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Summary: The success of CD19 Chimeric antigen receptor (CAR) T‐cell therapy in large B‐cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off‐the‐shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the ʽstandard‐of‐care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020–2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression‐free survival (1‐year PFS 50% vs. 32%, p < 0.001) and overall survival (1‐year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high‐grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up‐to‐date clinical data when comparing CAR T against new treatment options for r/r LBCL. [ABSTRACT FROM AUTHOR]

Summary: Large B‐cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi‐cel) or tisagenlecleucel (tisa‐cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa‐cel versus axi‐cel (52% vs. 48%) compared to 20% versus 80% in ASCT‐fit patients; p < 0.0001. The drop‐out rate from approval to infusion was significantly higher in the ASCT‐unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression‐free and overall survival were similar in both cohorts. CAR T was well‐tolerated in ASCT‐unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real‐world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant. [ABSTRACT FROM AUTHOR]

Vasoactive peptides play an important role in a wide range of physiological and pathological conditions. Due to its known functions, the calcitonin gene-related peptide (CGRP) has been suggested as a possible modulator of the hyperimmune response in COVID-19 and thus, blocking its action may lessen the pulmonary effects of COVID-19. To compare the circulating levels of CGRPα and CGRPβ in healthy controls compared to hospitalized COVID-19 patients. The study also analyzed how different comorbidities and treatments may affect these concentrations in cases of COVID-19 infection with pulmonary involvement Serum samples were collected from the antecubital vein of 51 control subjects (mean age = 55 ± 14 years; range = 26–77; 56.9% female) and 52 patients hospitalized with COVID-19 infection (mean age = 55 ± 13; range = 23–77; 55.8% female) from December 2020 to May 2021. Enzyme-linked immunosorbent assays (ELISAs) were used for CGRPα (Abbexa, UK) and CGRPβ (CUSABIO, China) measurements. Comorbidities, symptoms, and treatments of infection were listed. The results showed that the serum levels of both isoforms of CGRP were significantly higher in patients with COVID-19 (α: 57.9 ± 35.8 pg/mL; β: 6.1 ± 2.6 pg/mL) compared to controls (α: 41.8 ± 25.4 pg/mL; β: 4.5 ± 2.4 pg/mL) (p <0.01). Also, the presence of arterial hypertension (HT), obesity, or corticosteroid treatment significantly alter the serum concentration of CGRPα in the subgroups compared to controls. The elevated serum CGRP levels found in our COVID-19 group compared to controls may suggest that CGRP plays a role in the pathophysiology of the disease, more specifically, in the cytokine storm and in the pulmonary involvement. Future studies should focus on the source of this CGRP elevation. [ABSTRACT FROM AUTHOR]

Summary: CD19 CAR‐T have emerged as a new standard treatment for relapsed/refractory (r/r) large B‐cell lymphoma (LBCL). CAR‐T real‐world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR‐T in the UK. Consecutive patients with r/r LBCL approved for CAR‐T by the National CAR‐T Clinical Panel between December 2018 and November 2020 across all UK CAR‐T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi‐cel), 112 tisagenlecleucel (tisa‐cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi‐cel, 57% (44% CR) for tisa‐cel. The 12‐month progression‐free survival was 41.8% (axi‐cel) and 27.4% (tisa‐cel). Median overall survival for the intention‐to‐treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi‐cel and 7.9%/3.9% for tisa‐cel. This prospective RW population of CAR‐T eligible patients offers important insights into the clinical benefit of CD19 CAR‐T in LBCL in daily practice. Our results confirm long‐term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR‐T failure. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID‐19) is a global health emergency. Despite the widely hypothesized role of a cytokine storm in disease severity, no study thus far has explored the association between immunosuppression and disease severity in patients hospitalized with COVID‐19. Objective: This study aimed to examine the association between the use of immunosuppressant medication and outcomes of patients hospitalized with COVID‐19. Methods: Nine hundred and eighty‐one consecutive patients hospitalized between 12 March 2020 and 15 April 2020, who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), were enrolled in this cohort study and subdivided by immunosuppression status. The patients were followed up for a minimum of 28 days (median 37 days) for the primary end‐point of mortality. Secondary end‐points included the composite of intubation or death, and the composite of mortality, intubation or continuous positive airway pressure (CPAP) requirement. Results: During the follow‐up period, 354 (36.1%) of study patients died. The immunosuppressed cohort (n = 31) had significantly higher mortality rates (aHR: 2.067, 95% CI: 1.20–3.57, P = 0.009). There was no association between immunosuppression and the composite end‐point of mortality or intubation (aHR: 1.49 95% CI: 0.88–2.51, P = 0.14) and of the composite end‐point of mortality, intubation or CPAP (aHR: 1.36 95% CI: 0.81–2.30 P = 0.245). Conclusion: In this cohort study of 981 confirmed COVID‐19 patients consecutively hospitalized at a large North West London hospital, immunosuppressant use was associated with significantly higher mortality rates. These results support the current UK government's early isolation ('shielding') policy for these individuals and should be used to guide future research. [ABSTRACT FROM AUTHOR]

Concern about the appropriate role of nonsteroidal anti-inflammatory drugs (NSAIDs) in COVID-19 speculate that NSAIDs, in particular ibuprofen, may upregulate the entry point for the virus, the angiotensin-converting enzyme (ACE) 2 receptors and increase susceptibility to the virus or worsen symptoms in existing disease. Adverse outcomes with COVID-19 have been linked to cytokine storm but the most effective way to address exaggerated inflammatory response is complex and unclear. The Expert Working Group on the Commission of Human Medicines in the UK and other organizations have stated that there is insufficient evidence to establish a link between ibuprofen and susceptibility to or exacerbation of COVID-19. NSAID use must also be categorized by whether the drugs are relatively low-dose over-the-counter oral products taken occasionally versus higher-dose or parenteral NSAIDs. Even if evidence emerged arguing for or against NSAIDs in this setting, it is unclear if this evidence would apply to all NSAIDs at all doses in all dosing regimens. Paracetamol (acetaminophen) has been proposed as an alternative to NSAIDs but there are issues with liver toxicity at high doses. There are clearly COVID-19 cases where NSAIDs should not be used, but there is no strong evidence that NSAIDs must be avoided in all patients with COVID-19; clinicians must weigh these choices on an individual basis. [ABSTRACT FROM AUTHOR]

Treatment of relapsed/refractory B-precursor acute lymphoblastic leukaemia (R/R B-ALL) in children remains a challenge, with only 30-50% of patients being salvaged by intensive chemotherapy and allogeneic haematopoietic stem cell transplantation (HSCT),1 with a dismal survival for those who relapse after HSCT.2 Results of immunotherapy with blinatumomab or autologous/allogeneic chimeric antigen receptor (CAR)-T cells hold out a promise of better outcomes3-6 and are now moving to the front-line of treatment protocols for selected high-risk patients (AALL1721/CASSIOPEIA, NCT03876769). The panel database included 230 patients with B-ALL, and for 138 patients (60%) the referring centre sought advice on curative treatment. The panel recommended antibody therapy for 47 patients (34%): blinatumomab for 34 patients, inotuzumab for eight, either blinatumomab or inotuzumab for five. [Extracted from the article]

Purpose/objective(s): Radiotherapy (RT) has potential synergistic effects with CD19 CAR-T but is not yet widely used as bridging therapy for lymphoma. Comprehensive outcome data of RT bridged patients are limited, and selection criteria for RT bridging and optimal dose / fractionation are unknown. We hypothesized that RT is a safe, well tolerated and effective bridging to CAR-T even in patients with advanced stage and high-risk features. We analyzed details of RT bridging in a prospective national CAR-T cohort, examining patient, disease and treatment factors which may affect outcome of RT bridging.Materials/methods: We analyzed consecutive patients with r/r high-grade lymphoma who had leukapheresis for axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between Dec 2018 - Nov 2020 in 10 UK centers and received RT bridging.Results: Of 371 leukapheresed patients, 76 (21%) received RT bridging (61 RT alone, 15 combined modality treatment (CMT)). Median age was 58 years. 65% had de novo diffuse large B-cell lymphoma, 7% primary mediastinal B-cell, and 28% transformed lymphoma. 64 were infused (50 axi-cel, 14 tisa-cel), with a median turnaround time of 44 days from apheresis to infusion. 12/75 (16%) patients did not proceed to CAR-T infusion (6 progressive disease (PD), 4 deaths (not related to RT), 1 manufacturing failure, 1 CR after bridging). The dropout rates were 11%, 33% & 22% for RT, CMT and chemotherapy-bridged patients respectively (P = 0.086). Disease characteristics were similar in RT & CMT groups; the majority had advanced stage (71% and 86%), 34% & 43% bulky disease, 59% & 73% extranodal involvement, 55% & 57% were primary refractory to R-CHOP, 75% & 67% had SD/PD as best response to last treatment, 18% & 13% had prior autologous transplant, and 31% & 33% had double/triple hit or -expression. In-field response in 53 cases bridged with RT alone (doses 20 - 40Gy) was 85% (11/14) for early stage (3 CR) and 63% (22/35) for advanced stage. Details of the radiation techniques and RT-related toxicities will be provided at the meeting. The ongoing overall response rate at 3 months post infusion was 63% (50% CR). With a median follow-up of 11.5 months, the median time to progression has not been reached. The 6- & 12-months event-free survival was 60% (95% CI: 47-71) and 58% (95% CI: 45 -69), respectively, with no significant difference between RT and CMT. The median overall survival (OS) was 17.8 months (95% CI: 8.9-NR), with 6- & 12-months OS rates of 77% (95% CI: 64 - 86) and 65% (95% CI: 50-76). Post CAR-T toxicity was favorable, with 7/64 (11%) experiencing G3/4 cytokine release syndrome, 8/64 (13%) G3/4 neurotoxicity. Treatment-related mortality was 4.6%.Conclusion: RT is a safe and effective bridging therapy prior to CD19 CART in lymphoma. In this large prospective real world national cohort with high proportion of advanced stage and high-risk features, RT bridging was given successfully with low dropout rate and excellent survival outcomes. [ABSTRACT FROM AUTHOR]

The novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the pathogen responsible for Coronavirus Disease 2019 (COVID-19). Whilst most children and young people develop mild symptoms, recent reports suggest a novel paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Case definition and classification are preliminary, treatment is empiric and disease-associated outcomes are unclear. Here, we report 29 patients with PIMS-TS who were diagnosed, admitted and treated in the English North West between March and June 2020. Consistent with patterns observed internationally, cases peaked approximately 4 weeks after the initial surge of COVID-19-like symptoms in the UK population. Clinical symptoms included fever (100%), skin rashes (72%), cardiovascular involvement (86%), conjunctivitis (62%) and respiratory involvement (21%). Some patients had clinical features partially resembling Kawasaki disease (KD), toxic shock syndrome and cytokine storm syndrome. Male gender (69%), black, Asian and other minority ethnicities (BAME, 59%) were over-represented. Immune modulating treatment was used in all, including intravenous immunoglobulin (IVIG), corticosteroids and cytokine blockers. Notably, 32% of patients treated with IVIG alone went into remission. The rest required additional treatment, usually corticosteroids, with the exception of two patients who were treated with TNF inhibition and IL-1 blockade, respectively. Another patient received IL-1 inhibition as primary therapy, with associated rapid and sustained remission. Randomized and prospective studies are needed to investigate efficacy and safety of treatment, especially as resources of IVIG may be depleted secondary to high demand during future waves of COVID-19. [ABSTRACT FROM AUTHOR]