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Thyroid abnormalities are well reported following childhood treatment for Hodgkin Lymphoma (HL). Limited information exists for adult patients and after modern treatments. We analyzed risks of thyroid disorders in 237 female participants treated at the Royal Marsden Hospital 1970-2015. Multivariable analyses of risk according to treatment and time-related factors, survival analyses, and Cox regression modeling were undertaken. Overall, 33.8% of patients reported thyroid disorders (hypothyroidism 30.0% and thyroid nodules 6.8%). Cumulative prevalence was 42.9% by 40 years follow-up. Risks were greatest after supradiaphragmatic radiotherapy (RR = 5.0, p

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Introduction: Patients (pts) with CLL may be at particular risk of severe COVID-19 given advanced age and immune dysregulation. Two large series with limited follow-up have reported outcomes for pts with CLL and COVID-19 (Scarfò, et al. Leukemia 2020; Mato, et al. Blood 2020). To provide maximal clarity on outcomes for pts with CLL and COVID-19, we partnered in a worldwide effort to describe the clinical experience and validate predictors of survival, including potential treatment effects. Methods: This international collaboration represents a partnership between investigators at 141 centers. Data are presented in two cohorts. Cohort 1 (Co1) includes pts captured through efforts by European Research Initiative on CLL (ERIC), Italian CAMPUS CLL Program, and Grupo Español de Leucemia Linfática Crónica. The validation cohort, Cohort 2 (Co2), includes pts from US (66%), UK (23%), EU (7%), and other countries (4%). There is no overlap in cases between cohorts. CLL pts were included if COVID-19 was diagnosed by PCR detection of SARS-CoV-2 and they required inpatient hospitalization. Data were collected retrospectively 2/2020 - 5/2020 using standardized case report forms. Baseline characteristics, preexisting comorbidities (including cumulative illness rating scale (CIRS) score ≥6 vs. The primary endpoint of this study was to estimate the case fatality rate (CFR), defined as the proportion of pts who died among all pts hospitalized with COVID-19. Chi-squared test was used to compare frequencies; univariable and multivariable analyses utilized Cox regression. Predictors of inferior OS in both Co1 and Co2 were included in multivariable analyses. Kaplan-Meier method was used to estimate overall survival (OS) from time of COVID-19 diagnosis (dx). Results: 411 hospitalized, COVID-19 positive CLL pts were analyzed (Co1 n=281, Co2 n=130). Table 1 describes baseline characteristics. At COVID-19 dx, median age was 72 in Co1 (range 37-94) and 68 in Co2 (range 41-98); 31% (Co1) and 45% (Co2) had CIRS ≥6. In Co1, 48% were treatment-naïve and 26% were receiving CLL-directed therapy at COVID-19 dx (66% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.6% chemo/chemoimmunotherapy (CIT), 1.4% PI3Ki, 4% other). In Co2, 36% were never treated and 49% were receiving CLL-directed therapy (65% BTKi ± anti-CD20, 19% Venetoclax ± anti-CD20, 9.4% multi-novel agent combinations, 1.6% CIT, 1.6% PI3Ki, 1.6% anti-CD20 monotherapy, 1.6% other). Most pts receiving CLL-directed therapy had it held at COVID-19 diagnosis (93% in Co1 and 81% in Co2). Frequency of most COVID-19 symptoms/laboratory abnormalities were similar in the two cohorts including fever (88% in both), lymphocytosis (ALC ≥30 x 109/L; 27% vs. 21%), and lymphocytopenia (ALC < 1.0 x 109/L; 18% vs. 28%), while others varied between Co1 and Co2 (p Median follow-up was 24 days (range 2-86) in Co1 and 17 days (1-43) in Co2. CFRs were similar in Co1 and Co2, 30% and 34% (p=0.45). 54% and 43% were discharged while 16% and 23% remained admitted at last follow-up in Co1 and Co2, respectively. The proportion of pts requiring supplemental oxygen was similar (89% vs. 92%) while rate of ICU admission was higher in Co2 (20% vs. 48%, p Conclusions : In the largest cancer dx-specific cohort reported, pts with CLL hospitalized for COVID-19 had a CFR of 30-34%. Advanced patient age at COVID-19 diagnosis was an independent predictor of OS in two large cohorts. This CFR will serve as a benchmark for mortality for future outcomes studies, including therapeutic interventions for COVID-19 in this population. The effect of CLL treatment on OS was inconsistent across cohorts; COVID-19 may be severe regardless of treatment status. While there were no significant differences in distribution of current lines of therapy between cohorts, prior chemo exposure was more common in Co1 vs. Co2, which may account for difference in OS. Extended follow-up will be presented. Disclosures Roeker: American Society of Hematology: Research Funding; Abbott Laboratories: Other: spouse with minority ownership interest ; AbbVie: Other: spouse with minority ownership interest . Scarfo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees. Abrisqueta:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau. Eyre:AbbVie: Consultancy, Honoraria, Other: travel support; Gilead: Consultancy, Honoraria, Other: travel support; Janssen: Consultancy, Honoraria, Other: travel support; KITE, AZ, Loxo Oncology at Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Muntañola Prat:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grants; participated in advisory boards. Villacampa:AstraZeneca: Other: advisory role; Merck Sharp & Dohme: Honoraria. Leslie:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Speakers Bureau; KitePharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Speakers Bureau; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria. Furman:Incyte: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy; Oncotarget: Consultancy; Janssen: Consultancy, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy; Beigene: Consultancy; AstraZeneca: Consultancy, Research Funding; Acerta: Consultancy; Verastem: Consultancy. Pagel:BeiGene, Astrazeneca, Loxo Oncology, Gilead: Consultancy. Hernandez-Rivas:Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees. Patel:Genentech: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Motta:Roche: Honoraria; Janssen: Honoraria. Lamanna:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Verastem: Research Funding; Bei-Gene: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vitale:Janssen: Honoraria. Kamdar:Roche: Research Funding. Österborg:BeiGene: Research Funding; Kancera: Current equity holder in publicly-traded company, Research Funding; Sanofi: Consultancy; Karolinska Univeristy Hospital, Stockholm, Sweden: Current Employment. Hanson:Janssen-Cilag: Research Funding; Gilead: Research Funding; AbbVie: Honoraria. Eichhorst:ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding. Reda:Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Varettoni:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses; AbbVie: Other: Travel/accommodations/expenses; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees. Marchetti:Gilead: Consultancy; Novartis: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Other: Sponsored meetings; Takeda: Other: Sponsored meetings; Pfeizer: Other: Sponsored meetings. Munir:F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria. Zabalza:Janssen: Honoraria, Other: travel grants; Roche: Other: travel grants; Novartis: Other: travel grants. Janssens:Amgen: Consultancy, Other: travel grants; speaker fees; Abbvie: Consultancy, Other: travel grants; speaker fees; Celgene: Consultancy, Other: travel grants; speaker fees; Janssen: Consultancy, Other: travel grants; speaker fees; Gilead: Consultancy, Other: travel grants; speaker fees; Novartis: Consultancy, Other: travel grants; speaker fees; Sanofi-Genzyme: Consultancy, Other: travel grants; speaker fees; Roche: Consultancy, Other: travel grants; speaker fees. Niemann:AstraZeneca: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Sunesis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Danish Cancer Society: Honoraria, Research Funding; Novo Nordisk Foundation: Honoraria, Research Funding. Perini:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Abbvie: Speakers Bureau. Patten:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria. Marasca:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Honoraria. Iyengar:Janssen: Honoraria; Gilead: Honoraria. Ferrari:Abbvie: Honoraria. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Itchaki:Abbvie Inc: Consultancy, Research Funding. Ma:Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding. Van Der Spek:AMGEN: Other: Teaching activities. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mauro:Roche: Other; Octopharma: Other; Takeda-Shire: Other; Gilead: Other; Janssen: Other; Abbvie: Other. Laurenti:Janssen: Honoraria; Gilead: Honoraria; AbbVie: Honoraria; Roche: Honoraria. Levin:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Špaček:Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Walewska:AbbVie: Other: sponsored for educational meetings, Speakers Bureau; Janssen: Other: sponsored for educational meetings, Speakers Bureau; Gilead: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Wiestner:Pharmacyclics LLC, an AbbVie Company; Acerta, Merck, Nurix, Verastem, and Genmab: Research Funding; National Institutes of Health: Patents & Royalties: and other intellectual property. Broom:Gilead: Other: Travel support, Speakers Bureau. Kater:Abbvie: Research Funding; Roche: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Genentech: Research Funding. Ujjani:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Verastem Oncology: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Atara: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Gilead: Other: travel grants, Research Funding; Abbvie: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Pu:Takeda Pharmaceuticals: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Gilead, Loxo, Sun, Verastem: Research Funding; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Farina:Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Sanchez:Abbvie: Other: travel grants; Amgem: Other: travel grants; Janssen: Other: travel grants; Celgene: Other: travel grants; Roche: Other: travel grants. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Foglietta:Janssen: Honoraria; Gilead: Honoraria. Jaksic:Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Sportoletti:AbbVie: Honoraria; Janssen: Honoraria. Barr:Morphosys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy, Research Funding; Verastem: Consultancy; Seattle Genetics: Consultancy; TG therapeutics: Consultancy, Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding; Celgene: Consultancy; Merck: Consultancy; Genentech: Consultancy; Janssen: Consultancy. Ruchlemer:Abbvie Inc: Consultancy, Research Funding. Kersting:Celgene: Other: travel grant; Janssen: Research Funding; Abbvie: Research Funding. Huntington:Pharmacyclics: Honoraria; AbbVie: Consultancy; Novartis: Consultancy; Genentech: Consultancy; DTRM: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Honoraria; Astrazeneca: Honoraria; TG Therapeutics: Research Funding. Herishanu:Roche: Honoraria; Sanofi: Honoraria; Medison: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria. Jacobs:TG Therapeutics, Inc.: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics: Research Funding, Speakers Bureau; Seattle Genetics: Consultancy; Verastem: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Sanofi Genzyme: Speakers Bureau. Portell:BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Xencor: Research Funding; Bayer: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; AbbVie: Research Funding. Rambaldi:Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.; Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.. Brander:Verastem: Consultancy, Honoraria, Other, Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; NCCN: Other; Novartis: Consultancy, Other; Teva: Consultancy, Honoraria; Tolero: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ArQule: Consultancy, Other, Research Funding; Ascentage: Other, Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; BeiGene: Other, Research Funding; DTRM: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; MEI Pharma: Other, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; Pfizer: Consultancy, Other; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding. Rossi:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Coscia:Karyopharm Therapeutics: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cuneo:Astra Zeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bosch:Jansen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Roche: Honoraria. Stamatopoulos:AstraZeneca: Honoraria; Janssen, Gilead, Abbvie: Honoraria, Research Funding. Ghia:Adaptive, Dynamo: Consultancy, Honoraria; Novartis: Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Gilead: Consultancy, Honoraria, Research Funding; ArQule: Consultancy, Honoraria; Acerta/AstraZeneca: Consultancy, Honoraria. Mato:Adaptive: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding.

Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with individuals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.

Non-Hodgkin's lymphoma (NHL) encompasses over 40 different haematological malignancies, including low and high-grade neoplasms, such as follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) respectively. A key clinical issue in the context of NHL is delayed and inaccurate diagnosis, which contributes adversely to patient morbidity and mortality. This article will address relevant imaging aspects, with particular reference to advancements in NHL imaging, including computed tomography (CT), integrated positron-emission tomography (PET)-CT, and magnetic resonance imaging (MRI). We provide multiparametric (anato-functional) imaging display items, including histological correlation. We will also introduce our original concept of “Specialist Integrated Haematological Malignancy Imaging Reporting” (SIHMIR), a paradigm shift in lymphoma radiology.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a new provisional category in the 2016 World Health Organization (WHO) classification of lymphoid neoplasms, and its incidence is rising owing to increasing recognition of this complication of breast implant insertion. At a median of 10 years after implant insertion, the typical presenting features are sudden-onset breast swelling secondary to peri-implant effusion and less frequently mass-forming disease. Histologic features comprise pleomorphic cells expressing CD30 and negative anaplastic lymphoma kinase (ALK) receptor, similar to systemic and cutaneous ALK-negative anaplastic large cell lymphoma (ALCL). The effusion-only subtype is generally indolent and curable with surgery, unlike the more aggressive mass-forming disease, for which systemic therapy is advocated. High clinical suspicion and pertinent use of radiologic and pathology modalities are essential for timely and accurate diagnosis of BIA-ALCL. Contemporary imaging techniques including US, mammography, breast MRI, CT, and PET/CT are routinely used in breast disease and lymphomas; however, the unique behavior of BIA-ALCL presents significant diagnostic and radiologic interpretative challenges, with numerous nuanced imaging features being pertinent, and current lymphoma staging and response guidelines are not easily applicable to BIA-ALCL. The authors evaluate available evidence in this evolving field; detail key indications, strengths, and limitations of the panoply of radiologic techniques for BIA-ALCL; and propose multiparametric imaging paradigms for management of the peri-implant effusion and mass-forming or advanced disease subtypes, with the goal of accurate optimal patient care. The authors also predict a future model of multimodal assessment using novel imaging and molecular techniques and define key research directions. ©RSNA, 2020.

Summary Background Chemoimmunotherapy is typically the standard of care for patients with Waldenstrom macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenstrom macroglobulinemia. Methods This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenstrom macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenstrom Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov , number NCT02180724 , and is ongoing, but no longer enrolling. Findings Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0–29·7), 13 (93% [95% CI 66–100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86–98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3–4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3–4 atrial fibrillation occurred in one (1%) patient and grade 3–4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). Interpretation This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenstrom macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. Funding Acerta Pharma.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Mantle cell lymphoma (MCL), an aggressive B-cell malignancy accounting for 6% of non-Hodgkin lymphomas, remains incurable with standard therapy. Despite the approval of bortezomib,[1][1] temsirolimus,[2][2] lenalidomide,[3][3] ibrutinib[4][4] and acalabrutinib,[5][5] patients with relapsed

Background Central nervous system (CNS) lymphomas are a rare subset of lymphoma, which are associated with a poor outcome. The gold standard for CNS imaging is with gadolinium-enhanced magnetic resonance imaging (MRI); however, there are a number of limitations, including some patients with small persistent abnormalities from scarring due to focal haemorrhage or from a previous biopsy, which can be difficult to discern from residual tumour. [18F]Fluoromethylcholine positron emission tomography–computed tomography (FCH-PET/CT) uses an analogue of choline, which due to the upregulation of choline kinase in tumour cells, allows increased uptake of FCH. As there is minimal background grey matter uptake of FCH, FCH-PET/CT can be used in CNS imaging and provide a useful tool for response assessment. Methods This is a cohort study, where we identified 40 patients with a diagnosis of primary or secondary CNS lymphoma between 1st November 2011 and 10th October 2019. Results 26 of the 40 patients (65%) had concordant results. Of the discordant results, 11 out of 14 had partial response (PR) on MRI but showed a metabolic complete response (mCR) on FCH-PET. The overall response rates (ORR) were similar between the two modalities (90% for MRI versus 95% with FCT-PET/CT). Conclusion We conclude that FCH-PET/CT is a reasonable alternative mode of imaging to gadolinium-enhanced MRI brain imaging, providing a new tool for assessment of CNS lymphoma.

Background: In the treatment of advanced Hodgkin lymphoma, it is increasingly common UK practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3) to reduce haematopoietic stem cell and gonadal toxicity. However, published data of the "escalated BEACOPDac (eBPDac)" regimen are very limited. Methods: This is a retrospective study of 225 patients from 20 centres in the UK, Ireland and France who were treated with eBPDac first line for advanced stage Hodgkin Lymphoma. Toxicity outcomes were compared with 58 matched patients treated with eBPP at 4 UK centres and survival outcomes were compared with 2073 eBPP patients in the HD18 trial 1 and with 1088 patients aged 18-59y in the RATHL trial 2,3. Most eBPDac patients were treated as per HD18 protocol. The 34 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD. Toxicity outcomes: Toxicity was compared between eBPDac patients (n=225; median follow-up 22.1 months) and matched real-world UK eBPP patients (n=58; median follow-up 52.7 months) over the first 4 cycles. eBPP and eBPDac patients were well matched with no significant differences in age (median 23 y vs 26 y), sex, stage (stage 3/4 82% vs 83%) and international prognostic score (IPS 3+ 74% vs 65%). 55% of eBPDac patients received only 4 cycles (vs 12% of eBPP patients; p Disease outcomes: The eBPDac patients (n=225) were younger than the HD18 patients (median age 26 y vs 35 y, p Figure 1 shows Kaplan-Meier plots for progression-free survival (PFS) and overall survival (OS). The PFS at 22 months (median follow-up) of eBPDac patients was 94.9% (91.7-98.3%) which is similar to HD18 3 year PFS of 92.3% (91.1-93.5%) and appears superior to RATHL 5 year PFS 81.4% (78.9-83.7%). The difference in PFS between eBPDac and RATHL is most marked in IPS3+ patients. The OS rates with all 3 regimens are excellent, with 22 month eBPDac OS estimate of 98.9% (97.4-100%). Summary/Conclusion: Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP and may have some toxicity benefits. Despite the clear preference of clinicians to offer this regimen to high-risk advanced stage patients, with nearly 2 years median follow-up we have observed similar PFS and OS compared to HD18 but superior survival estimates compared with 18-59y RATHL patients, suggesting that eBPDac is highly efficacious for the treatment of Hodgkin lymphoma. References: 1Borchmann P et al. Lancet 2017; 390:2790-2802 2Johnson P et al. NEJM. 2016; 374:2419-2429 3Russell J et al. Ann Hematol 2021; 100:1049-1058 Figure 1 Figure 1. Disclosures Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Menne: Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Astra Zeneca: Research Funding; Jazz: Other: Travel grants; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Bayer: Other: Travel grants; Kyowa Kirin: Other: Travel grants; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Atara: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Honoraria for Lectures; Roche: Other: Honoraria for Lectures. Osborne: Roche: Other; Takeda: Other; Pfizer: Other; Servier: Other; Gilead: Other; Novartis: Other; MSD: Other. Ardeshna: Gilead, Beigene, Celegene, Novartis and Roche: Membership on an entity's Board of Directors or advisory committees; Gilead, Beigene, Celegene, Novartis and Roche: Honoraria; Norvartis, BMS, Autolus, ADCT, Pharmocyclics and Jansen: Research Funding. Collins: Pfizer: Honoraria; Amgen: Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Celgene: 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. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Davies: Janssen: Honoraria, Research Funding; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma/AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; BioInvent: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel to scientific conferences, Research Funding. Furtado: Abbvie: Other: Conference support. Gallop-Evans: Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Iyengar: 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; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: conference support; Janssen: Other: conference support, Speakers Bureau. Linton: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; University of Manchester: Current Employment; Celgene: Research Funding; BeiGene: Research Funding; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Calle: Abbvie: Other. 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. Nagumantry: Takeda, Alexion, Abbvie: Other. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Uttenthal: Jazz: Other; Takeda: Other; Roche: Other. McMillan: Pfizer: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abvie: Membership on an entity's Board of Directors or advisory committees. Follows: Janssen, Abvie, Roche, AZ: Other.

Introduction Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a T-cell lymphoma associated with textured breast implants, recently recognized by the revised WHO Classification. Recommended management for BIA-ALCL involves a multidisciplinary team (MDT) approach with breast surgery, haemato-oncology, pathology, radiology and oncoplastic input. Definitive management for the 'effusion-only' subset is surgical implant and capsule removal; systemic therapy is reserved for 'mass-forming' and 'advanced-disease' cohorts. Overall prognosis is excellent with the vast majority achieving remission. Although the diagnostic and treatment paradigm is established, post treatment surveillance and follow-up guidance varies widely (globally); over-utilisation of imaging tests compromises the patient pathway, impacts limited health-care resources and is associated financial burdens on patients and providers. Recently, newly published consensus guidelines (UK MHRA and USA NCCN clarify follow-up and surveillance imaging (Table 1). The aim of this study was to review our BIA-ALCL specialist centre institutional practise; to quantify the direct economic cost (EC) of imaging surveillance and indirect EC of outpatient clinic (OPC) assessment compared EC if recent guidelines were followed. The secondary aim is to highlight and raise awareness of the latest international guidance to promote the standardisation of practise. Methods A retrospective analysis of a prospectively maintained patient database between July 2015 to October 2019 was conducted, with Institutional Review Board Approval. Data collection included patient demographics, tumour subset, treatment, clinical and imaging surveillance. Follow-up and imaging undertaken for symptomatic concerns / non-BIA-ALCL related pathology was excluded. Imaging costs were calculated using UK NHS tariffs. Results Eleven patients were treated for BIA-ALCL during the study period, with a median age of 49 at diagnosis (range 30-82years). Patients were diagnosed with: effusion-only (n=7), effusion and mass (n=2), mass-only (n=2) subtypes, at a median time of eleven years from implant insertion (IQR 8-12). All patients underwent explantation and en-bloc capsulectomy, with 1 patient required neo-adjuvant (CHOP, Brentuximab) and 1 adjuvant (CHOP) therapy (CHOP. Surveillance with imaging and OPC detected no disease recurrence to date (overall median follow-up 38 months, IQR 12-47). Post treatment episodes of surveillance imaging or follow-up related to patient symptoms were excluded. 8 patients underwent surveillance imaging at our institute (Table 2). Total cost of imaging was £10,396 ($14,396) with a median cost of £1,953 ($2,705) per patient [IQR £526-2029 ($728-2,810)]. 7 patients had completed at least 24 months follow-up since surgery during the study period (Table 3), with 3 patients having not yet completed their follow-up period of two years. Of those with completed follow-up, the median OPC follow-up per patient was 48 months (IQR 38-52), median number of OPC was 7 (IQR 6-11) and the median cost of clinic review was £982 (IQR 804-1395). The surplus cost per patient compared with recommended follow-up was £118 ($164) [IQR £0-531 ($0-738)]. Conclusions Our data shows the variable BIA-ALCL surveillance practise pattern and the associated additional direct and indirect EC of unnecessary asymptomatic surveillance imaging, with an excessive number of follow-up OPC and period of clinical follow-up after complete remission. With no recurrence detected in our patient cohort to date, this data supports the new UK and updated USA NCCN Guidelines (extrapolated from data in other NHLs, and analogous to principles of the ASH Choosing Wisely Campaign) that routine post-treatment surveillance imaging should not be performed in BIA-ALCL patients. Routine asymptomatic post-treatment surveillance imaging is clinically unnecessary and potentially leads to a 'Cascade Effect' of further tests, with increased radiation exposure, excess costs and impact on limited health-care resources. We also support open-access follow-up for patients in remission, to reduce unnecessary follow up appointments. With UK and USA guidelines now available for BIA-ALCL, we support training and education of health-care professionals, global consensus guidelines and a registry, for this rare however increasingly recognised new entity. Figure 1 Figure 1. Disclosures Iyengar: Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: conference support; Janssen: Other: conference support, Speakers Bureau. Nicholson: Pfizer: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; BMS/Celgene: Consultancy; Novartis: Consultancy, Other: Conference fees. El-Sharkawi: Kyowa Kirin: Other: Ad boards; Beigene: Other: Ad boards; ASTEX: Other: Ad boards; Novartis: Other: Travel Support; Takeda: Honoraria; Roche: Honoraria; Janssen: Honoraria, Other: Ad boards; AstraZeneca: Honoraria, Other: Ad boards; AbbVie: Honoraria, Other: Travel Support, Ad boards. Tasoulis: BMJ: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cunningham: Roche: Research Funding; Clovis Oncology: Research Funding; Celgene: Research Funding; Eli Lilly: Research Funding; Bayer: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees; 4SC: Research Funding; AstraZeneca: Research Funding; MedImmune: Research Funding.

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.

Introduction Following completion of chemotherapy with curative intent for DLBCL, for those in remission (CR), numerous national and international guidelines suggest on-going follow-up primarily to detect relapse of disease. For example, the NCCN guidelines suggest that clinical history, examination and blood investigations should be performed every 3-6 months for 5 years and as clinically indicated thereafter. This is essentially a "screening programme" for an at-risk population that continues based on historical routine rather than due to evidence it is of benefit to the patient. Numerous papers have been published suggesting that routine surveillance scans or bloods such as LDH are not useful in this setting. We sought to analyse whether the screening procedures that are performed in the follow-up setting are useful in the detection of relapse in patients followed up in a single centre. Uniquely, we examined each time point separately rather than group all follow-up events together. Methods Data was obtained retrospectively from electronic patient records for all patients in remission following treatment with frontline chemotherapy for DLBCL at the Royal Marsden Hospital between 2005-2016. Screening assessments analysed were symptoms check, clinical examination, LDH >upper limit of normal, lymphocyte: monocyte ratio (LMR) Results Complete data from 262 patients who achieved a CR and were followed up was available. Median age was 63 years (17-94) with 59 patients with stage 1 disease, and 100 with stage 4 disease. The relapse rate was 59/261 (23%), with a median time to relapse of 13 months (2-120). Of the 59, 52 had symptoms they had noted prior to clinic, of whom 28 requested an early appointment to clinic and 22 waited until their routine clinic appointment or sought advice from other health professionals initially. Only 7 patients were picked up only on investigations performed at the hospital, 1 with hypercalcemia and 6 on routine scan with no symptoms, 3 at 3-6months, 2 and 9-12months and 1 at 12-18 months. Of these, 4/7 patients achieved a CR with subsequent therapy. The remaining 202 patients had 2853 clinic appointments, median number per patient 13 (1-44). The negative predictive value of clinical history, examination, LDH, LMR and CT scan was consistently very high (>90%) at all time points. However, the positive predictive value was low for symptoms, 0-35% with the higher values being in the first year. Clinical examination had better PPV due to fewer positive results, including both true and false. LDH and LMR were associated with a poor PPV at all time points. PPV for CT scans was variable (Table 1). Conclusions The "screening" of patients who are in remission from DLBCL requires considerable health resources and cost and also leads to increased exposure of the patient to hospitals which during the COVID-19 pandemic is being discouraged. Likelihood of relapse (which decreases with time) has an impact on the effectiveness of a screening programme, the relapse rate in this cohort was 23% in keeping with other published data. Importantly, the majority of patients had symptoms suggestive of relapse and so the screening was not required. In the few that were asymptomatic when relapse was diagnosed, there was insufficient data to know whether this earlier detection led to a better outcome, however this has not been seen in other published cohorts. Finally the effectiveness of the screening is dependent on the predictive value of the "tests" being used and this dataset shows that whilst the negative predictive value is high, the positive predictive value is very variable and generally poor for all tools used. We propose that educating the patient regarding symptoms of relapse and having patient directed clinical follow-up rather than routine appointments would lead to marked savings in health resources, reduce hospital exposure of patients by eliminating unnecessary visits without compromising the outcome of the patients. Disclosures Cunningham: Lilly: Research Funding; MedImmune: Research Funding; Merck: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Merrimack: Research Funding; Amgen: Research Funding; 4SC: Research Funding; Clovis Oncology: Research Funding; Sanofi: Research Funding; OVIBIO: Membership on an entity's Board of Directors or advisory committees. Iyengar:Beigene: Consultancy; Janssen: Honoraria; Abbvie: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau. El-Sharkawi:Abbvie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Innate: Consultancy.

Introduction: Patients with leukemic indolent B-cell Non-Hodgkin Lymphomas (LI B-NHL) that do not easily fall into a distinct pathological category with standard diagnostics can pose a challenge as their optimal management is uncertain. Lack of a clear diagnostic label can deny patients access to novel therapies as regulatory approval of drugs is largely granted within histological categories. Moreover, these patients may be excluded from participation in clinical trials. We report findings from a prospective study evaluating targeted next generation sequencing (NGS) of circulating malignant B-cells in this setting. Methods: Over a period of 4 years, 108 patients with LI B-NHL, deemed unclassifiable on standard peripheral blood (PB) diagnostics, were prospectively enrolled from 14 centres around the UK including ours. Patients with non-clonal lymphocytosis, confirmed CLL-type MBL, CLL (Matutes score 4 or 5), MCL, HCL, high grade lymphoma on standard PB diagnostics were excluded. Clinical and morphological characteristics were analysed. PB immunophenotyping was used for characterisation including ROR1 expression. CD15+ cells were positively selected with magnetic beads for germline DNA. Tumor-germline pairs were analysed with theEuroclonality-NGS DNA capture panel, and ARResT/Interrogate and complementary pipelines, to characterise clonal immunoglobulin rearrangements, translocations and somatic mutations (Stewart et al. ASH annual meeting 2019). Germline variants were subtracted to improve somatic mutation detection. Results: Median age was 72yrs with M:F ratio of 2:1. Incidental lymphocytosis on a routine blood count was the commonest mode of presentation with only a third of patients symptomatic at presentation. Median lymphocyte count was 12.4 x 109/L at the time of sampling. Just under 50% of cases had partial or complete CD5 expression, CD19 and 20 expression was moderate to strong in most cases while ROR1 was negative in most cases. NGS was able to assign a diagnostic category in 11/90 (12%) cases based on detection of IGH;CCND1 (6), IGH;BCL2 (2), IGH;BCL3 (2) translocations and in one case a BRAF mutation with confirmation of hairy cell leukaemia on immuno-morphology. These tests were not triggered by standard diagnostic pathways at initial presentation. Two novel translocations of uncertain significance were detected - RAD51B:BIRC3 and IGHMswitch-MICALL2/INTS1. Clonal IGHV-IGHD-IGHJ rearrangements were detected by NGS and/or Sanger sequencing with predominantly IGHV3 and IGHV4 gene usage, IGHV4-34 being the most common with 15 cases. The majority of rearrangements showed somatic hypermutations above 2% and none could be assigned to the 19 major CLL-associated stereotyped subsets (using ARResT/AssignSubsets). Somatic mutations were detected in 74/108 cases. The most frequently mutated genes were TP53 in 16/108 (15%) and the hotspot MYD88 L265P mutation in 14/108 (13%) with VAF of 20-46%. Other variants detected were distributed among genes associated with NFkB signalling and chromatin remodelling (Figure 1). The MYD88 L265P mutation was present in a fifth of cases with mutations detected (14/74) and was the sole change seen in 7 cases. Accompanying mutations in the remaining cases included CD79B (2), POT1 (1), NFKBIE (1). No concomitant CXCR4 mutations were detected. Median age of the MYD88 L265P cohort was 68 years with male predominance (M:F=10:4). 9/14 presented with an incidental lymphocytosis and median count of 11.18 x 109/L. Lymphadenopathy was present in 3/14 (21%) while 7/14 (50%) had splenomegaly. A paraprotein was detected in 6/14 cases (4 IgM, 1 IgG, 1 IgA). CD5 was expressed in 6/14 cases by flow cytometry. CD19 and 20 were uniformly positive, CD79b was variable and 12/14 cases tested did not express ROR1. Conclusion: This prospective study outlines the value of a targeted NGS panel in enhancing the diagnosis of unclassifiable LI B-NHL thereby improving patient access to novel therapies and clinical trials. It highlights recurrent MYD88 mutations in a subset of patients that have splenomegaly as a frequent feature. 5 year clinical follow up data, currently being gathered in both the MYD88 mutated and overall cohort, will be valuable in further characterisation and risk stratification to inform management of these patients. Disclosures Furtado: Abbvie: Other: Conference Support. El-Sharkawi:Abbvie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Innate: Consultancy. Iyengar:Abbvie: Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria; Beigene: Consultancy.

e19574 Background: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) was recognised by the WHO in 2016 as a rare sub-type of peripheral T-cell, non-Hodgkin lymphoma (NHL), characterized by an indolent clinical course and excellent prognosis. Little evidence exists on the role of post-treatment imaging surveillance with variable practices across the world. Recent UK guidelines recommend that routine surveillance imaging should not be offered to BIA-ALCL patients, in line with national/international recommendations for other NHLs. The aim of this study was to quantify the direct economic costs (DEC) of post-treatment BIA-ALCL routine radiological surveillance at our institution compared to the DEC if UK guidelines were followed. Methods: Following IRB approval a retrospective analysis of a prospectively maintained database of BIA-ALCL patients at The Royal Marsden Hospital was performed. DECs were estimated using current (2020) NHS tariffs for radiological investigations. Imaging undertaken for symptomatic problems/non-BIA-ALCL related concerns was excluded. Results: Eleven patients [median age: 49 years (IQR 45-52)] were treated for BIA-ALCL between 2015-2020 following cosmetic augmentation (n = 6) or breast reconstruction (n = 5). Median time from first implant surgery to BIA-ALCL diagnosis was 11 years (IQR 8-12). Patients presented with effusion (n = 7), mass (n = 2) or effusion and mass (n = 2). One patient had neoadjuvant CHOP/brentuximab, all 11 had explantation with en bloc total capsulectomy, 1 had adjuvant CHOP. Median follow-up was 38 months (IQR 12-47) with no local or distant relapses. Two patients did not have any radiological surveillance and 1 had follow-up elsewhere. The remaining 8 patients had a combination of PET/CT (n = 10), CT (n = 2), breast ultrasound (n = 6), mammogram (n = 4) and breast MRI (n = 1) as routine imaging follow-up not guided by clinical concerns. This represents evolving practice at our institution as the UK guidelines were published in 2021. Total cost of routine imaging surveillance was £10,396 ($14,396) with median cost of £1,953 ($2,705) per patient [IQR £526-2029 ($728-2,810)]. This cost could have been saved based on current guidelines recommending no routine surveillance for patients with no symptoms or clinical concerns. Conclusions: This data demonstrates that omission of routine post-treatment imaging surveillance, as per the recent UK guidelines, would result in a median DEC saving of £1,953 ($2,705) per patient at our institution. No local or distant relapses where identified within the follow-up period, in line with the existing literature suggesting BIA-ALCL has a very low risk of relapse and excellent prognosis. These findings provide a value-based analysis to further support the recommendation not to perform routine post-treatment imaging surveillance in patients with BIA-ALCL.

Context Richter syndrome (RS) is the occurrence of an aggressive lymphoma on a background of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). It has an incidence of 0.5-1.0%/year with overall prevalence of 2-10% in CLL/SLL. Most cases are of diffuse large B-cell lymphoma subtype (DLBCL-RS) while 5-10% are Hodgkin variant RS (HvRS). Prognosis of patients developing RS is poor with reported overall survival of 1-2 years. In this study, we report the clinical characteristic, treatment and outcome of RS in a single center over a 12-year period. Design All patients with biopsy-confirmed high-grade lymphoma with a background of CLL/SLL between 2004-2015 were identified retrospectively from the histology database of The Royal Marsden Hospital. Information was extracted from Electronic Patient Records (EPR). We analyzed CLL/SLL treatments prior to RS, RS treatment, time from CLL/SLL diagnosis to RS, TP53 disruption status (deletion or mutation), and overall survival (OS). OS was defined as the time from RS to all-cause mortality or last clinic visit. Results 41 patients were identified. The median age at RS diagnosis was 68 years (range 37-85 years) with 3:2 male preponderance. 36 cases (88%) were DLBCL-RS while 5 (12%) were HvRS. Among 30 cases with known CLL TP53 status, 40% had TP53 disruption while 60% did not. 29 patients (71%) had received CLL/SLL treatment while 12 (29%) were treatment-naive. The median time from CLL/SLL diagnosis to RS was 5 years (range 0-26 years). Among DLBCL-RS cases, 75% received R-CHOP/CHOP as first-line treatment, 8% had other regimens, and 17% received supportive care. All HvRS patients received ABVD. The median OS for RS was 16 months (range 0-146). Patients who had received ≥2 CLL/SLL treatment lines had an inferior median OS compared to Conclusion Overall survival in our RS cohort was similar to other published reports. DLBCL-RS, TP53 disruption and ≥ 2 lines of previous CLL/SLL treatment lines were associated with a worse outcome.

7501Background: Bruton tyrosine kinase (BTK) is a clinically validated target in WM. Acalabrutinib is a highly selective, potent, covalent BTK inhibitor that we evaluated in a Phase 2 study of pts ...

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive, post thymic lymphoid malignancy, with an incidence of approximately 0.1/100,000 people. T-PLL accounts for ~2% of all mature lymphocytic leukaemias in adults >30 years. Median overall survival (OS) ~20 months and long term remissions are infrequent. Intravenous alemtuzumab, a monoclonal antibody directed against CD52 remains the most effective treatment in T-PLL. At the Royal Marsden Hospital (RMH) we have been using alemtuzumab for T-PLL since the early 1990s. We describe our experience over the last 3 decades. METHODS: We included 174 T-PLL patients that were diagnosed or treated at RMH between 1989-2019. Immunophenotyping data was available through our hematological malignancy diagnostic service (HMDS) from 1998 onwards. Kaplan-Meier analysis was used for OS and disease free interval (DFI) RESULTS: There were 174 patients in total. Mean age at diagnosis was 61 years old (range 32-88) and M: F ratio was ~2:1 (113:61). 90 patients had reliable information on complete blood count (CBC) at diagnosis with median white blood cell count of 74 x 109/L (range 10-918), median hemoglobin 126 g/L (range 59-175) and median platelet count 116 x 109/L (range 7-513). Sufficient immunophenotyping data was available for analysis in 135/174 patients. The results showed predictably high expression of CD2, CD3, CD5, CD7, CD52 and TCRαβ. CD25 was positive in 67/135 (50%) of cases which is higher than the 18-35% seen in the current literature. CD4+/CD8- cases comprised 83/135 (61%) with CD4-/CD8+ 19/135 (14%), CD4+/CD8+ 32/135 (23%) and CD4-/CD8- 2/135 (2%). These results are summarized in table 1. Karyotyping/FISH (fluorescent in-situ hybridization) records showed a clonal result in 84 patients and of these 65/84 (77%) had an aberration of chromosome 14. These comprised 48/65 with inv(14), 6/65 t(14;14), 2/65 t(X;14), 1/65 TCL1 gene rearrangement by FISH and 8/65 with TRA/TRD involvement by FISH. Other frequent abnormalities seen were i(8)(q10) in 31/84 (39%) and complex karyotypic abnormality in 40/84 (48%). Lower frequency abnormalities seen were monosomy 11 in 8/84 (9%), monosomy 12 in 8/84 (9%), trisomy 8 in 6/84 (7%), 17p loss in 5/84 (6%) and mononsomy 13 in 4/84 (5%). Alemtuzumab was used in 116 patients, 69/116 (59%) receiving it as frontline treatment and 47/116 (41%) as salvage therapy. In 50/116 (43%) alemtuzumab was used as single agent, the remaining 66/116 (57%) receiving combination therapy, mostly pentostatin. Mean time from diagnosis to receiving alemtuzumab was 6.8 months (range 0-53 months). Overall response rate (ORR) to alemtuzumab was 94/116 (81%) with complete remission (CR) 69/116 (59%), partial remission (PR) 25/116 (22%) and no response (NR) 20/116 (17%). Alemtuzumab produced better response rates when used as frontline therapy. Table 2 summarizes these results and OS and DFI are shown in figures B and C. Allogeneic stem cell transplant (allo-SCT) was performed in 34 patients. Median OS post allo-SCT was 22 months and median DFI 31 months. Relapse rate post allo-SCT was 47%, non-relapse mortality 38% and transplant related mortality 29%. Figures D and E show OS and DFI post allo-SCT. Although relapse rates are high post allo-SCT there is a small cohort of patients who are achieving long term remission. We analysed OS by decade of diagnosis covering 3 decades 1990-1999, 2000-2009 and 2010-2019. The median OS for the whole cohort was 20.6 months with median OS of 21 months, 23 months and 19 months for each decade respectively. Results are shown in figure A. There was no statistically significant difference between the curves by log-rank analysis. DISCUSSION: Immunophenotyping results were similar to previous published data on T-PLL except for an increase in CD25 expression at 50%. Our data shows that outcomes in T-PLL have remained unchanged since the first decade of alemtuzumab usage, with no improvement in OS in the last 20 years. Despite improvements in diagnostic techniques and supportive care median OS is static at approximately 20 months. These results highlight the need for novel therapies in T-PLL. Given the rarity of T-PLL, international, multi-center, randomised trials are needed to improve outcomes. Disclosures Cross: Royal Marsden Cancer Charity: Other: MD Residency, Research Funding. Iyengar:Abbvie: Honoraria; Janssen: Honoraria. Dearden:Janssen: Honoraria; Genentech: Honoraria; Abbvie: Honoraria; Sanofi: Honoraria.

Introduction Since interim results from the EuroNet-PHL-C1 study1were published in 2013 showing that the gonadotoxic drug procarbazine in COPP can be safely replaced with dacarbazine (COPDac) it is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3), hoping to reduce haematopoietic stem cell and gonadal toxicity. However, published data of 'escalated BEACOPDac (eBPDac)' regimen are very limited. Methods We collected retrospective data from 15 centres in the UK, Ireland and France, that offer eBPDac therapy for first line advanced stage Hodgkin Lymphoma, and compared outcomes with matched patients treated with eBPP at 4 UK centres. Most patients were treated as per HD15 or HD18 protocol. The 24 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD. Results From 2009, 141 patients were managed first line with either eBPP (n=52) or eBPDac (n=89) with median follow-up 40 months for eBPP and 12.7 months for eBPDac patients. Patients were well matched with no significant differences in age (median: 28), sex, stage (stage 3/4: 82%) and international prognostic score (IPS3+:65%). More patients treated with eBPDac received only 4 cycles of treatment (43% vs 12%; p Toxicity was compared over the first 4 cycles. There was no difference in day 8 ALT between the two regimens although the mean day 8 neutrophil count was lower in eBPDac than eBPP patients (1.84 vs 2.35; p=0.043; G-CSF given day 9). There was a trend to fewer non-elective days of in-patient care for eBPDac compared with eBPP (mean: 2.78 vs 6.00; p=0.0846), and eBPDac patients received fewer red cell transfusions during cycles 1 to 4 compared with eBPP patients (Mean 1.87 units vs 4.33 units; p 6 months post chemotherapy follow-up had a similar rate of return of menstrual cycles (eBPP: 20/21; eBPDac: 13/16), although eBPDac patients appeared to restart menstruation earlier post chemotherapy completion (mean: 3.85 months vs 8.65 months, p=0.0018). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.67; p Conclusions Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP in frontline therapy of patients with advanced Hodgkin Lymphoma and may have some toxicity benefits. As it is highly unlikely that this single drug substitution will ever be tested in a prospective trial, publishing real-world data from eBPDac patients is important. References 1. EuroNet-PHL-C1 study interim report published 14/08/2013 http://www.anzchog.org/docs/public-resources/euronet-recommendation.pdf?sfvrsn=0 2. Borchmann P et al. 2018;390:2790-2802 Disclosures Brice: BMS: Honoraria; Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding. Menne:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Osborne:Novartis: Other: Travel; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy; MSD: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Gilead: Consultancy; Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau. Ardeshna:Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Collins:Gilead: Consultancy, Honoraria. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau. Iyengar:Takeda: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Roche: Honoraria. Martinez-Calle:ABBVIE: Other: Travel support. McKay:Epizyme: Consultancy, Honoraria. Nagumantry:Takeda: Honoraria, Speakers Bureau; Alexion: Speakers Bureau; Abbvie: Honoraria. Shah:Abbvie: Consultancy. Uttenthal:Roche: Honoraria; Takeda: Honoraria; Jazz: Honoraria. McMillan:BMS: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Sandoz: Honoraria; Celgene: Honoraria, Speakers Bureau; Novartis: Honoraria; Gilead: Honoraria; MSD: Honoraria; Pfizer: Honoraria, Research Funding. Follows:Roche: Consultancy, Honoraria, Speakers Bureau; AZ: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau.

Introduction: Predicting the risk of histologic transformation (HT) from indolent follicular lymphoma (FL) to a more aggressive form of lymphoma represents a major challenge in managing patients with FL. We assessed the incidence of HT in the GALLIUM study (NCT01332968) and determined risk factors for transformation and impact on clinical outcomes. Methods: In the Phase III GALLIUM study, patients with previously untreated FL were randomized to receive either the anti-CD20 antibody rituximab (R; 375mg/m² on Day (D) 1 of each cycle) or obinutuzumab (G; 1000mg on D1, 8, and 15 of Cycle 1 and D1 of subsequent cycles) in combination with chemotherapy (CHOP, CVP or bendamustine). Patients who achieved at least a partial response at the end of induction therapy proceeded to maintenance therapy with the same antibody, every 2 months for 2 years, or until progression of disease. Repeat biopsies at progression were not mandatory but carried out in case of clinical suspicion of HT. The rate of HT, as assessed by the local pathologist, in patients with a repeat biopsy at the time of disease progression/relapse was an exploratory endpoint. Results: 1202 patients were enrolled. After a median follow up of 57.3 months, 315 (26.2%) patients progressed (median time to relapse, 25.3 months); of these 315 patients, 46 (14.6%) had a biopsy at first progression due to a clinical suspicion of transformation. Forty patients, corresponding to 3.3% of all patients enrolled in GALLIUM and 12.7% of those that progressed, had biopsy-confirmed HT. Among 153 patients with disease progression within 24 months (POD24), 31/153 (20.3%) had HT. Fewer patients transformed in the G-chemo arm (16/40; 40%) compared with R-chemo (24/40; 60%). In total, 116 patients relapsed in the G-chemo arm versus 159 in the R-chemo arm. Compared with no HT, patients with HT were more likely to be male and have bone marrow involvement, stage 3A FL, high FL International Prognostic Index risk, low hemoglobin (Hb), elevated serum lactate dehydrogenase (LDH), elevated beta-2-microglobulin, and high total metabolic tumor volume (Table). A comparison of chemotherapy backbones showed a trend towards higher HT incidence with bendamustine (5.8% [26/686]) compared with CVP, 4.3% (5/117) and CHOP, 2.3% (9/399). A multivariate cause-specific cox model identified several risk factors for HT, including elevated LDH levels (hazard ratio [HR], 4.27 [95% CI: 2.08─8.78]; p Conclusions: In GALLIUM, a low rate of HT was observed over 5 years, with the majority occurring within the first 2 years. Patients with POD12 had poor OS regardless of whether transformation occurred or not. Risk factors for HT included elevated LDH, anemia, and male gender. Patients with HT, especially those with progression of disease within 24 months, had poor OS compared to patients who relapsed with persistent FL. Disclosures Casulo: Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Herold:Roche: 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; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Hiddemann:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria. Iyengar:Roche: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Marcus:Roche / Genentech: Honoraria, Speakers Bureau; Gilead: Consultancy. Seymour:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy; Acerta: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding. Launonen:F. Hoffmann-La Roche Ltd: Employment. Knapp:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mir:Roche: Other: Previous employment.

Mantle cell lymphoma (MCL) is a clinically heterogeneous, but often aggressive lymphoma characterized by the IGH:CCND1 translocation and cyclin D1 (CCND1) over‐expression. Chromosomal instability, due to disrupted DNA damage response, in conjunction with abnormal activation of cell survival mechanisms underlies the aggressive clinical course in MCL (Jares et al, 2012). In recent years, improved understanding of lymphoma biology has led to the development of a number of small molecule inhibitors. However, the relative rarity of MCL (incidence 0·55 per 100 000) (Smedby & Hjalgrim, 2011) poses a challenge in effectively evaluating these drugs in patients. In vitro studies have been limited by the difficulty of culturing primary MCL cells. Murine models of MCL cell lines are relatively easy to establish in SCID or NOD/SCID/IL2Rγ null (NSG) mice (Wang et al, 2007, 2008a; Weston et al, 2010) but have their limitations. Until a couple of years ago, the only primary mouse model of human MCL described in the literature was established by injection of primary MCL cells into subcutaneous human bone grafts implanted in SCID mice (SCID‐Hu model) (Wang et al, 2008b). Recently, however, disseminated models of human primary MCL have been established in NSG mice (Iyengar et al, 2012; Klanova et al, 2014). We report our experience here in further detail, focussing on the characteristics of MCL engraftment in this model. We used 8‐ to 12‐week‐old NSG mice that were sub‐lethally irradiated (3·75 Gy) 24 h prior to transplantation. Before undertaking xenograft studies with primary cells, we used the MCL cell line JEKO‐1 to assess kinetics, disease burden and distribution of MCL cells in NSG mice. JEKO‐1 cells were transduced with firefly luciferase and injected intravenously into irradiated mice at two doses – 0·5 × 106 and 2 × 106 cells. Bioluminescent imaging was performed at weekly intervals following injection of D‐luciferin. All mice became ill with marked weight loss and had to be sacrificed by day 29. Bioluminescence was observed in the bone marrow and spleen in all mice. Mice injected with the higher cell dose had more rapid disease progression, developed hind leg weakness and had bioluminescence in the central nervous system (CNS) on imaging, indicating involvement (Fig 1). Figure 1 Longitudinal quantitative analysis of bioluminescent imaging (BLI): NSG mice were injected intravenously with the JEKO‐1 cell line transduced with luciferase (Luc) reporter constructs. (A) Representative dorsal view (upper panels) and ventral ... Following this, seven cryopreserved primary MCL samples were identified from the Barts Cancer Institute tissue bank. An additional fresh primary sample derived from a splenectomy was included in the cohort. Ethical approval was obtained from East London and the City Local Research Ethics Committee. Written informed consent was obtained from patients according to the Declaration of Helsinki. All samples had a classical MCL phenotype with CD5/CD20 positivity and were confirmed to have the IGH:CCND1 translocation by fluorescence in situ hybridization (FISH). Irradiated NSG mice were injected intravenously with a dose of 107 unselected MCL cells each. Flow cytometry was performed for mouse CD45 and human CD45, CD3, CD5 and CD20 on peripheral blood samples taken from mice at 3, 6 and 12 weeks. Mice were sacrificed at 20 weeks, or earlier if they met Home Office guidelines, and tissue was harvested for immunohistochemistry (IHC). Cells were flushed from mouse femur for flow cytometry. At 20 weeks, MCL cells were found in the bone marrow and spleen of mice injected with 2 out of the 7 cryopreserved primary samples. Both samples that engrafted had blastoid morphology and one was obtained from a patient with relapsed disease. FISH for IGH:CCND1 on cell suspensions prepared from spleen of NSG mice further confirmed engraftment. None of the mice that engrafted appeared to have bowel involvement as assessed by IHC. Lymphadenopathy was not found at sacrifice. Scattered human CD20‐positive cells were seen in the liver but this was not a consistent feature. Mice remained relatively well until sacrifice (Fig 2A–F). As a next step, secondary transplantation of MCL cells isolated from NSG spleen (107 cells per mouse) was undertaken. Once again, engraftment was seen in mouse spleen and bone marrow on sacrifice at 20 weeks (Fig 2G). Figure 2 Engraftment of human primary mantle cell lymphoma (MCL) in NSG mice: T‐cell depleted human primary mononuclear cells were injected intravenously at a dose of 107 cells per mouse. Peripheral blood was sampled from mice at 3, 6 and 12 weeks, ... In addition to the two cryopreserved samples, evidence of engraftment was also seen in the spleen of NSG mice injected with the fresh primary sample (non‐blastoid). Interestingly, there appeared to be co‐existence of MCL cells and T‐cells in the spleen of mice injected with fresh MCL cells, with tumour cells concentrated around blood vessels. However, these mice had to be sacrificed at 7 weeks due to illness and T‐cell infiltration was found in the liver and bone marrow, without evidence of MCL. We found a similar proliferation of T cells but without evidence of MCL in one of the seven cryopreserved samples that had high T‐cell content (>10%), indicating T‐cell depletion may be important in this scenario. Therefore, similar to the recent report by Klanova et al (2014), we demonstrate human primary MCL engraftment in NSG mice. In contrast to their study where mice were injected with a variable cell dose (1–8 × 107 cells), we injected all mice with a fixed dose of 107 cells. This may explain the lower rate of engraftment in our study. Both cryopreserved samples that engrafted in our study had blastoid morphology, suggesting that a higher cell dose may be required for engraftment of non‐blastoid MCL in this model. In our experiments, mice with primary MCL engraftment were not visibly ill at 20 weeks and disease burden was heaviest in the spleen. In contrast, disease progression was rapid in the JEKO‐1 xenograft, with CNS involvement and hind leg weakness developing by 4 weeks. These findings mirror those of Klanova et al (2014), and are important considerations when designing pre‐clinical experiments involving these models. The longer overall survival of NSG mouse models of primary human MCL could be an advantage for pre‐clinical testing of newer agents, which often require longer periods of administration for efficacy. Finally, our study demonstrates, similar to the findings of Klanova et al (2014), that secondary transplantation can be successfully carried out in this model, highlighting the self‐renewal and tumour‐initiating capacity of primary MCL cells. In summary, this NSG model of human primary MCL is a promising in vivo model for both pre‐clinical drug testing and further understanding MCL biology. Our research provides further insight into the advantages and limitations of this model, which will be crucial for its effective use in pre‐clinical research.

The accurate detection and precise assessment of therapeutic responses is critical to the optimal management of patients with lymphoma. Over the past 50 years, dramatic advances in technology have established imaging as the cornerstone of disease evaluation. However, the appropriate application of current techniques requires acknowledgement of their strengths and weaknesses, and appreciation of the full diversity of lymphoid neoplasms. The role of anatomical and functional imaging in detection, treatment escalation/de-escalation and prognostication of patients with lymphoma can be misinterpreted. The development of disease assessment criteria, without an appreciation of the limitations of current imaging technologies, reflects a potential overreach of imaging science. Furthermore, the introduction of various novel therapies adds to the complexity of disease monitoring. In this Perspectives, the authors evaluate the available evidence in this rapidly evolving field and propose a reporting framework, named 'Specialist Integrated Haematological Malignancy Imaging Reporting' (SIHMIR), with a goal of providing a robust and adaptable system for lymphoma assessment. We predict a future model of multimodal disease assessment using novel molecular and imaging techniques, and highlight the key outstanding research questions in this field.

Introduction: Primary mediastinal B Cell Lymphoma (PMBL) is a high-grade non-hodgkin lymphoma with distinct clinical and biological features. Optimal chemotherapy for this lymphoma is not established but some centres favour more intensive regimes such as DA EPOCH-R over R-CHOP. The role of consolidation radiotherapy is yet to be clarified and whether it can be omitted in those patients with a negative end-of-treatment PET scan (EOT PET) regardless of induction chemotherapy. Furthermore, the occurrence of false positive EOT PET scans may lead to overtreatment. The aim of this study was to establish the outcomes of patients (pts) with PMBL who had been treated in a single centre. Methods: Pts diagnosed with PMBL between 2003 and 2015 in Royal Marsden Hospital were included. Data was collected from electronic patient records and PET CT images review. Survival was defined from date of diagnosis until date of death or date of last follow up. Results: Thirty-four pts were identified with characteristics as shown in the table. Median diameter of the mediastinal mass was 12cm (range 5.5 - 24cm); 25 (74%) pts had a mass of ≥ 10cm. The majority of pts received R-CHOP chemotherapy (2 had 14 day cycles, 30 had 21 day cycles), 1 R-GCVP and another R-PACEBOM. Median number of cycles of chemotherapy was 6 (range 1-8). Seven out of 32 (22%) pts received involved field radiotherapy (IFRT). EOT PET was available for 30 pts. Median time to obtaining EOT PET from completion of chemotherapy was 31 days (20-81). Twenty-three out of 30 pts had EOT PET negative disease with a Deauville score (DS) of 1-3. Twenty-one of these 23 pts did not receive IFRT. Two of these 21 pts relapsed in the mediastinum and were treated with salvage chemotherapy followed by autologous stem cell transplant (ASCT) of whom 1 died due to their lymphoma. The 2 patients who received consolidation radiotherapy remain in remission. Seven out of 30 pts had a positive EOT PET (DS 4-5); of whom 5 received IFRT. Two out of 5 patients relapsed and proceeded with further chemotherapy of whom 1 died due to treatment-related causes while the other 4 patients were alive at time of last follow-up. Two pts with a positive EOT PET did not have IFRT, 1 proceeded with salvage chemotherapy but died due to lymphoma and the other patient was followed up with serial PET scans and ultimately the residual avidity was considered to be due to thymic hyperplasia. Conclusion: Our analysis demonstrates that for the 23 patients who achieved a complete metabolic response on EOT PET the risk of relapse was low (9%) (despite that only 2 patients received consolidation radiotherapy) and only one patient (4%) died of lymphoma. Thus the majority of patients with a negative EOT PET scan following R-CHOP chemotherapy may not need consolidation radiotherapy. This finding should be taken into account when considering the risk/benefit of adding radiotherapy treatment to patients who are already in metabolic CR after chemotherapy. Consolidation radiotherapy is currently being investigated in a prospective IELSG37 trial, NCT01599559. Table. Table. Disclosures Chau: Eli-Lilly: Honoraria, Other: Advisory Board, Research Funding; Bristol Meyers Squibb: Other: Advisory Board; MSD: Other: Advisory Board; Bayer: Other: Advisory Board; Roche: Other: Advisory Board; Merck Serono: Other: Advisory Board, Research Funding; Five Prime Therapeutics: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Janssen-Cilag: Research Funding; Sanofi Oncology: Research Funding. Cunningham:Roche pharmaceuticals: Research Funding.

Phosphoinositide-3 kinase (PI3K) pathway activation contributes to mantle cell lymphoma (MCL) pathogenesis, but early-phase studies of the PI3K p110δ inhibitor GS-1101 have reported inferior responses in MCL compared with other non-Hodgkin lymphomas. Because the relative importance of the class IA PI3K isoforms p110α, p110β, and p110δ in MCL is not clear, we studied expression of these isoforms and assessed their contribution to PI3K signaling in this disease. We found that although p110δ was highly expressed in MCL, p110α showed wide variation and expression increased significantly with relapse. Loss of phosphatase and tensin homolog expression was found in 16% (22/138) of cases, whereas PIK3CA and PIK3R1 mutations were absent. Although p110δ inhibition was sufficient to block B-cell receptor-mediated PI3K activation, combined p110α and p110δ inhibition was necessary to abolish constitutive PI3K activation. In addition, GDC-0941, a predominantly p110α/δ inhibitor, was significantly more active compared with GS-1101 against MCL cell lines and primary samples. We found that a high PIK3CA/PIK3CD ratio identified a subset of primary MCLs resistant to GS-1101 and this ratio increased significantly with relapse. These findings support the use of dual p110α/p110δ inhibitors in MCL and suggest a role for p110α in disease progression.

International audience; BACKGROUND: The first-in-class small molecule inhibitor OTX015 (MK-8628) specifically binds to bromodomain motifs BRD2, BRD3, and BRD4 of bromodomain and extraterminal (BET) proteins, inhibiting them from binding to acetylated histones, which occurs preferentially at super-enhancer regions that control oncogene expression. OTX015 is active in haematological preclinical entities including leukaemia, lymphoma, and myeloma. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results from a cohort of patients with lymphoma or multiple myeloma (non-leukaemia cohort). METHODS: In this dose-escalation, open-label, phase 1 study, we recruited patients from seven university hospital centres (in France [four], Switzerland [one], UK [one], and Italy [one]). Adult patients with non-leukaemia haematological malignancies who had disease progression on standard therapies were eligible to participate. Patients were treated with oral OTX015 once a day continuously over five doses (10 mg, 20 mg, 40 mg, 80 mg, and 120 mg), using a conventional 3 + 3 design, with allowance for evaluation of alternative administration schedules. The primary endpoint was dose-limiting toxicity (DLT) in the first treatment cycle (21 days). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity of OTX015. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01713582. FINDINGS: Between Feb 4, 2013, and Sept 5, 2014, 45 patients (33 with lymphoma and 12 with myeloma), with a median age of 66 years (IQR 55-72) and a median of four lines of prior therapy (IQR 3-5), were enrolled and treated. No DLTs were observed in the doses up to and including 80 mg once a day (first three patients). We then explored a schedule of 40 mg twice a day (21 of 21 days). DLTs were reported in five of six patients receiving OTX015 at this dose and schedule (all five patients had grade 4 thrombocytopenia). We explored various schedules at 120 mg once a day but none was tolerable, with DLTs of thrombocytopenia, gastrointestinal events (diarrhoea, vomiting, dysgeusia, mucositis), fatigue, and hyponatraemia in 11 of 18 evaluable patients. At this point, the Safety Monitoring Committee decided to establish the feasibility of 80 mg once a day on a continuous basis, and four additional patients were enrolled at this dose. DLTs (grade 4 thrombocytopenia) was noted in two of the patients. In light of these DLTs and other toxicities noted at 120 mg, the dose of 80 mg once a day was selected, although on a schedule of 14 days on, 7 days off. Common toxic effects reported in the study were thrombocytopenia (43 [96%] patients), anaemia (41 [91%]), neutropenia (23 [51%]), diarrhoea (21 [47%]), fatigue (12 [27%]), and nausea (11 [24%]). Grade 3-4 adverse events were infrequent other than thrombocytopenia (26 [58%]). OTX015 plasma peak concentrations and areas under the concentration versus time curve increased proportionally with dose. Trough concentrations increased less than proportionally at lower doses, but reached or exceeded the in-vitro active range at 40 mg twice a day and 120 mg once a day. Three patients with diffuse large B-cell lymphoma achieved durable objective responses (two complete responses at 120 mg once a day, and one partial response at 80 mg once a day), and six additional patients (two with diffuse large B-cell lymphoma, four with indolent lymphomas) had evidence of clinical activity, albeit not meeting objective response criteria. INTERPRETATION: The once-daily recommended dose for oral, single agent oral OTX015 in patients with lymphoma is 80 mg on a 14 days on, 7 days off schedule, for phase 2 studies. OTX015 is under evaluation in expansion cohorts using this intermittent administration (14 days every 3 weeks) to allow for recovery from toxic effects. FUNDING: Oncoethix GmbH (a wholly owned subsidiary of Merck Sharp & Dohme Corp)

Abstract 1565 Background: The relatively low incidence of MCL (0.55 per 100,000) poses a challenge for effective evaluation of novel therapies in patients affected by this aggressive and incurable lymphoma. A xenograft model of human MCL provides a useful model for pre-clinical evaluation of novel drugs, rational drug combinations and biomarkers. The only mouse xenograft model of primary human MCL reported was established by injecting CD19 selected PBMCs in a subcutaneously implanted human embryonic bone graft in SCID mice and SCID mice without subcutaneous bone grafts did not show engraftment. NOD/SCID/IL2Rγ chain null (NSG) mice, which lack mature T or B cells and are also deficient in NK cells, permit engraftment of a wider range of primary human cells compared to SCID mice. In view of recent reports of successful engraftment of human CLL in NSG mice, we hypothesised that primary human MCL can be established in these mice. Methods: We initially introduced luciferase transduced Jeko-1 cells at 2 concentrations – 0.5 and 2 million cells by tail vein injection of 8 to 12 week old γ-irradiated (3.75 Gy) NSG mice in an attempt to track the kinetics and distribution of MCL cells. Bioluminescent imaging (BLI) following injection of luciferin was performed weekly for 4 weeks. We then injected NSG mice (4 replicates) with 107, T-cell depleted, previously cyropreserved human MCL cells from 3 patients. Mice were bled at 3, 6 and 12 weeks and flow cytometry was performed on PBMCs for human CD45, CD5 and CD20. Mice were sacrificed at 20 weeks and immunohistochemistry (IHC) for human CD20 and cyclin D1 was performed on formalin fixed paraffin embedded spleen, ileo-caecal junction and liver while FACS for human CD45, CD5 and CD20 was performed on bone marrow cells flushed from the femur. Tissues harbouring CD20 and cyclin D1 positive cells were stained with Ki-67 to assess proliferation and FISH for t(11;14) was performed on fresh cells isolated from the spleen to further confirm engraftment. Results: NSG mice injected with Jeko-1 cells showed rapid engraftment at both concentrations (0.5 and 2 million) on assessment with BLI, with a more rapid progression after 3 weeks in mice injected with 2 million cells. Mice had to be sacrificed at 4 weeks because of illness. Bioluminescence was seen primarily in the bone marrow, spleen and along the spine. Consistent engraftment was also seen in all mice injected with sample 1 - PBMCs from a patient in 1st relapse with blastoid morphology, classic immunophenotypic features and the IgH:CCND1 translocation. CD5 and CD20 double positive cells were consistently detected at 6 and 12 weeks in the peripheral blood of all 4 mice examined. Mice were not visibly ill at 20 weeks but had gross splenomegaly at sacrifice. No lymph node or abdominal masses were found. A clear human CD5/CD20 population was found on flow cytometry of bone marrow cells. The splenic architecture was disrupted in mice that engrafted, compared to those that did not and a heavy infiltration of CD20 and cyclin D1 positive cells was found with proliferation estimated at 35–40% by Ki-67 staining. Interphase FISH on fresh cells derived from the spleen showed the IGH/CCND1 [t(11;14)] rearrangement in all cells examined. Scattered CD20 positive cells were observed in the liver but no polyps or submucosal infiltration was found in the ileo-caecal regions of these mice. NSG mice injected with samples 2 and 3 had no evidence of engraftment in peripheral blood, bone marrow or other tissues. Conclusion: Our studies demonstrate that a mouse model of human MCL can be established in NSG mice and are encouraging for developing this model for pre-clinical evaluation of novel drugs. The lymphoma cells that engrafted were from a patient with relapsed, blastoid MCL suggesting that a more aggressive phenotype may favor engraftment as seen with AML xenografts in NSG mice. Ongoing studies are examining additional patient samples and the need for T cell depletion. This model will also provide an opportunity to investigate the role of tumor-initiating side populations in this disease. Disclosures: Gribben: Celgene: Honoraria; Roche: Honoraria; Pharmacyclics: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria.

Abstract 1654 Background: Mantle cell lymphoma (MCL) is an incurable, aggressive subtype of non-Hodgkin lymphoma in which there is a need for novel targeted therapies. Activation of the PI3K-Akt pathway and its role in the pathogenesis of MCL has been highlighted in a number of studies. Constitutive activation of the PI3K pathway inactivates GSK-3β, a downstream target of Akt, that can phosphorylate cyclin D1 resulting in its nuclear export. There is also evidence that cyclin D1 mRNA stability and translation is enhanced by this pathway. The class Ia PI3K p110 catalytic subunit isoforms α, β and δ are primarily implicated in oncogenesis. While the PI3K p110δ isoform is known to be enriched in lymphocytes, a gain of PIK3CA (the gene encoding PI3K p110α) copy number has been shown to be a frequent alteration in MCL. The expression and relative importance of the individual Class Ia PI3K isoforms has not been documented in this disease. With the development of isoform selective inhibitors, this is an important issue that needs to be addressed. Aims: We studied the expression of class Ia PI3K isoforms in primary MCL with relation to morphological variants and disease status. We also compared the efficacy of PI3K inhibition in MCL cell lines and primary samples using two novel inhibitors, GDC-0941(predominantly p110α/δ-selective) and CAL-101 (δ-selective), both of which are in early phase clinical trials. Methods: Tissue microarrays were constructed from triplicate 1mm cores from 144 MCL biopsies and 16 tonsil controls. The levels of p110α, p110β and p110δ isoforms were then determined by immunohistochemistry using isoform-specific antibodies. The in vitro effect of PI3K inhibitors on cell viability and apoptosis was studied in 4 MCL cell lines, (Jeko-1, Granta519, REC-1 and JVM-2), and 15 primary MCL samples. Expression of the class Ia PI3K isoforms and changes in downstream targets of PI3K were determined by western blotting. Results: P110δ was expressed at a consistently higher level in MCL samples and normal tonsil controls compared to the α and β isoforms, while p110β expression was weak and significantly lower than p110α expression. On comparing expression of isoforms at diagnosis and relapse, p110α expression was significantly increased beyond 1st relapse compared to diagnostic biopsies (p=0.04) and tonsil controls (p=0.02), an observation that was even more apparent in 6 paired samples [p=0.008, median IHC score 19.6 (5.0−53.2) at diagnosis vs. 91.5 (38.6 − 129) beyond 1st relapse]. No significant change was found in the expression of p110β or p110δ between diagnostic and relapse samples. There was no significant difference in expression levels of the 3 isoforms between blastoid and non-blastoid morphological variants. Expression of both the p110α and δ isoforms was detected by western blotting in 4 MCL cell lines, but only Jeko-1 cells were sensitive to inhibition with GDC-0941. CAL-101 produced little or no apoptosis in all 4 cell lines. In primary MCL samples, GDC-0941 was consistently more potent than CAL-101, with decrease in cell viability of 32 vs. 20% at 1μM (p=0.15), 51 vs. 25% at 5μM (p=0.02) and 67 vs. 35% at 10μM (p Conclusion: Our studies demonstrate that although p110δ is the most consistently expressed isoform, the expression of the p110α subunit increases significantly in multiply relapsed MCL. This observation, in combination with significantly greater in vitro sensitivity of MCL primary samples to GDC-0941, compared to the p110δ-selective inhibitor CAL-101, provides strong evidence for further evaluation of GDC-0941 in this disease. Disclosures: Gribben: Roche: Honoraria; Celgene: Honoraria; GSK: Honoraria; Mundipharma: Honoraria; Gilead: Honoraria; Pharmacyclics: Honoraria. Joel:Astra Zeneca: Research Funding; Intellikine: Research Funding.

We read with interest on the above case report by Khera et al (Hospital Medicine, 66(4): 246). We wish to highlight that there appears to be an error on the colonoscopic pictures showing faecaloma.