's Board of Directors or advisory committees; NIL: Employment; NIL: Other: leadership; NIL: Other: Stock & other ownership interests; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees. Liberati:Incyte: Consultancy; Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Zucca:Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

Mantle cell lymphoma (MCL) is an uncommon B-cell neoplasm with male predominance and a median age at presentation in the mid-60s. The majority of patients follow an aggressive clinical course with ...

Primary cutaneous B-cell lymphomas displaying a prominent follicular growth pattern are rare and remain poorly defined, particularly in terms of the frequency of detection of t(14;18) and whether or not, as a group, they represent an entity distinct from follicular lymphoma arising in lymph nodes. The morphologic, immunophenotypic, and clinical features of 16 cases of primary cutaneous follicular lymphoma, identified during a review of all PCBCL in the Scotland and Newcastle Lymphoma Group database, were studied and the number of cases harboring t(14;18) assessed by polymerase chain reaction using primers to the major breakpoint cluster region. Comparisons were made with stage I follicular lymphoma arising in lymph nodes and follicular lymphoma secondarily involving the skin. All cases of primary cutaneous follicular lymphoma had undergone thorough staging, including physical examination and CT scans of chest and abdomen, with 15 of 16 cases also having bone marrow aspiration and/or trephine performed. The morphology and immunophenotype of the lesions were similar to that expected in lymph nodes. All cases displayed a follicular architecture complete with follicular dendritic cell networks and comprised an admixture of CD10 and/or bcl-6-positive neoplastic centrocytes and centroblasts with 13 of 16 cases also expressing bcl-2 protein. None harbored t(14;18), a significantly different finding compared with cases of stage I nodal follicular lymphoma (p0.001) and secondary cutaneous follicular lymphoma (p0.039). Relapses occurred in five of 15 patients with a median time to first relapse of 20 months (range 1-73 months; mean 27.2 months). These were multiple in two patients and involved extracutaneous sites in two patients. The propensity for relapse was similar to that in a comparative cohort of stage I nodal follicular lymphoma, but the group of primary cutaneous follicular lymphoma were significantly more likely to attain complete remission; all cases of primary cutaneous follicular lymphoma were in complete remission when last seen compared with 49 of 87 patients with stage I nodal follicular lymphoma (p0.005). No lymphoma-related deaths were encountered in 15 cases with a mean follow-up60 months (range 5-119 months). These results support the concept of a subtype of follicular lymphoma lacking t(14;18) involving the major breakpoint cluster region, and with a propensity to arise in the skin. Despite a high relapse rate patients with primary cutaneous follicular lymphoma are more likely to achieve complete remission and may ultimately have a more favorable long-term prognosis than those with equivalent nodal disease.

The guideline group was selected to be representative of UK-based medical experts. Ovid MEDLINE, EMBASE and NCBI Pubmed were searched systematically for publications in English from 1980 to 2012 using the MeSH subheading 'lymphoma, CNS', 'lymphoma, central nervous system', 'lymphoma, high grade', 'lymphoma, Burkitt's', 'lymphoma, lymphoblastic' and 'lymphoma, diffuse large B cell' as keywords, as well as all subheadings. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of ~50 UK haematologists, the BCSH and the British Society for Haematology (BSH) Committee and comments incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the optimal prevention of secondary central nervous system (CNS) lymphoma. The guidance may not be appropriate to patients of all lymphoma sub-types and in all cases individual patient circumstances may dictate an alternative approach. Acronyms are defined at time of first use.

Positron emission tomography (PET) has added considerably to the management of Hodgkin lymphoma (HL). PET is of value in staging disease, response assessment and evaluation of a residual mass post-treatment. Full staging of advanced disease has traditionally required a bone marrow biopsy and this is still considered standard practise, although some authors argue that this rarely alters patient management. It had been hoped that the use of PET imaging at diagnosis would clearly define bone marrow involvement in HL and remove the need to perform bone marrow biopsies. It is clear, however, that PET cannot readily differentiate between ‘reactive’ and ‘involved’ bone marrow when the PET signal is diffusely increased in bone. The substrate, 2-fluoro-2-deoxyD-glucose (FDG), is readily taken up by metabolically active tissue and a reactive bone marrow with expansion of myeloid and lymphoid activity can show a degree of uptake very similar to that of bone marrow involved by disease. The first image (left) shows the FDG-PET signal from a patient with HL with a reactive bone marrow biopsy at diagnosis. The diagnosis of a reactive bone marrow was made from a single iliac crest bone marrow biopsy in association with a normocytic anaemia, neutrophilia and raised erythrocyte sedimentation rate. The second (centre) shows the FDG-PET signal from a patient with Stage 4 HL with heavy bone marrow infiltration shown by biopsy at diagnosis. The third (right) shows a normal bone marrow FDG-PET signal for comparison. PET is an invaluable imaging tool used in the assessment of patients with HL. However, it should be used to compliment bone marrow trephine biopsy, rather than replace it, if patients are to be accurately staged prior to therapy.

Socio-economic deprivation is known to be associated with poorer survival from non-Hodgkin lymphoma (NHL) but routine data have not been able to determine whether this can be explained by differences in disease severity at presentation. We examined survival in all patients diagnosed with NHL in Scotland between 1979 and 1996 and between 1994 and 1996 used Scotland and Newcastle Lymphoma Group data, which include detailed clinical staging information. Compared with individuals from the most affluent areas, survival is 10% poorer in intermediate, and 19% poorer in patients living in the most deprived areas. Deprivation is associated with more B symptoms and poorer performance status but not with other indicators of more advanced disease, suggesting that the disease may be more aggressive or immunocompetence poorer among more deprived populations. We also noted improvements in relative survival from NHL over time.

Classification and subdivision of primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) are a matter of ongoing debate. In this study we assessed the morphologic, immunophenotypic, and clinical features of 30 cases of PCDLBCL identified during a review of all primary cutaneous B-cell lymphomas in the Scotland and Newcastle Lymphoma Group database. We also determined the number of cases harboring t(14;18) using a polymerase chain reaction and primers to the major breakpoint cluster region. The effect on prognosis of a variety of clinical and pathologic factors was assessed for the group of 30 PCDLBCL and the 5-year disease-specific survival (DSS) of this cohort compared with that of 195 cases of stage I diffuse large B-cell lymphoma arising primarily in lymph nodes, also identified from within the Scotland and Newcastle Lymphoma Group database. Location on the leg was the only independent prognostic factor for determining outcome in PCDLBCL (67% 5-year DSS compared with 100% for the upper body; P = 0.0047). The presence of multiple lesions, involvement of more than one body site, and expression or not of CD10, bcl-2, bcl-6, and CD10 and bcl-6, had no effect on survival. Compared with cases arising above the waist, those on the leg were more often female, were of an older age, and had a significantly higher incidence of bcl-2 expression (P = 0.002) as well as the aforementioned poorer prognosis. They also showed more frequent co-expression of CD10 and bcl-6, supporting a follicle center cell origin for some, but this difference was not statistically significant. Although there was no significant difference in the 5-year DSS between the group of PCDLBCL and the cases of stage I nodal diffuse large B-cell lymphoma (88% 5-year DSS vs. 78%; P = 0.06), the latter were generally treated with more aggressive therapy. Moreover, a significant difference in 5-year DSS was seen when the nodal DLBCLs were compared with PCDLBCLs arising above the waist (78% vs. 100% respectively; P = 0.0135). These results support the current EORTC approach of subdividing PCLBCL on the basis of site to produce prognostically relevant groupings.

Learning points A 55 year old man had a full blood count undertaken when he presented with fatigue. There was no significant medical history of note. He was a non-smoker who took no medications. He was noted to have a lymphopenia of 0.8×109/L (reference interval 1.5-4.0×109/L). Otherwise his results were normal, with haemoglobin of 135 g/L (130-180 g/L), white cell count 4.2×109/L (4-12×109/L), and platelet count 150×109/L (140-400×109/L). He did not return for follow-up but presented to a local hospital emergency department six months later with a short history of increasing breathlessness. He was diagnosed with a severe bacterial pneumonia, from which he recovered after prolonged therapy with intravenous antibiotics. His lymphocyte count during admission ranged between 0.5 and 1.0×109/L. ### Lymphopenia and its causes T lymphocytes make up most (60-80%) of the total peripheral …

The aim of this study was to evaluate the influence of duration of first remission (FR) on overall survival (OS) of patients (pts) with DLBCL in a population-based setting, and further to assess the possible differences in clinical features or IPI between pts with different duration of FR. We analyzed all DLBCL pts registered on the database of the Scotland and Newcastle Lymphoma Group. Further inclusion criteria were age >18 yrs and defined clinical stage (CS) at presentation, treatment with anthracycline based chemotherapy, and no immunotherapy or stem cell transplantation in first line treatment. According to duration of FR four groups were defined; “refractory”-pts who did not respond to first line treatment or relapsed within 9 months from diagnosis, “early relapse”-pts who relapsed within 9–18 months from diagnosis, “late relapse”-pts who relapsed after 18 months from diagnosis and “no relapse”-pts who did not relapse. From 1990 to 2003, 2025 DLBCL pts were registered within the database and 1391 pts fulfill inclusion criteria. The median age at diagnosis was 64 yrs, 40% of pts were aged ≤60yrs, 51% of pts were male, 79% of pts had ECOG 60 yrs 46%, 7%, 9% and 38%, respectively. 5 yrs OS was 8% in “refractory–group”, 16% in “early relapse–group”, 50% in “late relapse–group” and 90% in “no relapse–group”, differences between the groups were statistically significant, p60yrs 4%, 6%, 40% and 85%, respectively, p60yrs 32%, 50%, 76% and 68%, respectively, p60yrs, however there were no statistically significant differences between “early relapsed” and “late relapse” groups. To assess the further potential differences in clinical features at presentation between “primary refractory” vs “no relapse” pts and “early relapse” vs “late relapse” pts, the groups were compared for the following factors: age, sex, CS, B-symptoms, ECOG, extranodal and bone marrow involvement, bulky disease, haemoglobin, leukocytes, LDH, albumin, urea, and alkaline phosphatase serum level. In evaluation of all pts and pts ≤60 years the “primary refractory–group” differed statistically significantly from the “no relapse group” in all evaluated factors except of sex and in evaluation of pts >60yrs in all factors. The “early relapse group” differed statistically significantly from the “late relapse group” only in ECOG performance status in evaluation of all pts, CS and bulky disease in evaluation of pts ≤60 years and age and CS in evaluation of pts >60yrs. In a population-based study of pts with DLBCL treated with anthracyclines, duration of FR defined groups of pts with statistically different OS. It was impossible to distinguish entirely by clinical features or IPI at diagnosis. We conclude, that the currently used prognostic indices based on clinical factors need to be enhanced using biological features of the tumor.