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Summary Patients with haematological malignancies have a high risk of severe infection and death from SARS‐CoV‐2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS‐CoV‐2 infection and active haematological cancer. The primary end‐point was all‐cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1–2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96–1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09–5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08–2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti‐CD19/anti‐CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS‐CoV‐2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti‐CD19/anti‐CD20 treatments.

Haematology patients receiving chemo- or immunotherapy are considered to be at greater risk of COVID-19-related morbidity and mortality. We aimed to identify risk factors for COVID-19 severity and assess outcomes in patients where COVID-19 complicated the treatment of their haematological disorder. A retrospective cohort study was conducted in 55 patients with haematological disorders and COVID-19, including 52 with malignancy, two with bone marrow failure and one immune-mediated thrombotic thrombocytopenic purpura (TTP). COVID-19 diagnosis coincided with a new diagnosis of a haematological malignancy in four patients. Among patients, 82% were on systemic anti-cancer therapy (SACT) at the time of COVID-19 diagnosis. Of hospitalised patients, 37% (19/51) died while all four outpatients recovered. Risk factors for severe disease or mortality were similar to those in other published cohorts. Raised C-reactive protein at diagnosis predicted an aggressive clinical course. The majority of patients recovered from COVID-19, despite receiving recent SACT. This suggests that SACT, where urgent, should be administered despite intercurrent COVID-19 infection, which should be managed according to standard pathways. Delay or modification of therapy should be considered on an individual basis. Long-term follow-up studies in larger patient cohorts are required to assess the efficacy of treatment strategies employed during the pandemic.

The cornerstone of life-saving therapy in immune-mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti–von Willebrand factor nanobody trialed in 2 multicenter randomized controlled trials (RCTs) leading to European Union and US Food and Drug Administration approval, has been available in the United Kingdom (UK) through a patient access scheme. Data were collected retrospectively from 2018 to 2020 for 85 patients (4 children) receiving caplacizumab from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial end points and historical outcomes in the precaplacizumab era. Eighty-four of 85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalization (3 days), duration of PEX (7 days), and hospital stay (12 days) were comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalization were favorable compared with historical outcomes (P < .05). Thrombotic thrombocytopenic purpura (TTP) recurred in 5 of 85 patients; all had persistent ADAMTS13 activity < 5 IU/dL. Of 31 adverse events in 26 patients, 17 of 31 (55%) were bleeding episodes, and 5 of 31 (16%) were thrombotic events (2 unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4 of 5 deaths, caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients, including pediatric patients, receiving caplacizumab outside of clinical trials. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.

Background IgM paraprotein-associated peripheral neuropathies (PN) are a heterogenous group of disorders seen in patients with IgM MGUS and Waldenström's Macroglobulinaemia (WM). Anti-myelin associated glycoprotein (MAG) antibodies are causally identified in ~50% of such cases, but other neuropathies with other IgM-targets are described, along with AL amyloidosis and cryoglobulinaemic vasculitis amongst others. Presence of neuropathy alone is typically not an indication for treatment, but progressive disability is. Due to their relative rarity and heterogeneity, the true prevalence and optimal management of these neuropathies is currently unclear. Methods The Rory Morrison WMUK Registry, a national IgM-related disorders database incorporating 18 centres, was searched for all patients with PN and retrospective data clinical data extracted. Research ethics approval was obtained. Results IgM-related PN was identified 153 patients, of whom 99 (64.7%) had underlying WM and 54 (35.3%) had IgM MGUS. Anti-MAG neuropathy was present in 83 (54.6%) patients, anti-ganglioside in 3 (2%), AL amyloid in 7 (4.3%), cryoglobulinemia in 6 (3.7%), one (0.6%) case of CANOMAD syndrome, and a non-MAG IgM-neuropathy in 53 (34.5%%). PN was present at diagnosis in 143 (93.5%) whereas 10 (6.5%) were diagnosed during the course of their disease. Median age at diagnosis was 64 years (30-92) and 101/153 (66%) were male. Table 1 details results at diagnosis. κ-light chain was present in 80.3%, λ in 11.8% and 7.9% had multiple M-protein bands expressing both light chains. MYD88L265P was identified in 44/55 tested patients (80%) and in 23/30 (76.7%) cases of anti-MAG. In those with an IgM-related disorder, 13/20 (65%) had MYD88L265P, higher than in other IgM MGUS patients (7/14, 50%). CXCR4MUT were found in 3/22 (13.6%). Median bone marrow infiltration on trephine was 13% (range 0-85%), but 10 patients had no evidence of disease, 5 had disease on flow cytometry only, 2 an isolated finding of MYD88L265P and 1 isolated CXCR4MUT on PCR. IgM-related PN was seen in 99/719 (13.8%) of all registry patients with WM. At diagnosis, the bone marrow burden, M-protein and B2M were all significantly lower (p Therapy had been required in 81 (53.3%) patients, including at time of diagnosis in 23 (15%). Median time from diagnosis to treatment was long, at 6.7 years (95% CI 3.2-9.1 years). PN was the sole treatment indication in 64/81 (79%) cases. Time to treatment commencement did not appear to be affected by M-protein quantity or marrow burden, but patients with WM were more likely to have received treatment for their PN (59/108, 54.6%). Frontline treatment incorporated rituximab (R) in 66/81 (81.5%) patients, including R-monotherapy in 30, DRC 20, R-CHOP/R-CVP eight and BR in seven. A major biochemical response was seen in 19/34 (55.9%) patients. Clinical response was seen in 34 of 45 evaluable cases (75.6%), with improvement in 13 (28.9%) and stabilisation in 21 (46.7%). Clinical response or stabilisation was significantly more likely with R-containing therapy (82.1% vs 33.3%, p 0.04), non-amyloid related PN (82% vs 0%, p = 0.01) and attainment of ≥ partial response. All patients (n=12) with normal BMAT or isolated MYD88L265P responded to R-containing frontline therapy, another positive prognostic factor (p = 0.08). Progression of PN occurred after an initiation period of clinical response in 7/34 (20.5%), necessitating re-treatment at a median of 4.3 years after frontline therapy. Median time to 2nd line therapy was 6.7 years, longer than for other WM treatment indications (p = 0.04). Conclusions IgM-related PN is a cause of morbidity for a significant proportion of patients with WM, with a prevalence of 13.7%. However, a third of cases occur in those with IgM MGUS and even very small clonal populations seem capable of causing disease but appear responsive to rituximab therapy. Patients typically have comparatively low systemic disease burden and low rates of CXCR4MUT, perhaps representing a more indolent phenotype or a product of earlier diagnosis. PN is frequently the sole indication for treatment, reflecting this. Clinical improvement or stabilisation was seen in 75% of treated patients, and attainment of ≥50% reduction in IgM (PR) and treatment with rituximab is associated with a more favourable outcome, whereas AL amyloid neuropathy appears to be more treatment resistant. Disclosures Lindsay: Amgen: Other: Travel Expenses; Takeda: Honoraria, Other: Travel Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Carr:Lupin: Honoraria; CSL: Honoraria; Grifols: Other: Travel support. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pratt:Binding Site Ltd: Other: Personal fees; Amgen: Other: Personal fees; Janssen: Other: Personal fees; Celgene: Other: Personal fees; Takeda: Other: Personal fees; Gilead: Other: Personal fees; Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. D'Sa:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; BeiGene: Honoraria, Research Funding.

BACKGROUND Bing-Neel Syndrome (BNS), characterised by the direct infiltration of central nervous system (CNS) with clonal lymphoplasmacytic lymphoma cells, is a rare cause of neurological complications in patients with Waldenström Macroglobulinaemia (WM). The pathophysiology/neurotropism of BNS is not well understood. Various treatments that appear to cross the blood-brain barrier are used, including chemoimmunotherapy combinations and Ibrutinib. High-dose methotrexate (HDM)-based regimens, including MATRix (methotrexate [MTX], cytarabine, thiotepa, rituximab)1and R-IDARAM (rituximab, MTX [intrathecal and intravenous], cytarabine, dexamethasone) are also used, based on the experience in high-grade CNS lymphoma; however, there are concerns regarding the appropriateness of these regimens in the indolent setting, largely due to their toxicity. This study aimed to determine the efficacy and tolerability of HDM-based, frontline treatment in a large cohort of BNS patients. METHODS A single-centre retrospective review of consecutive patients with BNS treated with HDM based regimens was undertaken. Comprehensive laboratory and CNS imaging results were collated (including whole-brain/spine MRI, bone marrow biopsy, and CSF biochemistry, cytology and MYD88 L265P mutation). Best responses achieved, according to IWWM response assessment criteria, were determined. RESULTS Between 2011 and 2020, 27 patients were treated with HDM-based chemoimmunotherapy: 14 (51.9%) with MATRix, 5 (18.5%) with MTX/cytarabine/rituximab (MAR), 2 (7.4%) with HDM only, and 6 (22.2%) with R-IDARAM. Median time from WM diagnosis to BNS diagnosis was 60 months (0-572 months), including 10 patients (37.0%) who were diagnosed with WM at the time of BNS presentation/diagnosis. Median age at diagnosis with BNS was 66 years (43-75 years), and 15/27 (55.6%) were male. CR was achieved in 6 patients (22.2%), PR in 7 (25.9%), and non-response in 8 (29.6%); PD on therapy occurred in 4 cases (14.8%) and 2 patients died before response could be assessed. Of the 14 patients who received MATRix, 5 (31.2%) achieved PR, 6 (42.9%) had stable disease and 3 (21.4%) progressed while on treatment (Figure 1A). Of the 7 who received MAR or HDM only, 4 (57.1%) achieved CR, with 1 PR and 1 SD; 1 patient died before response could be assessed. Response was not affected by prior chemotherapy (for WM), and no biological or radiological feature predicted response in this highly heterogenous population. Predicted overall survival plateaued at 71.5% 1 year after start of treatment (Figure 1B). At a median follow up of 19.4 months, 7 patients (25.9%) had died: 3 (11.1%) from progressive BNS (1 patient had received each of MATRix, R-IDARAM and HDM only), and 4 (14.8%) from treatment-related toxicity (including infection). Of the latter 4 patients (all male), 2 had received MATRix and 1 had received each of MAR and R-IDARAM. No objective response was seen in 6 of the 7 deceased patients; the remaining 1 patient achieved PR following full-dose MATRix, but subsequently relapsed and died of BNS 7 months later. Regarding dose intensity, 5/15 MATRix recipients (33.3%) received full-dose regimens (i.e. 3.5mg/m2 of MTX per cycle for 3-4 cycles); a further 5 patients received a dose reduction of MTX (to 50-75%) and 9 patients (60%) received CONCLUSION In the setting of indolent CNS lymphoma, the rationale for chemoimmunotherapy is unclear. Although HDM-based therapy is used in BNS, its administration is limited by toxicity, and dose reductions may undermine dose intensity in the CSF. We observed higher rates of treatment-related mortality and only modest response rates with MATRix vs other HDM-based regimens; this primarily related to treatment related toxicity necessitating dose reduction requirements. These data suggest MATRix offers no response benefit over MAR or HDM only; indeed, the omission of thiotepa appears to allow dose optimisation of MTX and cytarabine, and does not negatively impact on outcome. If patients survive the first year of their disease/treatment, survival outcome is excellent. 1. Ferreri, A.J.M., et al.The Lancet Haematology3, e217-e227 (2016). Figure 1 Disclosures Carr: Lupin: Honoraria; Grifols: Other: Travel support; CSL: Honoraria. Wechalekar:Janssen, Takeda, Caelum, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Sa:Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) is a rare paraneoplastic phenomenon secondary to plasma cell dyscrasia. Treatment is aimed at the underlying plasma cell clone and its survival factors. Autologous stem cell transplantation (ASCT) is selected for patients who have multifocal skeletal disease and/or bone marrow involvement with adequate performance status (Dispenzieri, 2017). Because of the rarity of the disease, there are relatively few papers describing outcomes following ASCT. This analysis seeks to add further to the emerging evidence and elucidate prognostic factors.

Introduction The importance of endoscopic evaluation as part of the management of ulcerative colitis (UC) is becoming increasingly appreciated. However, the quality and completeness of UC endoscopy reports is variable. Previous studies have demonstrated that standardisation of reporting can optimise practice and there now exists expert consensus on which items should be included in a high quality UC endoscopy report. Our aim was to identify areas of suboptimal practice which could inform the design of an intervention bundle to improve reporting. We also aimed to identify any groups of endoscopists to whom the interventions should be specifically directed. Methods Reports of 227 lower GI endoscopies (103 flexible sigmoidoscopies, 124 colonoscopies) performed on UC patients at UCLH between April-October 2018 were reviewed. Reports were evaluated against 10 endoscopic reporting items recommended by the Building Research in Inflammatory Bowel Disease Globally (BRIDGe) groups expert consensus exercise1, as well as documentation of UCEIS scores. Thus, each report was given a mark out of 11. Subgroup analyses were carried using Mann-Whitney (continuous) or Fishers exact (categorical) tests. Results The rate at which each reporting item was documented is shown in table 1. Description of previous disease extent (3%), UC therapy (10%) and symptoms (9%) at the time of the procedure were all infrequently reported. However, perhaps the most clinically relevant finding was that an objective measure of disease activity was missing in nearly half of reports. Subgroup analysis demonstrated that non-consultants (trainees and nurse endoscopists) were significantly more likely to report UC therapies (p=0.045) and biopsy location (p=0.031). No other significant differences were observed for individual reporting items or overall score (median 5/11 in both groups, p=0.07). Conclusions Our data demonstrates that many endoscopic UC reports are not consistent with optimal practice based on expert consensus. We identified areas that could potentially be optimised using an interventional bundle. Most importantly, the use of an endoscopic index. The interventional bundle should involve all endoscopists and could include such measures as local training sessions, hard-copy and online training materials, pooling of UC procedures on dedicated lists and integration of template reports into reporting software. Reference Devlin SM, Melmed GY, Irving PM, et al. Recommendations for Quality Colonoscopy Reporting for Patients with Inflammatory Bowel Disease: Results from a RAND Appropriateness Panel. Inflamm Bowel Dis 2016;22:1418–24.

Introduction Waldenström's macroglobulinaemia (WM), an indolent IgM-secreting non-Hodgkin's B-cell lymphoplasmacytic lymphoma, has a reported average age of diagnosis of 65-70 years. and it is often regarded as a disease of the elderly. However, a significant proportion of patients are diagnosed at a younger age and data about this cohort is relatively limited, partly because of the low disease incidence. We seek to further elucidate the characteristics and impact of the disease in the younger patient cohort. Methods The WMUK Rory Morrison Registry (RMR) was searched for all patients younger than 60 years on day of diagnosis. Demographics, disease characteristics, treatment information and survival status were collected retrospectively. Results of patient reported outcome measures (PROMs) were collated. Results 269 patients from 16 UK centres were identified, with years of diagnosis between 1978 and 2018. Analysis focused on 235 patients who fulfilled diagnostic criteria for WM. Patient characteristics are shown in table 1. M:F ratio was 1.61:1 of which 158 patients were Caucasian, 17 Asian, 5 Black, 3 mixed and 6 of other ethnicity, 56 unrecorded. Bone marrow results were available in 156 patients from time of diagnosis, with a median infiltration of 40%. MYD88 L265P was found in 61/74 patients (82.4%) and CXCR4 mutation in 14/39 patients (35.9%). Median Hb was 114/L (range 33-170), platelet count 250x109/L (range 24-689), IgM 19 (range 0-65) and B2-microglobulin 2.7mcg/mL (range 0.5-56.3). The baseline IPSSWM scores were available for 115 patients. 9 patients were anti-MAG antibody positive and 11 had cryoglobulins. Treatment was received by 164 patients (69.8%). The median time from diagnosis to treatment was 2.5 months, range 0-312 months; 69 patients had one line, 32 two lines, 31 three lines, 12 four lines, and 20 five or more lines.14% received R-CHOP as first line therapy, 12.2% DRC,12.2% R-Bendamustine, 7.3% Rituximab monotherapy, 6.7% R-CVP and 6.7% chlorambucil. However, since 2010 DRC and R-Bendamustine were the most frequent. Following first line treatment, 14.7% achieved CR, 55.3% PR or VGPR, 11.9% MR and 14% had SD or PD. At some point in their disease course, high-grade transformation (HGT) was noted in 2 patients and CNS involvement in 10. 30 patients had undergone autologous and six patients allogenic transplantation. Complete, up to date survival information was available for 188 patients, of who 40 patients were deceased (median time from diagnosis 116 months, range 14-451 months). Unfortunately, cause of death was available for only 8 patients at time of analysis, including disease-related in 4, sepsis in 2, HGT in 1 and subdural haemorrhage in 1. One-, 5- and 10-year overall survival (OS) rates were 99.5%, 90% and 81.1%. There was a significant difference in OS according to IPSSWM risk (log rank, P Of 164 patients asked about their level of disease understanding on a scale of 0-10, the median rating was 0 (average rating 1.85). Only eight patients rated it as 10. Functional information was available for 62 patients, of who 42 (67.7%) had impairment in their ability to go for a walk outside, eight patients (12.9%) required assistance with self-care and one patient (1.6%) was fully dependent on others for personal care. 32 patients (51.6%) needed to spend some or most of their day in a bed or chair. 29 patients (47.8%) had suffered significant financial difficulties because of their diagnosis. Of 59 patients who responded about psychological wellbeing, 36 patients (61%) described feeling depressed. One patient described feeling 'very' depressed, 8 patients 'moderately' depressed and 27 patients 'slightly' depressed. Conclusion A significant proportion of patients with WM are diagnosed under the age of 60 years, and despite its limitations, this retrospective analysis of a large cohort of younger patients illustrates the evolving treatment landscape in the UK. To be expected, WM significant impacts on quality of life and psychological and financial wellbeing in a cohort who would expect to be in work. Encouragingly, OS rates are generally good, although a high IPSSWM risk carries a markedly lower 5-year OS rate also in the younger cohort. A more detailed analysis is underway to explore these issues further. Disclosures McCarthy: Janssen: Honoraria, Other: Educational grant to attend meetings . Pratt:Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support. D'Sa:Janssen: Honoraria, Research Funding.

Background Waldenström's macroglobulinaemia (WM) is a rare non-Hodgkin B cell lymphoma. Given its rarity, information about both patient demographics and disease characteristics are limited. Treatment is indicated for symptomatic patients and treatment regimens have evolved significantly in recent years. The Rory Morrison Registry (RMR) has comprehensive patient data available for analysis. We seek to draw conclusions about UK patient demographics and disease characteristics, and evaluate how treatment practices have evolved. Methods The RMR was searched for all patients with a diagnosis of WM. Patient demographics, disease characteristic, pathology results, treatment information and survival status retrieved. Kaplan Meier and log rank analysis was performed. Results 671 patients were identified from 19 different UK centres. Median age at diagnosis was 64 years (range 27-92, figure 1). Year of diagnosis ranged from 1978 to 2019, with 7 patients diagnosed Median haemoglobin at diagnosis was 112g/L (range 33-170), platelet count 242 (3-806), B2M 3 (range 0.2-56.3) and M-protein 17g/L (range 0-110.5). Median bone marrow infiltration was 40% (range 0-100%), with 35% lymphocytes and 5% plasma cell. MYD88 L265P mutations were detected in 160/190 patients (84.2%). CXCR4 mutations, for which testing is not widely available, were detected in 20/76 patients (26.3%). Peripheral neuropathy was seen in 74 patients, with 28 anti-MAG antibody positive. Other manifestations at diagnosis included cryoglobulinaemia (26), amyloidosis (12) and Schnitzler's syndrome (7). 2/317 patients were HIV positive, 4/341 HCV antibody positive, 27/334 HBSAb positive, and 12/327 HBCAb positive. IPSSWM score at diagnosis was available for 352 patients, with a low score in 122 (34.7%), intermediate score in 103 (29.3%), and high score in 123 (45%). 440 patients (65.6%) had received treatment, with a median time from diagnosis to treatment of two months (range 0-312). Indications for first line treatment initiation were: 35% paraprotein-related, 30% lymphoma-related , 2.1% B-symptoms, and a combination of indications for the remainder. Hyperviscosity was the treatment indication in 24.8% of patients, fatigue in 21.6% and peripheral neuropathy in 9.8%. At treatment commencement, 47% of patients had a haemoglobin of Lines of therapy received was one in 43.6%, two in 24.1%, three in 4.8%, four in 6.6% and ≥5 in 10.9%. In the past decade, 27.8% received DRC, 16.4% R-Bendamustine, 8.9% rituximab monotherapy, 7.7% R-CHOP and the rest varying combinations. 2.2% had received Bortezomib-containing therapy. Before 2010, chlorambucil (21.8%), R-CHOP (10.9%) and FC (9.3%) were the most frequently used first line treatments. BTK-inhibitors have become the most commonly used second line therapy, representing 23% of second line therapy after 2010, reflecting the availability of Ibrutinib on the Cancer Drugs Fund from 2017 and the availability of BTKi trials since 2015. 88 patients had received a BTKi at some point. 118 patients had deceased. Only 30 patients had a cause of death available; this included 7 patients who died from WM itself, 6 from pneumonia, 5 from sepsis (2 were neutropaenic), 3 from HGT, 2 from haemorrhage, 2 from thrombotic events, and 1 from CNS relapse. 5- and 10-year OS rates from diagnosis were 90.5% and 79.4%, with a significant difference in OS rates according to IPSSWM risk at diagnosis (p Conclusions The median age at diagnosis was 64 years, with a third of patients diagnosed under the age of 60. Although diverse, the most frequent indications for treatment in this cohort are hyperviscosity, fatigue and peripheral neuropathy. OS rates are high and correlate with IPSSWM risk, but a majority of patients had received multiple lines of therapy reflecting the chronically relapsing nature of WM. Treatment practices are clearly evolving, with increasing first line use of DRC and R-Bendamustine, as well as BTK inhibitors for relapsed disease. Disclosures McCarthy: Janssen: Honoraria, Other: Educational grant to attend meetings . Pratt:Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support. D'Sa:Janssen: Honoraria, Research Funding.