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

Mantle cell lymphoma (MCL) presenting in elderly, unfit patients represents a clinical challenge. Front-line 'attenuated' or low-intensity immunochemotherapy is often employed, although outcomes are relatively unexplored. We report outcomes of attenuated immunochemotherapy in 95 patients with MCL across 19 centres in the UK and Ireland considered unfit for full-dose rituximab-bendamustine or rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone (R-CHOP). Regimens examined were rituximab-cyclophosphamide, vincristine, prednisolone (R-CVP) (n = 19), dose-attenuated R-CHOP (n = 22), dose attenuated rituximab-bendamustine (n = 24) and rituximab-chlorambucil (n = 30). The primary outcome was progression-free survival (PFS). The secondary outcomes included overall response, overall survival (OS) and toxicity. The median (range) age was 79 (58-89) years and 50% were aged ≥80 years. The median (range) Cumulative Illness Rating Scale-Geriatric score was 6 (0-24). The median PFS for all patients was 15 months [95% confidence interval (CI) 8·7-21·2) and median OS was 31·4 months (95% CI 19·7-43·2). By multivariable analysis (MVA), the only clinical factor associated with an inferior PFS was blastoid morphology [hazard ratio (HR) 2·90, P = 0·01). Notably, higher treatment intensity (R-CHOP/R-bendamustine composite) provided an independently superior PFS compared with R-CVP/R-chlorambucil (MVA HR 0·49, P = 0·02). Factors associated with inferior OS by MVA were Eastern Cooperative Oncology Group Performance Status (HR 2·14, P = 0·04), blastoid morphology (HR 4·08, P = 0·001) and progression of disease at

Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients., Plasmablastic lymphoma (PBL) is an aggressive lymphoma subtype characterized by poor prognosis but the molecular knowledge of the disease is limited. Here, the authors perform whole exome sequencing and copy number determination of primary samples highlighting IRF4 and JAK-STAT pathways as therapeutic targets for PBL.

High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post–R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.

There is a Blood Commentary on this article in this issue., Key Points Both watch-and-wait and treated CLL patients have high mortality rates when admitted for COVID-19. Receiving a BTKi for CLL at COVID-19 diagnosis severe enough to require hospitalization did not influence case fatality rate in this study., Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive (“watch and wait”), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi’s; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi’s at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi’s in COVID-19 are needed to provide definitive evidence of benefit., Visual Abstract

Introduction: Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is uncommon but is associated with poor outcomes. In selected high risk patients (pts), high dose methotrexate (HDMTX) is often used as CNS prophylaxis with frontline (1L) DLBCL therapy despite uncertain efficacy, optimum dose and timing of delivery. A recent UK study (Wilson et al 2020) showed that intercalated HDMTX (i-HDMTX) was associated with increased toxicity and R-CHOP delays compared to end of treatment (EOT) delivery. Although hypothesis generating, the study size was insufficient to determine whether EOT was non-inferior in terms of CNS relapse risk. Methods: We conducted an international, multicentre retrospective analysis of consecutive DLBCL or high grade BCL pts between 2007-20 from 47 centers in Europe, Australia and N. America. Pts were included if they received R-CHOP or R-CHOP-like 1L therapy with curative intent as well as HDMTX CNS prophylaxis (≥1 cycle). Concurrent intrathecal (IT) prophylaxis was permitted. Pts with known CNS involvement at baseline and those treated with more intensive protocols (e.g. R-DA-EPOCH) were excluded. i-HDMTX was defined as any pt receiving a HD-MTX cycle before the final R-CHOP cycle. CNS relapse events were excluded if occurring after first systemic lymphoma relapse/progression. Time to event endpoints were measured from diagnosis to first event or censor and analysed using Kaplan-Meier and Cox regression methods. Time to CNS relapse was analysed using competing risk Fine and Gray method (for death and non-synchronous systemic relapse). To mitigate for possible immortality bias in the EOT arm, a landmark analysis for pts alive and free from progression at 6 months was conducted. We aimed to exclude a 5% difference in 2-year (y) CNS relapse rates. Results: 1,384 pts were analysed. 750 received i-HDMTX and 634 received EOT HDMTX. Key baseline characteristics are summarised in Table 1. Median follow up was 37.9 months. 44.2% had high CNS IPI (4-6) with no significant difference between i-HDMTX and EOT groups (45.1% vs 43.1%, p=0.087). ≥2 cycles of HDMTX were used in 86.6% with no difference between groups (85.6% vs 87.9%, p=0.22). Concurrent IT prophylaxis use was higher for EOT pts (55.6% vs 38.1% p 78 CNS relapses (42 i-HDMTX, 36 EOT) were observed: parenchymal in 41 (53%), parenchymal and leptomeningeal in 16 (21%) and isolated leptomeningeal in 21 (27%). There was no significant difference in 2y CNS relapse rates between i-HDMTX and EOT in all pts: 5.2% vs 3.9%, adjusted hazard ratio (HR) 0.92 (95% CI 0.58-1.47), p=0.74, 2y difference -0.2% (-2.0-2.5) or landmark analysis: 2.8% vs 4.1%, HR: 0.93 (0.56-1.55), p=0.79, 2y difference: -0.3% (-1.8-2.2%) (Fig 1a/b). Exploratory analyses focusing on pts with isolated CNS relapse (n=57) demonstrated similar results (2y rates 3.6% vs 3.0%, p=0.99). On multivariable analysis (MVA) of risk factors for CNS relapse, renal/adrenal involvement was the only variable associated with increased CNS relapse risk (adjusted HR 1.74 (1.03-2.92), p=0.038). Notably, IT prophylaxis was not associated with reduction in CNS relapse. In 600 high CNS IPI (4-6) pts, there was no difference in CNS relapse risk between i-HD-MTX and EOT (3y rates 9.4% vs 8.6%, HR 0.92 (95% CI 0.52-1.62)). In a composite high risk group including CNS IPI 4-6 and/or any of the following: ≥3 extranodal sites, renal, adrenal, testicular or breast involvement (n=885) there was no difference in 3y CNS relapse rates between groups (i-HDMTX 7.6% vs EOT 7.4%, HR 0.94 (0.58-1.53)). Progression-free survival (PFS) and overall survival (OS) in the i-HDMTX and EOT groups were as follows: 3y PFS 70.7% vs 76.7% (p=0.098), 3y OS 79.9% vs 87.0% (p=0.0016). However, there were no PFS/OS differences between groups on landmark analysis (n=1259) (Fig 1c). On analysis of pts experiencing ≥1 R-CHOP delay of ≥7 days, use of i-HDMTX was the only factor on MVA associated with increased delays (p Discussion: We found no evidence that EOT delivery increases CNS relapse risk when compared to i-HDMTX in this large analysis of pts treated with 1L R-CHOP. Delays to R-CHOP cycles were increased with i-HDMTX. Findings in a high risk subgroup were unchanged and rates of CNS relapse in this HDMTX treated group were similar to published comparable high risk cohorts receiving infrequent CNS prophylaxis. Where HDMTX prophylaxis is used, delivery could be deferred until R-CHOP completion. Figure 1 Figure 1. Disclosures Wilson: Takeda: Other: Conference fees; Janssen: Other: Conference fees; Abbvie: Honoraria. Eyre: Janssen: Honoraria; Secura Bio: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Beigene: Honoraria, Research Funding. Ahearne: Pfizer: Research Funding; Takeda: Honoraria; Roche: Honoraria. Schorb: Roche: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding; AbbVie: Research Funding. Ku: Antegene: Consultancy; Roche: Consultancy; Genor Biopharma: Consultancy. Narkhede: Genentech/Roche: Research Funding; Gilead: Research Funding; Genmab: Other: Medical writing support, Research Funding; TG Therapeautics: Research Funding. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Øvlisen: Abbvie: Other: Travel expenses. Santarsiere: Janssen: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roulin: Janssen: Other: Travel and meetings. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Celgene: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Novonordisk: Other: Speaker Honoraria. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cheah: Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Ferreri: Gilead, Novartis, Juno, PletixaPharm, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, Pfizer: Research Funding. Fox: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: speaker fees. Cwynarski: Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. 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.

Quality and predictors of anticoagulant control with vitamin K antagonist for stroke prevention in atrial fibrillation

1. Proper patient selection with appropriate rectal lesions for TAMIS. 2. Patient positioning in high lithotomy position under general anesthesia. 3. Access the distal rectum with transanal multichannel port and establishment of pneumorectum. 4. Mark out appropriate resection margin of target lesion. 5. Excision of lesion beginning with distal margin and performing submucosal or full-thickness resection. 6. Closure of rectal defect.

A 79 year old man was referred to the medical assessment unit by his general practitioner. Over the previous four weeks he had experienced progressive discolouration of both lower legs. His GP had given two courses of antibiotics for possible cellulitis but there was no clinical improvement. He was systemically well and had no history of fever. He denied any trauma to the legs and had no dermatological history. He was taking no regular medication. The man lived alone and was fully independent. His diet lacked fruit and vegetables. On examination he had normal pulse, blood pressure, and oxygen saturations and no fever. Chest and abdominal examination were unremarkable. There was widespread bruising (ecchymosis) of the lower legs with “woody” oedema (fig 1⇓). Inspection of the legs more proximally revealed perifollicular haemorrhage and “corkscrew” hairs (fig 2⇓, fig 3⇓). The right leg appeared larger than the left but the calf was soft and non-tender. Fig 1 Right lower leg Fig 2 Skin changes above the right knee Fig 3 Close-up of skin changes above the right knee A coagulation screen, renal, and liver function tests were normal. Doppler ultrasound of the leg showed no evidence of deep vein thrombosis. Urinalysis was normal. …

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

Background: Ibrutinib has transformed the clinical approach to relapsed mantle cell lymphoma (MCL) with those receiving ibrutinib at first relapse obtaining the greatest benefit encouraging use earlier in the treatment algorithm (Rule et al, 2019). However, the general applicability of clinical trial findings is not established and concerns regarding ibrutinib tolerability persist, especially in non-trial populations enriched for frailer patients with multiple co-morbidities. In the United Kingdom, ibrutinib is funded as standard of care at first relapse. This study has analysed the clinical effectiveness and tolerability of this approach in a non-clinical trial real world population. Method: 23 centres across the United Kingdom contributed data from consecutive patients treated with ibrutinib for MCL at first relapse. Patients received standard dose 560 mg OD, unless documented, and commenced treatment between August 2014 and April 2019. Response to therapy was defined as per Lugano classification (Cheson et al, 2014), although CR assessment by bone marrow biopsy was not always undertaken. Data was collected on baseline characteristics, including response to prior therapy, and MIPI at time of relapse. The study primary outcome was PFS. Predictors of progression were determined using univariate Cox regression. Results: 169 patients were included in the study. Median age at start of ibrutinib was 72 years (range 33 to 97) and 122 (72.2%) were male. At diagnosis 13.5% had blastoid histology; 59.3% Ki67 ≥30%; 32.0% received cytarabine based induction and 27.8% HSCT consolidation; 11.2% received low intensity frontline therapy (i.e. not fit for R-CHOP) due to frailty. Median PFS following frontline therapy was 21.4 months (95% CI 14.6 to 28.3) and 52.1% progressed within 2 years. At start of ibrutinib 52.2% were MIPI high risk; 23.9% were ECOG 2 or higher and 2.4% had CNS involvement. Overall response rate (ORR) to ibrutinib was 71.6% with 30.4% achieving CR/CRu. Estimated median PFS from start of ibrutinib was 16.5 months (95% CI 11.5 to 21.5) and estimated OS 23.9 months (95% CI 13.0 to 34.8), with median follow up 26 months. Median PFS for patients with early relapse to frontline therapy (progression of disease 1 were also negative predictors of PFS (see table 1 for univariate analysis). 10 patients (5.9%) received attenuated dose from start of therapy due to frailty and 20 patients (11.8%) underwent dose reductions while on therapy due to drug toxicity. Of 109 patients to discontinue ibrutinib 72 (66.1%) were due to progressive disease, 15 for consolidation alloHSCT (13.8%), 13 due to medical co-morbidities and unrelated death (11.9%), and 9 due to drug toxicity (8.3%), including 1 bleed. Only 5.3% of all patients stopped therapy due to drug toxicity. Patients ≥80 yrs were more likely to stop therapy early for reasons other than progressive disease or alloHSCT (OR 2.92, p=0.02), but frailer patients who received low intensity frontline therapy also showed a trend for more durable response with second-line ibrutinib (PFS 10.0 months versus 4.0 months, p=0.36) justifying use in this patient group. Conclusion: This study population is enriched for several recognised adverse prognostic markers, including older age and poor performance status, which is likely to explain differences in PFS relative to clinical trial data. Despite these features response rates were similar, and it is notable that 46.7% of evaluable pts achieved longer PFS with ibrutinib than preceding front-line therapy. It is reassuring that the proportion of patients stopping ibrutinib due to toxicity was similar to trial data and bleeding events that required alterations to therapy were rare (3 cases, 1.8%). Although ibrutinib represents a significant breakthrough with clear benefit to most patients the results also highlight that outcome for many remains poor. 40% of patients progressed within 1 year of starting ibrutinib and median OS post ibrutinib was only 3.6 months. 35.2% of patients died within 1 month of documented relapse suggesting many, predominantly older patients, were not fit for further therapy. Of the 53 pts surviving beyond 1 month median OS was 7.5 months and 21.9% lived beyond 1 year. Improved treatment strategies in the post-ibrutinib setting remains a priority. Disclosures Rule: Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Roche: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Kite: Consultancy. Eyre:Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Furtado:Abbvie: Honoraria. Shah:ABBVIE: Consultancy. Campbell:Novartis: Consultancy, Other: Educational support; Takeda: Consultancy, Other: Educational support; Bristol Myers-Squibb: Other: Educational support; Roche: Other: Educational support; Celgene: Other: Educational support. McCarthy:Janssen: Honoraria, Other: Educational grant to attend meetings . Lambert:Takeda Pharmaceuticals: Other: Funding to attend a scientific conference in 2018. McKay:Epizyme: Consultancy, Honoraria. Osborne:Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Gilead: Consultancy; MSD: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Novartis: Other: Travel; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy. Bishton:Takeda: Other: Travel support, Research Funding; AbbVie: Research Funding; Celltrion: Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Other: Travel support, Research Funding. Crosbie:Janssen: Honoraria.

Summary The precise biological mechanisms that caused the TGN1412 clinical trial tragedy (also known as ‘The Elephant Man Clinical Trial’) in March 2006 remain a mystery to this day. It is assumed widely that the drug used in this trial (TGN1412) bound to CD28 on T lymphocytes and following activation of these cells, a massive ‘cytokine storm’ ensued, leading ultimately to multi-organ failure in all recipients. The rapidity of this in vivo response (within 2 h), however, does not fit well with a classical T lymphocyte response, suggesting that other ‘faster-acting’ cell types may have been involved. In this study we have activated purified human peripheral blood leucocyte populations using various clones of mouse monoclonal anti-CD28 presented to cells in the form of a multimeric array. Cytokines were measured in cell-free supernatants at 2 h, and specific mRNA for tumour necrosis factor (TNF)-α, thought to be the initiator of the cytokine storm, was also measured in cell lysates by reverse transcription–polymerase chain reaction (RT–PCR). Monocytes were the only cell type found to show significant (P < 0·05) up-regulation of TNF-α at 2 h. Eleven other monocyte cytokines were also up-regulated by anti-CD28 within this time-frame. It therefore seems likely that monocytes and not T cells, as widely believed, were probably responsible, at least in part, for initiating the cytokine storm. Furthermore, we propose that a multimeric antibody array may have formed in vivo on the vascular endothelium via an interaction between TGN1412 and CD64 (FcγRI), and we provide some evidence in support of this hypothesis.

The traditional anticoagulants in clinical use for the prevention or treatment of thromboembolic disease are heparin (and its analogs) and warfarin. However, these drugs have major limitations: a narrow therapeutic index; high interindividual variability in a variable dose-response relationship that requires monitoring by laboratory testing; and numerous drug–drug interactions. These limitations have provided the impetus not only for pharmacogenomic studies of efficacy and toxicity for warfarin, but also for the development of other antithrombotic agents that target discrete factors in the coagulation cascade. In this chapter, we outline the coagulation cascade and describe the pharmacology of traditional and novel anticoagulants.

Background.Kikuchi-Fujimoto disease (KFD) is typically a self-limited, benign illness which presents with fever and lymphadenopathy. It is rare in Caucasians, normally occurring in those of Asian descent. The aetiology is poorly understood, but it appears to be an autoimmune disorder with a possible infectious trigger. The clinical features are such that it is often mistaken for infectious diseases or malignancy.Case Report.Here we describe a case of a 36-year-old Asian man who presented following a recent trip to Delhi, India. He described fever, neck swelling, and arthralgia. Given his travel history an infectious cause for his presentation was presumed but multiple investigations were negative. Persistence of his symptoms led to lymph node biopsy to investigate for malignancy; surprisingly this revealed a necrotizing lymphadenitis in keeping with KFD. The patient made a full recovery with supportive treatment only.Conclusion.This case presented an opportunity to reflect on two common presenting complaints—fever in the returning traveller and unexplained lymphadenopathy. Both presentations have a wide range of aetiologies to consider. Although KFD is rare, it is an important diagnosis to make as it can prevent further expensive and invasive investigations, as well as potentially harmful treatments and psychological stress to the patient.

Aims To audit compliance with Scottish Intercollegiate Guidelines Network (SIGN) guideline 107: diagnosis and management of headache in adults for assessment and investigation of possible subarachnoid haemorrhage (SAH) in a 30 bedded medical assessment unit (MAU). Methods All cases presenting to the MAU in which SAH was a differential diagnosis were identified prospectively over a 4 week period. Medical notes, PACS and the computer lab results system were assessed for the following audit parameters: documentation of relevant symptoms and examination, performance of and timing of brain imaging, appropriately timed, documented and analysed lumbar puncture (LP). The results of the audit were relayed and discussed at the departmental teaching meeting and re–audit performed following this. Results 17 patients in 1st cycle and 24 in 2nd cycle identified during audit period. Time to peak headache intensity documented in 10/17 (58%) 1st cycle and 3/25 (12.5%) 2nd cycle. Full cranial nerve and peripheral nerve examination documented in 15/17 (88%) 1st cycle and 23/24 (96%) 2nd cycle. 16/17 (94%) 1st Cycle and 24/24 (100%) 2nd cycle patients received a CT Head with an average door–to–CT time of 8.2 hours 1st cycle and 6.5 hours 2nd cycle. 12/17 (70%) 1st cycle and 19/24 (79%) 2nd cycle received a LP. LP was performed>12 hours post headache in 11/12 (91%) 1st cycle and 19/19 (100%) 2nd cycle. LP opening pressures documented in 6/12 (50%) 1st cycle and 11/19 (58%) 2nd cycle. CSF spectrometry performed in 100% 1st and 2nd cycle (12/12 and 19/19 respectively). Conclusions Many aspects of assessment and investigation of SAH in the MAU were done very well such as a large proportion of patients getting timely brain imaging and performance of CSF spectrometry on all LP samples. Some aspects were suboptimal such as documentation of important red flag headache symptoms, LP not performed in a large portion of cases and LP opening pressures often not documented. There was an almost universal improvement on all parameters in the 2nd cycle after audit meeting and educational intervention. Further educational and organisational intervention is planned with a 3rd audit cycle following this.