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OBJECTIVE To evaluate the effectiveness and safety of prothrombin complex concentrates (PCCs) in approved and off-label indications. BACKGROUND PCCs are approved for the urgent reversal of vitamin K antagonists (VKAs). Data concerning the efficacy, safety and dosing for off-label indications are limited, but they are included in massive bleeding protocols. METHODS This was a retrospective review of cases treated with four-factor PCCs (4F-PCCs) between January 2009 and 2016. Efficacy end-points include: (i) VKA reversal efficacy assessed by international normalised ratio (INR) normalisation (

Introduction: Venetoclax (VEN) based therapy has become a standard of care in front line and relapsed-refractory (R/R) CLL based on favorable efficacy and toxicity. Whereas prospective data regarding activity of therapies following ibrutinib (IBR) or idelalisib (IDE) are available in the settings of progression (VEN, non-covalent BTKi) and intolerance (acalabrutinib), how best to manage patients (pts) who discontinue (dc) VEN remains a key unanswered question. With the increased use of VEN in early lines of therapy (LOT; CLL 14, MURANO), the activity of BTK inhibitors (BTKi) and cellular therapies following VEN becomes a critical issue. No prospective study has addressed this question, and currently reported VEN clinical trials have limited information about subsequent treatments. While recent data describe VEN resistance mechanisms (Guieze 2018, Blombery 2019), the impact of VEN resistance on efficacy of post VEN therapies is unknown. To address this gap, we conducted an international study to identify a large cohort of pts who dc VEN and have been subsequently treated. Methods: We conducted an IRB approved multicenter (31 US, EU, South American sites, in partnership with UK CLL Forum and CORE registry), retrospective cohort study of CLL pts who dc VEN for any reason. We examined demographics, dc reasons, responses, survival, adverse events (AEs) and activity of post VEN therapies. Primary endpoints were overall response rate (ORR) and progression free survival (PFS) for the post VEN treatments stratified by treatment type (BTKi, PI3Ki and cellular therapy: CAR-T or alloHSCT). ORR was defined by iwCLL criteria and PFS was defined from VEN dc to disease progression (PD), death, or last follow up for next treatment. Pts were further stratified by BTKi (resistant / intolerant) and PI3Ki exposure prior to VEN. PFS-2 was defined as time from VEN start to tumor progression on IBR or death from any cause. Results: 326 CLL pts who dc VEN in the front line (4%) and R/R settings (96%) were identified. The cohort was 69% male, 87% white, median (med) age 66 (38-91) at VEN start, 27% treated with VEN based combinations (n=88, med 6 cycles anti-CD20 abs). Pre VEN prognostic features: 82% IGHV unmutated (n tested=166), 47% del17p (n=306), 45% TP53 mut (n=217), 39% complex karyotype (n=273), 23% BTK mut (n=79), 18% NOTCH1 mut (n=103), 10% PLCγ2 mut (n=74). Pts received med 3 therapies (0-11) prior to VEN; 40% were BTKi naïve (n=130), 60% were BTKi exposed (196) and 81% were IDE naïve (n=263). Most common reasons for VEN dc were PD (38%), AE (20%), Richter's transformation (RT, 14%), 8% pt preference, and HSCT 5%. Of 326 pts who dc VEN, 188 (58%) were treated with a subsequent LOT, 61 are alive and untreated and 77 died prior to a subsequent LOT. Post VEN sequencing analyses focused on BTKi, PI3Ki and cellular therapy (CAR-T or alloHSCT) activities following VEN dc (Table1). ORR to BTKi was 84% (n=44) vs. 54% (n=30, p Conclusions: In the largest experience of therapies following VEN dc in CLL, we demonstrated that therapy selection following VEN requires consideration of prior novel agent exposure and reasons for discontinuation. For BTKi naïve pts, selection of a covalently binding BTKi results in high ORR and durable remissions. PFS-2 data provide reassurance for using VEN prior to IBR. For BTKi exposed pts, BTK inhibition is not effective in the setting of BTKi resistance but should be considered if prior BTKi intolerance. PI3K inhibition following VEN does not appear to result in durable remissions even in PI3Ki naïve pts, suggesting possible overlap in resistance mechanisms (BTK or VEN with PI3K). We conclude that BTKi in naïve or previously responsive pts and alloHSCT following VEN appear to be the most effective strategies with durable responses. These data suggest that a number of effective regimens exist for post VEN pts, providing support for VEN use earlier in the course of CLL. Disclosures Mato: Acerta: Consultancy; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Janssen: Consultancy; Gilead: Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Celgene: Consultancy. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Eyre:Gilead: Consultancy, Other: Research support, Speakers Bureau; Roche: Honoraria; Abbvie: Honoraria, Other: Travel to Conferences; Janssen: Honoraria, Other: Travel to Conferences ; Takeda: Other: Travel to Conferences . Jacobs:Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; JUNO: Consultancy; Gilead: Consultancy; TG Therapeutics: Honoraria, Research Funding. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Brander:Tolero: Research Funding; MEI: Research Funding; BeiGene: Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Acerta: Research Funding. Shadman:AbbVie: Consultancy, Research Funding; Astra Zeneca: Consultancy; BeiGene: Research Funding; TG Therapeutic: Research Funding; ADC Therapeutics: Consultancy; Atara Biotherapeutics: Consultancy; Verastem: Consultancy; Acerta Pharma: Research Funding; Sunesis: Research Funding; Mustang Bio: Research Funding; Celgene: Research Funding; Pharmacyclics: Consultancy, Research Funding; Sound Biologics: Consultancy; Genentech: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Ujjani:AstraZeneca: Consultancy; Genentech: Consultancy; Rigel: Consultancy; Gilead: Consultancy; Abbvie: Research Funding; Pharmacyclics: Research Funding. Perini:Janssen: Other: Advisory Board; Abbvie: Other: Advisory Board; AstraZeneca: Other: Advisory Board. Pinilla Ibarz:Sanofi: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy. Barrientos:Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Consultancy; Genentech: Consultancy. Skarbnik:Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Acerta: Research Funding. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Choi:Abbvie: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy, Research Funding; Gilead: Consultancy, Speakers Bureau; Oncternal: Research Funding. Coombs:H3 Biomedicine: Research Funding. Barr:Janssen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Merck: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Celgene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy. Portell:Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Schuster:AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Loxo Oncology: Honoraria; Pfizer: Honoraria; Nordic Nanovector: Honoraria; Pharmacyclics: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; Merck: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Martinez-Calle:ABBVIE: Other: Travel support. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Nabhan:Aptitude Health: Employment. King:Astrazeneca: Other: Advisory board; Genentech: Other: Advisory Board ; Incyte: Other: Advisory Board. Zelenetz:Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cheson:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Fox:Gilead: Consultancy; Janssen: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Allan:Sunesis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Consultancy; Verastem Oncology, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy.

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

BACKGROUND Outcomes for patients (pts) with primary CNS diffuse large B cell lymphoma (PCNSL) have improved over recent years, largely through optimisation of first-line methotrexate (MTX)-containing protocols and dose-intensive chemotherapy consolidation. However, 30-50% of pts experience refractory or relapsed (r/r) disease, which confers very poor outcomes and short survival. By contrast to systemic DLCBL, there is no accepted standard approach for r/r PCNSL. Thiotepa is an alkylating agent highly efficient at crossing the BBB and widely incorporated within high-dose therapy and autologous stem cell transplantation (HDT-ASCT) protocols for PCNSL, but has not undergone dose-finding studies nor been incorporated within salvage regimens for PCNSL. The TIER study investigates the safety and efficacy of adding thiotepa, in a dose-escalation design, to the Rituximab, Ifosphamide and Etoposide (R-IE) salvage regimen1. METHODS TIER is an open label, phase I/II UK NCRI TAP study for pts with r/r PCNSL, previously treated with a high-dose MTX-based regimen. In phase I, the RP2D of thiotepa within the TIER combination was established using a 3+3 design, with dose escalations of 30, 40 and 50mg/m2 (dose level 2 (n=4), 3 (n=5) and 4 (n=27) respectively), given on day 5 of R-IE cycle1. The Phase II primary endpoint was overall response rate (ORR) after cycle 2 of TIER (C2) by centrally reviewed contrast-enhanced MRI2, on an intention-to-treat (ITT) basis. Further treatment and consolidation after the primary endpoint MRI was at the discretion of investigators. Key secondary end-points were 2-year PFS, EFS and OS. RESULTS Thirty-six pts were recruited from Jun 2015-Apr 2019 at 13 centres (characteristics: Table 1). The median number of prior lines was 2 (range 1-4) with 44% of patients deemed refractory to their previous line of therapy. During phase I (n=10) no dose limiting toxicities (DLTs) were observed up to and including 50mg/m2 thiotepa, constituting the RP2D (n=27). 56 cycles of TIER were administered across both phases; 5 pts had >1 dose reductions. Median time between C1D1 and C2D1 was 24.7 days (range 22-38). Relative mean dose intensity of thiotepa, ifosphamide and etoposide was 71.8 (SD 44.9), 76.4 (SD 41.6), and 76.8 (SD 41.8) respectively. Further therapy after 2 cycles of TIER was delivered to 41.7% of pts (16.7% ASCT, 22.2% TIE, and 2.8% WBRT). The most common grade 3 / 4 adverse events were thrombocytopenia and neutropenia (47.2 and 55.6% occurring in 15 and 18 pts respectively). 17 serious adverse events (SAEs) were reported in 12 pts, of which 4 were haematological. Of these, 13 were considered related to TIER. Commonly occurring non-haematological SAEs were respiratory tract infections (23.5%) and seizures (11.8%). At data lock, 10/27 pts had responded to treatment as assessed by local investigators (ORR 37%, CR rate 15%). 13 pts were non-evaluable (7 progressed prior to C2 scan, 2 withdrew consent, and 4 awaiting scans) and classed as non-responders. Following data lock, responses were reported for 3 further pts (2 by local investigators and 1 by central review), resulting in a provisional ORR of 13/27 (48%). For the ITT population, median OS time was 3.52 months (95% CI 2.50, 14.17), and median PFS 2.86 months (95%CI 2.34, 6.05) (Figure 1). 6 pts underwent ASCT consolidation after TIER, of whom 2 have relapsed. CONCLUSIONS This is an early analysis of data from the phase I/II TIER study for a heavily pre-treated group of r/r PCNSL; the first such dose-escalation study for this patient group. Phase I determined a RP2D of 50mg/m2 of thiotepa incorporated in the R-IE regimen. There were no DLTs and toxicities, consistent with an intensive ifosphamide-based regimen. ORR was 10 pts (37%) with 3 further responses reported after data lock. If confirmed by central review, the primary endpoint of activity (ORR 40%) will have been reached. However, notwithstanding the response endpoint, most pts experienced very poor survival outcomes. These data describe the feasibility of TIER as a salvage regimen for r/r PCNSL but question the utility of this approach as a standard option, given the short PFS and OS times, except for the minority of pts who received ASCT. Biological and imaging sub studies are underway to identify predictors of outcome. In the modern era of effective first line immunochemotherapy approaches, pts with r/r PCNSL remain a major area of unmet need for whom novel experimental approaches are urgently required. Disclosures Fox: Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sunesis: Consultancy; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; Adienne: Other: Travel Support. Martinez-Calle:ABBVIE: Other: Travel support. Collins:Gilead: Consultancy, Honoraria. Ferreri:Novartis: Consultancy; Celgene: Consultancy, Research Funding; Roche: Research Funding; Kite: Consultancy. Davies:BioInvent: Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Bayer: Research Funding; ADCT Therapeutics: Honoraria, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Johnson:Roche: Consultancy, Honoraria, Speakers Bureau; Takeda: Other: Travel, accomodations, expenses. Cwynarski:Adienne: Consultancy; Takeda: Consultancy, Other: conference and travel support , Speakers Bureau; Roche,: Consultancy, Other: conference and travel support, Speakers Bureau; Autolus: Consultancy; KITE: Consultancy; Gilead: Consultancy, Other: conference and travel support, Speakers Bureau; Celgene: Consultancy; Atara: Consultancy; Janssen: Other: conference and travel support, Speakers Bureau.

Objective To audit the impact upon mortality of a massive bleeding management protocol (MBP) implemented in our center since 2007. Design A retrospective, single-center study was carried out. Patients transfused after MBP implementation (2007–2012, Group 2) were compared with a historical cohort (2005–2006, Group 1). Background Massive bleeding is associated to high mortality rates. Available MBPs are designed for trauma patients, whereas specific recommendations in the medical/surgical settings are scarce. Patients After excluding patients who died shortly ( n = 20), a total of 304 were included in the data analysis (68% males, 87% surgical). Interventions Our MBP featured goal-directed transfusion with early use of adjuvant hemostatic medications. Variables of interest Primary endpoints were 24-h and 30-day mortality. Fresh frozen plasma-to-red blood cells (FFP:RBC) and platelet-to-RBC (PLT:RBC) transfusion ratios, time to first FFP unit and the proactive MBP triggering rate were secondary endpoints. Results After MBP implementation (Group 2; n = 222), RBC use remained stable, whereas FFP and hemostatic agents increased, when compared with Group 1 ( n = 82). Increased FFP:RBC ratio ( p = 0.053) and earlier administration of FFP ( p = 0.001) were also observed, especially with proactive MBP triggering. Group 2 patients presented lower rates of 24-h (0.5% vs. 7.3%; p = 0.002) and 30-day mortality (15.9% vs. 30.2%; p = 0.018) – the greatest reduction corresponding to non-surgical patients. Logistic regression showed an independent protective effect of MBP implementation upon 30-day mortality (OR = 0.3; 95% CI 0.15–0.61). Conclusions These data suggest that the implementation of a goal-directed MBP for prompt and aggressive management of non-trauma, massive bleeding patients is associated to reduced 24-h and 30-day mortality rates.

Congenital coagulopathies are hemorrhagic diseases which show up during childhood and have a known familiar background. The most frequent ones are von Willenbrand's disease, which presents with mucocutaneous hemorrhages in both sexes and hemophilia A (Factor VIII deficit), which shows up with hemorrhages in joints and muscles of male patients. Diagnosis is made by functional, immunological and genetic testing. Treatment in severe cases is usually substitutive by administration of the lacking factor along with primary prophylaxis strategies. The main complication in the treatment of hemophilia is the development of inhibitors. In mild cases the chosen treatment is desmopressin. As for other less frequent congenital coagulopathies, the treatment is based in administering fresh frozen plasma, prothrombin complex factor concentrate recombinant activated factor VII.

Resumen La trombofilia, una predisposicion genetica o adquirida a la trombosis, se considera una enfermedad multifactorial resultado de la combinacion de factores geneticos y adquiridos. A pesar de su baja prevalencia en la poblacion general, puede encontrarse en hasta en un 10–50% de los pacientes con eventos tromboembolicos espontaneos y/o mujeres con complicaciones obstetricas. La trombosis idiopatica recurrente, en pacientes menores de 50 anos con historia familiar o de localizacion inusual, asi como mujeres con abortos recurrentes debe elevar la sospecha clinica y realizar estudios complementarios con pruebas especiales de hipercoagulabilidad: antitrombina, proteinas C y S, factor V Leiden, mutacion de la protrombina, anticoagulante lupico, anticuerpos antifosfolipidos y otras adicionales. Los resultados anormales de las pruebas de trombofilia se deben confirmar siempre, y un hallazgo positivo aconseja estudiar a familiares de primer grado para establecer profilaxis primaria si es pertinente y determinar la conducta terapeutica de cara a la anticoagulacion en sujetos con trombosis.

Introduction Very few studies have assessed the incidence and risk factors associated with CNS progressive disease (PD) in elderly DLBCL. The CNS IPI (international prognostic index) uses the standard IPI with an additional point for renal/adrenal (R/A) involvement to define CNS risk in DLBCL patients (pts). The CNS IPI is validated in younger DLBCL pts (Schmitz et al, 2016) but little is known about CNS risk in the elderly. Few data exist outwith a single study of pts >80 years (y) pooled from 2 LYSA mini CHOP trials (Cabannes-Hamy et al 2018). CNS PD risk from 270 pts >80y was 1.8% at 2y and 3% overall. CNS PD risk did not differ according to CNS IPI in this study. No real world data outside of these trials exists. Few studies have assessed the risk of CNS prophylaxis (intrathecal (IT) +/- high dose intravenous (IV) methotrexate (HDMTX)) in the elderly. Methods Data on consecutively treated new DLBCL pts ≥70y were retrospectively collected across 6 UK centres (2009-2018). We compiled a detailed database of CNS-IPI, extranodal disease sites, CNS prophylaxis, adverse events related to IV HDMTX, rate and timing of CNS PD, outcome post CNS PD and associations with CNS PD risk. Results 529 pts received Rituximab (R) chemotherapy with curative intent (513 R-CHOP/attenuated R-CHOP (97.0%), 13 R-PMitCEBO, 3 R-GCVP). 80.7% (427/529) received no CNS prophylaxis, 14.7% (78/529) received intrathecal (IT) MTX prophylaxis, 2.1% (11/529) received HDMTX only, and 2.5% (13/529) received both IV HDMTX and IT MTX. The median age of all pts was 76.7y and median follow up 2.9y (range 0.4 - 10.9y). The CNS IPI was 1 in 11.8% (60/510), 2 in 21.2% (108/510), 3 in 24.3% (124/510), 4 in 26.1% (133/510), 5 in 12.9% (66/510) and 6 in 3.7% (19/510). 19 pts were unclassifiable due to a missing LDH (Table 1). Extranodal sites (ENS) were noted in 64.7% (342/529). Median ENS were 1 (range 0-5). Commonest sites were bone 24.2% (128/529), liver 9.6% (51/529), renal 7.6% (40/529), and gastric/oesophageal 7.0% (37/529). R/A involvement was present in 9.3% (49/529). Pts with higher CNS IPI were more likely to receive CNS prophylaxis (IT and/or MTX); CNS IPI 0-1; 13.3%, 2-3; 10.9%, 4+; 29.9% (p Of 24 pts receiving IV HDMTX, median age was 72.4y, mean CNS IPI 3.6 (median 4), and median eGFR 83 (range 47 - 90) ml/min/1.73m2. 21% (5/24) were readmitted with complications directly post HDMTX (Neutropenic fever (NF) (n=1), non-NF (n=1), mucositis (n=1), pericarditis (n=1), and pneumonia/SIADH (n=1)). A single CNS PD occurred in this cohort (4.2%). When pts that received IT MTX were compared to pts receiving no IT MTX, the readmission rate during R-chemo with all-cause infection was 53.8% (42/78) vs 25.9% (105/405; 22 unknown) (p The overall rate of CNS PD was 2.7% (14/527). These included isolated CNS PD (n=11) and concurrent CNS and systemic PD (n=3). The rate of CNS PD was 2.2% (4/178 including (1 concurrent relapse)) in ≥80y and was not statistically different at 2.9% (10/349 including 2 concurrent PD) in 70-80y (p=0.87). 71% (10/14) CNS PD had a CNS IPI 4-6. 12/14 of CNS PD occurred The rate of CNS PD according to CNS IPI was: CNS IPI 1-3: 1.3% (4/300), CNS IPI 4: 2.3% (3/133), CNS-IPI 5: 4.5% (3/66) and CNS IPI 6: 21.1% (4/19) (CNS IPI 4-6: 4.6% (10/218)). CNS PD risk with R/A involvement was 8.2% (4/49). Significant Univariate risk factors for CNS PD include higher CNS IPI, ECOG 3-4, ≥2 ENS and R/A involvement as higher risk pts (Table 1). The overall survival (OS) post CNS PD (CNS only) was short (median of 2.7 months (m) (range 23 days - 8.6 m)) which was similar to OS of systemic PD (median 3.3 m) (Fig D). Conclusions The rate of CNS PD in elderly pts receiving RCHOP or RCHOP-like treatment is low and consistent with LYSA data. There were no differences in CNS PD incidence in 70-80y vs ≥80y. Increase risk was particularly apparent in CNS IPI 5-6 and R/A involvement. IV HDMTX in ≥70y was associated with a 21% readmission rate and its benefit is unclear. Readmission with infection was statistically higher in those receiving IT MTX although this is confounded by higher IPI in these pts. Prophylaxis requires a careful risk assessment in the elderly, evaluation of individual pt factors and consideration of the risks. On the basis of these data, consideration of prophylaxis should be confined to CNS IPI 5-6 and/or R/A involvement. Disclosures Eyre: Celgene: Other: travel support; Janssen: Consultancy, Other: travel support; Roche: Consultancy; Abbvie: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support. Djebbari:Celgene: Honoraria, Other: travel support, Research Funding; Takeda: Honoraria, Other: travel support; Pfizer: Other: conference registration. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Bishton:Abbvie: Research Funding; Roche: Research Funding; Takeda: Other: travel support to ASH; Gilead: Research Funding. Fox:Roche: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: travel support, Speakers Bureau; Sunesis: Consultancy; Gilead: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Abbvie: Consultancy, Other: travel support, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: travel support, Speakers Bureau. Collins:ADC Therapeutics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; Amgen: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria.

INTRODUCTION Primary central nervous system lymphoma (PCNSL) in patients (pts) over 65 years old have poorer outcome compared to younger cohorts, as comorbidities, baseline performance status and susceptibility to iatrogenic toxicity impede adequate drug delivery (Kasenda et al, Ann Oncol, 2015). Balancing toxicity against treatment benefits remains a challenge in this age group. Recent trials have attempted to rationalize treatment aiming for reduced toxicity whilst maintaining CNS penetration. Efficacy of additional agents, such as oral alkylators (Fritsch et al, Leukemia 2017) has also been demonstrated. Most clinical trial cohorts underrepresent elderly pts and thus analysis of real-world outcomes and therapeutic practice is warranted. METHODS Consecutively diagnosed pts between 01/10/12 and 01/10/17, ≥65 years old in 14 tertiary UK centres were analysed retrospectively. Radiological exclusion of systemic disease and histological diagnosis were mandatory. Pts receiving any form of 1st line treatment including palliative (whole-brain radiotherapy [WBRT]/oral chemotherapy), best supportive care (BSC) or clinical trial were included. Diagnostic and referral pathways were audited. Baseline patient characteristics and treatment received was recorded in order to document current UK practice. Pts. were stratified into 4 treatment groups: single agent MTX; MTX with oral alkylator; high-intensity HI-MTX (MTX/AraC and MATRix) or palliative intent treatment (WBRT/oral alkylator/BSC). The study primary outcome was overall response rate (ORR) after induction. Secondary outcomes were PFS and OS. Additional variables were MTX clearance and the relative dose intensity (RDI) of MTX normalised with a reference of 14mg/m2. UV/MVA for ORR and Cox-regression for PFS and OS were used for identification of baseline predictors of response and survival. RESULTS 244 pts were included in the analysis with median age 71yrs (range 65-91) and 123 (50%) male. LDH (Elevated:104, 42%) and ECOG performance score (PS) (3-4: 87, 36%) were the only prognostic markers recorded. Median time from presenting scan to treatment was 33 days (IQR 22-48). Demographic characteristics are summarised in table 1. 80% of pts (n=192) received MTX based chemotherapy. 68% of pts >70yr and 50% >75yr received >1 cycle of MTX. MTX median cumulative dose delivered was 10.6 g/m2 (range 1.5-21), median number of cycles was 4 (range 1-6). Dose reductions of MTX occurred in 53/176 pts. (30%). Median time to MTX clearance was 3 days (range 1-18) and median RDI was 0.75 (range 0.11-1.5). TRM for MTX treated pts was 7.2%. 112 pts received rituximab (46%; 11% pre-2015 vs. 64% post-2015). 73 pts. (38%) received ORR after induction was 63%. HI-MTX (HR 3.4; CI 95% 1.5 - 7.6; p=0.003) was independently associated with superior ORR compared to HD-MTX alone (Table 1). Median follow up for survival was 25 months. 2-yr PFS and OS were both 39%, median OS after progression was 80 days. MTX RDI (HR 0.18; p 52 pts (21%) received upfront palliative treatment and compared to MTX cohort, were older (median 76y vs. 70y), had a poorer PS (ECOG 3-4: 62% vs. 28%) and higher incidence of impaired renal function (GFR < 60ml/min: 15% vs. 5%). CONCLUSION MTX can be delivered to the majority of pts >70 years with manageable TRM rates. Notably, early treatment discontinuation was relatively frequent with outcomes in this group comparable to palliative care. By contrast, pts who completed >3 cycles of HI-MTX and underwent consolidation experienced comparable outcomes to younger trial cohorts. MTX combination chemotherapy and MTX dose intensity were the strongest predictors of survival whilst rituximab was not a covariate for response or survival despite an increase in its use. Maximising cumulative MTX dose, particularly within more intensive protocols, may translate into improved ORR and survival in older pts with PCNSL. Table. Table. Disclosures Kassam: AbbVie: Equity Ownership. Culligan:Merck Sharp & Dohme (MSD): Honoraria; Celgene: Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences; JAZZ: Honoraria; Abbvie: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Pfizer: Honoraria. McKay:Epizyme: Consultancy, Honoraria. Eyre:Roche: Consultancy; Janssen: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support; Abbvie: Consultancy, Other: travel support; Celgene: Other: travel support. Osborne:Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy; MSD: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Other: Travel to conference. Yallop:Servier: Other: Travel funding; Pfizer: Consultancy. Fox:Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Sunesis: Consultancy; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau. Cwynarski:Roche: Consultancy, Other: Conferences/Travel support, Speakers Bureau; Autolus: Consultancy; Kite: Consultancy; Gilead: Consultancy, Other: Conferences/Travel support, Speakers Bureau; Janssen: Other: Conferences/Travel support.

Introduction The impact of RCHOP dose attenuation in elderly patients (pts) with DLBCL is poorly understood. 1% of DLBCL 1st line pts in trials are ≥80 years (y). Attenuated R-CHOP (25mg/m2 doxorubicin (DOX); 400mg/m2 cyclophosphamide (CYCLO), 1mg vincristine) cure 50-60% in phase II trials (Peyrade et al, 2011, 2017). Full dose RCHOP compared to attenuated RCHOP does not improve outcome in ≥80y (Juul et al, 2018) or may worsen survival via toxicity (Eyre et al, 2016, Carson et al 2015). Methods We systematically collected data on IDI (cycle (C)1 dose) and RDI of CYCLO/DOX in consecutively treated pts ≥70ys across 6 UK centres (2009-18). Untreated de novo DLBCL and untreated transformation (HGT) of indolent NHL (iNHL) receiving ≥C1 were included. RCHOP was given at a minimum interval of 21 days. G-CSF was routine. The following were excluded: HIV+, prior solid organ transplant, isolated leg type DLBCL, pre-treated HGT, central nervous system involvement with DLBCL, and pts unfit for anthracycline. Data were collected on Cumulative Illness Rating Scale for Geriatrics (CIRS-G), CIRS-G severity index (total/no. categories), age-adjusted international prognostic index ((aa)IPI), Hb, albumin, LDH, B symptoms, bulk ≥10cm, major operation at diagnosis, and extranodal sites (ENS). Predictors of progression free (PFS), disease free (DFS), and overall survival (OS), were determined using univariable (UVA) and multivariable (MVA) Cox regression. Factors were analysed as continuous (denoted *); additionally IDI (full dose: ≥80% of weight based dose vs attenuated: Results 511 pts received R-CHOP with curative intent. 49% were male and 51% were female. Median follow up was 1.67y. Median age was 77y. 32% had stage I-II and 68% stage III/IV. 14% had concurrent iNHL, 20% bulk, 33% >1 ENS, and 66% IPI 3-5. 46% had CIRS-G ≥6. When comparing age/IDI categories, in 70-80y, pts with IDI80% (2-4; 30%), higher IPI 3-5 (71% vs 64%), higher CIRS-G≥6 (59% vs 40%), and higher CIRS-G severity index. ≥80y receiving IDI>80% had better ECOG (0-1 67% vs IDI For all pts, median PFS was 5.4y (95% confidence interval (CI) 4.1 - 6.9), median DFS was not reached, and median OS 5.5y (95% CI 4.5 - 6.7). When analysed by 70-80 vs ≥80y: 2y PFS was 71.8% (95% CI 66.4-76.4%) vs 60.3% (95% CI 51.5-68.0%), 2y DFS 79.4% (95% CI 74.3-83.6%) vs 76.7% (95% CI 68.4-83.1%) (p = 0.23) and 2y OS 74.6% (95% CI 69.4-79.1%) vs 60.2% (95% CI 51.2-68.1%). Unlike OS and PFS, DFS was not significantly different when 70-80y vs ≥80y were compared, suggesting >80y have a worse outcome due to toxicity and/or unrelated causes of death. 15 deaths in >80y with IDI>80 were: infection (n=5), systemic progressive disease (PD) (n=7), CVA leading to stopping RCHOP post C1 (subsequent PD) (n=1), unknown (in remission) (n=1), dementia (n=1). In 70-80y, IDI>80% had significantly improved PFS, DFS and OS. In ≥80y, there was no difference in PFS, DFS or OS according to IDI 80% (Fig A-F). UVA Univariable predictors of worse PFS and OS included age*, ECOG PS*, DOX IDI*, CYCLO IDI*, combined IDI*, IPI 3-5, aaIPI 2-3, raised LDH, male gender and B symptoms (all p MVA IDI* remained an independent predictor of PFS, DFS and OS. Using 70-80y IDI>80 (HR 1.0) as the comparator, the following were associated with significantly increased risk of PD and / or death in PFS and OS in MVA: 70-80y IDI80. Compared to 70-80y IDI>80 (HR 1.00), the HR for DFS in ≥80y IDI>80 approached significance (p = 0.07) vs PFS and OS, suggesting that causes other than PD account in part for inferior OS and PFS (Table 1). Conclusions To our knowledge, this is the largest series that has systematically analysed RDI, IDI (DOX, CYCLO and combination) and co-morbidities in consecutive unselected DLBCL ≥70y. Consistent with recent literature (Juul et al, 2018), there is no clear benefit to PFS, DFS or OS in dose intensifying (IDI>80) in ≥80y. IDI is a clear independent predictor of outcome across all pts. Pts 70-80y with IDI Disclosures Eyre: Janssen: Consultancy, Other: travel support; Roche: Consultancy; Abbvie: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support; Celgene: Other: travel support. Fox:Celgene: Consultancy, Other: Travel, Speakers Bureau; Sunesis: Consultancy; Abbvie: Consultancy, Other: Travel, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel, Speakers Bureau; Gilead: Consultancy, Other: Travel, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Travel, Research Funding, Speakers Bureau. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Bishton:Abbvie: Research Funding; Roche: Research Funding; Takeda: Other: travel support to ASH; Gilead: Research Funding. Collins:Celleron: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Celgene Corporation: Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding; Pfizer: Consultancy, Honoraria.

We describe a Schistosoma haematobium infection with asymptomatic eosinophilia, persistently negative urine microscopy, and late seroconversion (7.5 months) in a traveler returning from Mali. After initial negative parasitological tests, travel history led to diagnostic cystoscopy, allowing final diagnosis with urine microscopy after the bladder biopsy. The patient was successfully treated with praziquantel. Difficulties in making the diagnosis of schistosomiasis in asymptomatic returning travelers are discussed; we propose a trial treatment in these cases.

Fundamento. Los concentrados de factores del complejo protrombínico (CCP) están indicados para reversión del efecto de antagonistas de vitamina K (AVK). Recientemente se han utilizado en el manejo de la coagulopatía de la hemorragia masiva. El objetivo del presente trabajo es evaluar la seguridad y eficacia del CCP en dos situaciones clínicas, para reversión de AVK y manejo integral de la hemorragia masiva. Material y métodos. Revisión retrospectiva de los casos tratados con CCP entre enero de 2010 y febrero de 2013 en un único centro universitario. El objetivo primario fue la seguridad de administración del CCP en cuanto a reacciones inmediatas y episodios trombóticos. El objetivo secundario fue la eficacia, en 2 grupos: 1) Reversión de AVK y 2) Corrección de coagulopatía en hemorragia masiva. Resultados. El análisis de seguridad incluyó 31 pacientes (22 varones), edad mediana 61 años (rango 30-86). No se registraron reacciones adversas durante la infusión y solo se observó un evento trombótico. La eficacia en la reversión de AVK fue del 100% (6/6 pacientes), alcanzando normalización del INR en todos los pacientes. En hemorragia masiva, la supervivencia a las 24 horas fue 64% (16/25). Se requirieron procedimientos invasivos adicionales en 28% de los pacientes (7/25). El uso de CCP se asoció a cese de hemorragia en 44% de los pacientes (11/25), que correlacionó positivamente con la supervivencia (p=0,01). Conclusión. El uso de CCP es una alternativa segura y eficaz, para la reversión urgente del efecto de AVK, así como para el control de sangrado en situación de hemorragia masiva Background. Prothrombin complex concentrates (PCC) are approved for urgent reversal of vitamin K antagonists (VKA). Recently, PCC have been used in the management of massive bleeding-associated coagulopathy. The present work evaluates safety and efficacy of PCC in a case series of both VKA reversal and massive bleeding. Methods. Retrospective review of cases treated with CCP (January 2010 to February 2013). Safety endpoints were infusion reactions and incidence of thromboembolic events. Efficacy endpoints were: 1) VKA reversal efficacy and 2) Massive bleeding coagulopathy reversal and 24h mortality. Results. Thirty-one patients were included (22 male), median age 61 years (range 30-86). No infusion reactions were detected, and only 1 thrombotic episode was observed. VKA reversal was effective in 100% of patients (6/6), all of them with complete reversal of INR value. In massive bleeding, 24-hour survival was 64% (16/25). Invasive hemostatic procedures were required in 28% of patients (7/25). CCP use was correlated with bleeding control in 44% of cases (11/25), and also significantly associated with survival (p=0.01). Conclusion. CCP are safe and effective for the novel indication of adjuvant treatment in massive bleeding patients, as well as for traditional urgent reversal of VKA.

The CD20 marker continues to be exploited as a therapeutic target for non-Hodgkin's lymphoma. Obinutuzumab is part of a new generation of anti-CD20 monoclonal antibodies, which are synthesized using molecular engineering technology, resulting in novel target epitopes and unprecedented optimization of antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Rituximab is the current gold standard for anti-CD20 therapy, yet despite outstanding results published over the past decade, many patients continue to relapse after anti-CD20 regimens. Obinutuzumab is slowly positioning itself in the treatment of CD20+ B-cell neoplasms. On the basis of favorable results from the phase III GADOLIN trial, obinutuzumab was recently approved by the U.S. Food and Drug Administration in combination with bendamustine followed by obinutuzumab maintenance, for the treatment of follicular lymphoma (FL) patients who relapsed or are refractory to a rituximab-containing regimen. Additional phase III trials are underway to test obinutuzumab as a first-line anti-CD20 agent in FL with good preliminary results (GALLIUM trial); thus, it is likely that obinutuzumab will soon achieve a first-line indication. It is plausible that obinutuzumab will replace rituximab as the gold standard for chemoimmunotherapy in FL, although some safety concerns still need to be resolved. This review will address the preclinical pharmacology and the main aspects of the clinical development of obinutuzumab for the treatment of FL.

Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has beenrecently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.