Idiopathic Multicentric Castleman Disease Occurring Shortly after mRNA SARS-CoV-2 Vaccine.

Idiopathic Multicentric Castleman Disease (iMCD) is a potentially life-threatening systemic disease whose complex symptomatology is due to cytokine dysregulation. We, herein, present a case of severe iMCD occurring in a previously healthy young man shortly after mRNA SARS-CoV-2 vaccination, responding to interleukin-6 blockade with siltuximab. Six months after the completion of siltuximab, the patient remained without any signs of iMCD or inflammation, indicating a temporal trigger of the disease. This case not only adds to the potential pathogenetic spectrum of MCD, but also extends the clinical picture of potential but rare adverse events following COVID-19 immunization.

JAK ANTAGONISTS AND IL-6 INHIBITORS FOR MANAGEMENT OF SARS-COV-2 INFECTION: A SYSTEMIC REVIEW AND NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

SESSION TITLE: Medications and Pulmonary Rehabilitation in COVID-19 Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: 10/18/2022 01:30 pm - 02:30 pm PURPOSE: JAK-antagonists and IL-6 inhibitors are immunomodulators indicated for inflammatory pathologies. With the COVID pandemic, these drugs have been utilized in management of hospitalized patients with SARS-CoV-2. Selection between the two drug classes has been attributed to availability and physician comfort. No existing comparative randomized trial to date. METHODS: We performed a systematic review and network meta-analysis using PRISMA guidelines. Randomized controlled trials evaluating various IL-6 inhibitors and JAK-antagonists were included. Outcomes were 28-day mortality and progression, defined as advancement to mechanical ventilation or ECMO. Subgroup analysis of concomitant steroid and remdesivir usage was also analyzed. P-scores were used to rank treatment groups in class and drug specific classifications. RESULTS: We identified 33 RCTs with 13,680 patients that met our selection criteria. Our analysis revealed that IL-6 inhibitor versus JAK antagonists, IL-6 was associated with greater odds of mortality (OR = 1.23 (1.13, 1.34), p = 0.01). This finding was also evident in the subgroup receiving concomitant steroids and remdesivir (OR = 1.41 (1.00, 2.00), p = 0.049) but no significant differences observed for the outcome of progression in this group. Baricitinib is associated with a significant 30% reduction in 28-day mortality compared to Tocilizamab CONCLUSIONS: JAK-a vs control and IL-6 inhibitors vs control exhibit mortality reducation but JAKs did so at a greater rate. Similarly, for drug specific comparisons, Baricitinib reduced mortality by the greatest amount. Only IL-6 inhibitors seemed to have a significant effect on preventing progression. Siltuximab and Tocilizumab were both effective against control but Tocilizumab reduced progression the best. As a secondary goal, a sub-group analysis on concomitant steroid and Remdesivir usage demonstrated that for drug specific comparisons, Baricitinib performed better for reducing mortality & Tocilizumab continued to be the most effective in preventing progression. However, with Remdesivir and steroids, there was no significant difference between Baricitinib and Tocilizumab in decreasing mortality. This is contrary to the findings without steroids. CLINICAL IMPLICATIONS: We hope to use this data to help clinical decision making between JAK-a and IL-6 inhibitors which are currently being used interchangeably for the management of COVID-19 in hospitalized patients. Through our study results and analysis, we recommend that Baricitinib be used to decrease mortality rates and disease progression for the treatment of COVID-19 with concomitant therapy corticosteroids and Remdesivir. Moving forward with this data, we aim to help restructure COVID-19 treatment algorithms regarding IL-6 and JAK antagonists. DISCLOSURES: No relevant relationships by Monica Bhagavan No relevant relationships by rukhsaar khanam No relevant relationships by Anant Naik No relevant relationships by Aashka Shah

Long-term treatment outcome of Castleman's disease: A real-world experience.

Background: Castleman disease (CD), classified as unicentric CD (UCD) or multicentric CD (MCD), is a rare non-neoplastic lymphoproliferative disorder of unknown origin. Owing to its rarity, the clinical characteristics, therapeutic modalities, treatment outcomes, and prognostic factors related to UCD or MCD are not well defined. Method: We retrospectively analyzed 88 patients with CD, including those with hyaline-vascular, plasma-cell, mixed type, hypervascular, and plasmablastic subtypes, for presenting symptoms, physical, laboratory, and radiologic findings, and treatment response in the Korean population. Results: The median patient age was 44 years (range: 18-84 years) with slight predominance of women (53.4%). UCD and MCD accounted for 38.6% (n=34) and 61.4% (n=54) of cases, respectively. Histopathologically, UCD patients were classified as 88.2% (n=30) hyaline-vascular and 11.8% (n=4) plasma cell types, whereas MCD patients were classified as 27.8% (n=15) hypervascular, 61.1% (n=33) plasma cell, 7.4% (n=4) mixed, and 3.7% (n=2) plasmablastic types. Twelve (13.6%) patients exhibited a poor performance status with an Eastern Cooperative Oncology Group score of 2. The most common presenting symptom was sustained fever, followed by fatigue, anorexia, peripheral edema, and weight loss. Furthermore, splenomegaly, pleural effusion, and ascites were observed to be associated with CD. Surgical resection and siltuximab were the preferred treatment modalities for UCD and MCD, respectively, with favorable symptomatic, laboratory, and radiologic outcomes and safety profiles. The overall survival was 90.2%, with no significant difference between the UCD and MCD groups (p=0.073), but progression-free survival was significantly poorer in the MCD group (p=0.001). Age ≥60 years and splenomegaly significantly affected the overall and progression-free survival rates. Conclusion: Patients with UCD had favorable outcomes with surgical resection of a solitary mass, whereas in patients with MCD, old age and splenomegaly were identified as independent prognostic factors. Further well-designed prospective studies under advancing knowledge of the pathophysiology of MCD are warranted to establish suitable guidelines for the discontinuation or prolonging infusion intervals of siltuximab and treatment modalities for HHV-8 positive MCD patients or patients with siltuximab failure.

Immune-related adverse events of biological immunotherapies used in COVID-19.

The use of biological immunotherapeutic drugs is one of the options currently being evaluated and employed to manage COVID-19, specifically monoclonal antibodies, which have shown benefit by regulating the excessive immune response seen in patients with severe infection, known as a cytokine storm. Tocilizumab has received particular importance for this clinical application, as has sarilumab. Both drugs share a substantial similarity in terms of pharmacodynamics, being inhibitors of the interleukin six receptor (IL-6Rα). Furthermore, sotrovimab, a neutralizing anti-SARS CoV-2 antibody, has gained the attention of the scientific community since it has recently been authorized under certain circumstances, positioning itself as a new therapeutic alternative in development. However, despite their clinical benefit, biological immunotherapies have the potential to generate life-threatening immune-related adverse events. Therefore it is essential to review their incidence, mechanism, and risk factors. This review aims to provide a comprehensive understanding of the safety of the biological immunotherapeutic drugs currently recommended for the treatment of COVID-19, provide a review of the known immune-mediated adverse events and explore the potential immune-related mechanisms of other adverse reactions.

Multisystem Inflammatory Syndrome in Children Associated with COVID-19 Infection: A Comprehensive Review

The Multisystem Inflammatory Syndrome in Children (MIS-C) is a postinfectious syndrome associated with coronavirus disease 2019 (COVID-19) disease in children. The aim of this study is to conduct a thorough review to assist health care professionals in diagnosis and management of this complication of COVID-19 disease in children. A thorough systematic review was conducted through an on-line search based on MIS-C with the primary focus on epidemiology, clinical characteristics, diagnosis, pathophysiology, management, and long-term follow-up. This syndrome is characterized by an exaggerated and uncontrolled release of proinflammatory cytokines involving dysfunction of both innate and adaptive immunity. In this review, a summary of observational studies and case reports was conducted, in which we found that MIS-C generates multiple-organ failure frequently presenting with hemodynamic instability further characterized by Kawasaki-like symptoms (such as persistent high fever, polymorphic rash, and bilateral conjunctivitis) and predominance of gastrointestinal and cardiovascular signs and symptoms. Keys to effective management involve early diagnosis, timely treatment and re-evaluation following hospital discharge. Diagnosis is marked by significant elevation of inflammatory biomarkers, laboratory evidence of COVID-19 infection or history of recent exposure, and absence of any other plausible explanation for the associated signs, symptoms, and presentation. Management includes hemodynamic stabilization, empiric antibiotic therapy (de-escalation if cultures and polymerase chain reaction studies indicate no bacterial co-infection), immunomodulatory therapy (methylprednisolone, intravenous immunoglobulin, anakinra, tocilizumab, siltuximab, Janus kinase inhibitors, tumor necrosis factor-α inhibitors), antivirals (remdesivir), and anticoagulation (acetylsalicylic acid, unfractionated or low-molecular-weight heparin or new oral anticoagulants). In addition, we identified poor prognostic risk factors to include concurrent comorbidities, blood-component consumption and marrow suppression (lymphopenia, thrombocytopenia), depletion of homeostatic components (hypoalbuminemia), and marked evidence of a hyperinflammatory response to include elevated values of ferritin, C-reactive protein, and D-dimer. MIS-C constitutes a postinfectious syndrome characterized by a marked cytokine storm, characterized by fever, bilateral conjunctivitis, and multiple organ dysfunction. Promoting future research and long-term follow-up will be essential for the development of guidelines and recommendations leading to effective identification and management of MIS-C.

OFF-LABEL USE OF INTERLEUKIN-6 INHIBITORS IN PAEDIATRICS: A SYSTEMATIC REVIEW

Aim Elevated Interleukin-6 (IL-6) is associated with the pathogenesis of various chronic inflammation and autoimmune conditions. 1 Currently, only three IL-6 inhibitors, tocilizumab, siltuximab and sarilumab, are approved for a limited number of conditions in adults, and only tocilizumab is licensed in children.2 However, off-label use of these drugs has been reported in paediatrics. This review aimed to summarise the evidence base for the off-label use of these three IL-6 inhibitors in children, the indications for off-label use, and the doses prescribed. The nature of adverse events associated with the off-label use of these drugs and the clinical effectiveness were also identified. Method A systematic search was conducted on EMBASE, Medline, and PubMed;studies published in the English language between 2009-2020, reporting the off-label use of tocilizumab, siltuximab and sarilumab in children aged 18 years or under were included. Data screening and extraction were performed independently by two reviewers. The quality of included studies was assessed using the Newcastle-Ottawa quality assessment scale for cohort and cross-sectional studies, and the National Institutes of Health quality assessment tool for case series. The review was conducted and reported in accordance with the PRISMA guidelines for systematic reviews3 and was registered on PROSPERO with registration number CRD42021221631. Results In total 81 studies were included in the systematic review, with 18.5% (15/81) studies deemed of good quality, 24.7% (20/81) studies of fair quality, and 56.8% (46/81) studies of poor quality. Almost all of the studies (99%, 80/81) were on tocilizumab. Only one study investigated siltuximab and none were found for sarilumab. The total number of patients included in the identified studies was 211 (210-tocilizumab, 1 siltuximab). For tocilizumab, the most frequently reported clinical indication was the management of complications associated with hematopoietic stem cell transplantation (24.3%, 51/210) followed by its use in the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) (17.5%, 14/80). Overall, tocilizumab was prescribed for 28 unlicensed indications, and the dose varied from 4 to 12 mg/kg. Dosing frequency was reported in 98.7% (79/80) of tocilizumab studies, with 'every two weeks' prescribed most often (53.2%, 72/79). Adverse events were reported in 20.4% (43/211) of patients of which 32.6% (14/43) experienced adverse events, e.g. respiratory tract infections (n=2) and low platelet counts (n=2). The clinical outcome of the off-label use of tocilizumab was described to be successful in 55% (44/80) of studies, with reported success in the treatment of SARS-COV-2 and uveitis (13.6%, 6/44, each). The article on siltuximab reported no clinical outcomes. Conclusion This is the first systematic review of the off-label use of IL-6 directed therapies in children. The limited data suggest that tocilizumab may be effective in a number of offlabel indications, but the quality of available evidence is low and there remains the need for adequately powered and welldesigned studies to support its use in clinical practice. The findings of this review should be used as a basis to inform future clinical trials in paediatrics.

A BRIEF SYNOPSIS OF MONOCLONAL ANTIBODY FOR THE TREATMENT OF VARIOUS GROUPS OF DISEASES.

Monoclonal antibodies (mAbs) are increasingly being prescribed to patients and investigated in the field of medicine and research. This class of medication is unique due to its ability to be engineered into targeting a specific receptor. Numerous studies and reviews have reported the efficacy, potency, and clinical usage of mAbs in the treatment of a variety of diseases ranging from autoimmune disorders to malignant cancers. However, very few publications classify and provide a brief synopsis of mAbs that includes their pharmacological profiles. mechanisms of action, uses, and side effects in a concise manner. Therefore, this review aims to classify the current mAbs drugs used in clinical practice according to system diseases by providing a brief summary for each of them. For example, regarding cardiovascular disorders, mAbs such as Abciximab, Bevacizumab, and Digoxin Immune Fab will be reviewed. Denosumab, used to treat musculoskeletal disorders, will be also discussed. In addition, mAbs such as Adalimumab, Eculizumab, Natalizumab used in autoimmune disorders and Alemtuzumab, Trastuzumab, Cetuximab, and Rituximab that are prescribed for tumors will be reviewed. Finally, we shall discuss two mAbs that are IL-6 antagonists, Tocilizumab and Siltuximab, which are in ongoing clinical trials as potential treatments of COVID-19. The mAbs have profound benefits against chronic and malignant conditions, and the overall purpose of this review is to illustrate the basic pharmacological profiles of mAbs that physicians may find useful in establishing their management protocols.

Association between Insufficient Interleukin-6 (IL-6) Inhibition and Worsening Outcomes in COVID-19 and Idiopathic Multicentric Castleman Disease (iMCD), and a Mathematical Model to Predict Optimal Dosing to Completely Block IL-6 Activity

Dysregulated inflammatory responses are characterized by inappropriate levels of inflammatory markers, speed of generation, degree, and major site of production, such as a vital organ. COVID-19 severity and mortality are strongly associated with interleukin (IL)-6 levels. High IL-6 levels are also observed in idiopathic Multicentric Castleman Disease (iMCD). Previously, we developed the first anti-IL-6 monoclonal antibody (mAb) treatments and showed that C-reactive protein (CRP) production could be fully controlled by IL-6 in humans. Using mathematical modeling, with CRP as an IL-6 surrogate marker, we predicted the ability of an anti-IL-6 mAb to block plasma IL-6 activity and showed IL-6 inhibition was dependent on the extent of whole-body IL-6 production. We postulate that in patients (pts) in whom IL-6 concentration at the site of inflammation is higher than in the plasma, full blockade of plasma IL-6 activity, shown by complete CRP inhibition, is the minimum requirement to achieve clinical efficacy. CRP inhibition with tocilizumab (TCZ) in pts with COVID-19. We identified 35 published studies evaluating the efficacy or potential role of anti-IL-6 therapy in pts with severe COVID-19. Surprisingly, only one (Luo et al. J Med Virol 2020;92:814) reported dynamics of CRP reduction for individual patients throughout treatment. We fitted a hypothetical curve of CRP reduction required to completely block IL-6, based on the half-life of CRP, and added data points of CRP serum levels from pts treated with anti-IL-6 receptor (IL-6R) therapy, TCZ, in this study. Complete reduction of CRP was not achieved in all patients: 3 pts who died had CRP levels ≥12.8 mg/l. Of 2 pts whose disease worsened, CRP levels were 93.5 mg/l and 6.3 mg/l. However, pts whose condition stabilized (n=9), or whose symptoms improved (n=1), had CRP levels close to the theoretical curve that is likely required to fully block IL-6 (CRP levels ≤5.0 mg/l). Half of these pts had been given repeated doses of TCZ. Siltuximab (SIL) treatment (NCT01024036 trial) for pts with iMCD. To assess the impact of baseline CRP levels on response to anti-IL-6 therapy, SIL, patients were divided into low and high CRP groups based on a baseline CRP level threshold of 40 mg/l (corresponding to ~40 pg/ml of IL-6;Fig 1). In patients with low baseline CRP levels (<40 mg/l;n=35), CRP levels were significantly reduced with SIL treatment on day 8 (n=26;P=0.0003) and day 15 (n=22;P=0.0043) post-dosing. In patients with high baseline CRP levels (>40 mg/l;n=17), CRP levels were significantly reduced on day 8 (n=17;P<0.0001) and day 15 (n=15;P<0.0001) post-dosing (Fig 1). A significant increase in CRP levels from day 8 to day 15 was observed in these patients (P=0.0120);this increase was not observed in patients with low baseline CRP levels (P=0.243;Fig 1). There was a negative correlation between maximum CRP and hemoglobin change (P<0.001). Inhibition of IL-6 activity by anti-IL-6 (SIL 700 mg) and anti-IL-6R (TCZ 800 mg) as monotherapy, intensified, or combined therapy. To evaluate the effect of therapy on IL-6 activity, our algorithm modeled inhibition of IL-6-(IL-6R/soluble IL-6R)-gp130 transducer complexes. This serves as a proxy for IL-6 bioactivity and accounts for the buffering capacity of gp130, which can be overwhelmed in inflammatory situations with high IL-6 concentrations. Due to uncertainty over the concentration of mAbs in alveoli relative to plasma, we modeled the effects of SIL and TCZ at local concentrations of 100%, 10%, and 1% (Fig 2) of those in plasma. Our model demonstrated that anti-IL-6 was associated with stronger inhibition of CRP than anti-IL-6R. However, only the association of both anti-IL-6 and anti-IL-6R mAbs was associated with a total blockade of CRP, which is probably necessary when IL-6 levels are associated with high risk to the patient. Different administration schedules to intensify anti-IL-6 therapy were modeled, including the repeated or combined use of anti-IL-6 and anti-IL-6R mAbs. The results form a basis to optimize treatment trategies to avoid the cytokine storm in several diseases, including cancer, iMCD, and autoimmune disorders. The feasibility of the theoretically defined approaches needs to be evaluated, particularly the potential side-effect profile for a combined treatment approach. In conclusion, in clinical practice, IL-6 inhibition should be individualized based on pathophysiology and regular CRP monitoring. [Formula presented] Disclosures: Rossi: E-SANA Inc: Other: Co-founder of E-SANA Inc;EUSA Pharma: Consultancy;LEO Pharma: Consultancy;NPO Petrovax Pharm: Consultancy. Levon: E-SANA Inc: Other: Co-founder of E-SANA Inc. Kanhai: EUSA Pharma: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding;N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’;Pfizer: Other: Study drug for clinical trial of sirolimus. OffLabel Disclosure: Siltuximab is approved for the treatment of iMCD. Tocilizumab is approved for the treatment of Rheumatoid arthritis, Giant cell arteritis, Cytokine release syndrome, Systemic juvenile idiopathic arthritis and Polyarticular juvenile idiopathic arthritis. Combination therapy using Siltuximab and Tocilizumab has not yet been approved.

A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab.

Since the beginning of the pandemic, numerous national and international clinical trials have been conducted with a large number of drugs. Many of them are intended for the treatment of other pathologies; however, despite the great effort made, no specific drug is available for the treatment of the symptoms of respiratory disease caused by SARS-CoV-2 infection. The aim of this article is to provide data to justify the use of drugs to tackle the effects produced by IL-6 as the main inflammatory mediator in patients with COVID-19 with severe respiratory complications, considering all clinical evidence linking the poor prognosis of these patients with increased IL-6 levels in the context of cytokine release syndrome. Furthermore, data are provided to justify the proposal of a rational dosing of siltuximab, a monoclonal antibody specifically targeting IL-6, based on RCP levels, considering the limited results published so far on the use of this drug in COVID-19. A literature search was conducted on the clinical trials of siltuximab published to date as well as on the different IL-6 signalling pathways and the effects of its overexpression. Knowledge of the mechanisms of action on these pathways may provide important information for the design of drugs useful in the treatment of these patients. This article describes the characteristics, properties, mechanism of action, therapeutic uses and clinical studies conducted with siltuximab so far. The results confirm that administration of siltuximab downregulates IL-6 levels, thereby reducing the inflammatory process in COVID-19 patients with severe respiratory disease, suggesting that it can be successfully used to prevent cytokine release syndrome and death from this cause.

Analysis of Outcomes and Predictors of Response in Patients with Relapsed Mantle Cell Lymphoma Treated with Brexucabtagene Autoleucel

Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is require to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. [Formula presented] Disclosures: Gerson: TG Therapeutics: Consultancy;Kite: Consultancy;Abbvie: Consultancy;Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding;Celgene/BMS: Research Funding;BeiGene: Research Funding;Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy;BeiGene: Consultancy, Speakers Bureau;Morphosys: Consultancy, Speakers Bureau;Takeda: Research Funding;Genentech: Consultancy;AstraZeneca: Speakers Bureau;Roche: Consultancy;Karyopharm: Consultancy;Epizyme: Consultancy;Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau;BMS/Celgene/Juno: Consultancy, Research Funding;EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding;AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio and Atara Biotherapeutics: Consultancy;Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding;Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau;Karyopharma: Consultancy, Honoraria;Seattle Genetics: Consultancy, Honoraria, Speakers Bureau;Janssen: Consultancy, Honoraria, Speakers Bureau;TG Therapeutics: Consultancy, Honoraria, Research Funding;Incyte: Consultancy, Honoraria;Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau;Genmab: Consultancy, Honoraria;Epizyme: Honoraria, Speakers Bureau;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Consultancy, Honoraria, Speakers Bureau;ADC Therapeutics: Consultancy, Honoraria;Adaptive Biotech: Consultancy, Honoraria;AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau;Servier Pharmaceuticals: Consultancy;Seattle Genetics: Speakers Bureau;Sanofi: Speakers Bureau;Pharmacyclics: Consultancy;MorphoSys: Consultancy;Kite (Gilead): Speakers Bureau;KaryoPharm: Consultancy;CSL Therapeutics: Consultancy;Bristol-Myers Squibb: Speakers Bureau;Biogen: Consultancy;Beigene: Consultancy;AstraZeneca: Speakers Bureau;ADC Therapeutics: Consultancy;Adaptive Biotechnologies: Consultancy;AbbVie: Consultancy. Grover: Genentech: Research Funding;Novartis: Consultancy;ADC: Other: Advisory Board;Kite: Other: Advisory Board;Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months;BMS: Divested equity in a private or publicly-traded company in the past 24 months;Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months;Novatis: Divested equity in a private or publicly-traded company in the past 24 months;Janssen: Divested equity in a private or publicly-traded company in the past 24 months;Morphosys: Divested equity in a private or publicly-traded company in the past 24 months;ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months;Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months;Beigene: Divested equity in a private or publicly-traded company in the past 24 months;Merck: Divested equity in a private or publicly-traded company in the past 24 months;KITE: Divested equity in a private or publicly-traded company in the past 24 months;Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support;Humanigen: Consultancy, Honoraria, Other: Travel support;Celgene: Consultancy, Honoraria, Other: Travel support;Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding;Lonza: Consultancy, Honoraria, Other: Travel support;AbbVie: Consultancy, Honoraria;Precision Biosciences: Consultancy, Honoraria, Other: Travel support;Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support;Nkarta: Consultancy, Honoraria;Axis: Speakers Bureau;Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy;Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

Safety and Tolerability of Sars-Cov-2 Vaccination and Natural History of Infection Among Patients with Castleman Disease

Castleman Disease (CD) represents a group of rare and heterogeneous hematologic disorders that have common lymph node histopathology. Patients with CD are often immunosuppressed as a consequence of immunemodulating therapy or possibly due to an underlying immunologic dysfunction attributable to B-cell dysfunction. The most severe CD cases experience a cytokine storm disorder, a life-threatening exacerbation of circulating cytokines and immune-cell hyperactivation. Infection with SARS-CoV-2 progresses to a severe cytokine storm in the most severe cases of COVID-19. Interleukin-6 (IL-6) is central to the pathogenesis of CD, and increased IL-6 often accompanies severe COVID-19 cases;inhibition of IL-6 with monoclonal antibodies has been shown to be effective therapy for both CD and severe COVID-19. We therefore sought to understand the impact of COVID-19 infection on the natural history of CD and also examined the safety and tolerability of COVID-19 vaccines in this vulnerable patient population. Patients enrolled in a longitudinal natural history study of CD (N=298) were invited to participate in a survey designed to characterize their experience with COVID-19 disease and vaccination. Surveys were emailed to all eligible patients, and reminders were sent up to 3 times. All data is self-reported;descriptive analyses are reported herein. Of the 298 patients who received a survey, 101 (33.9%) completed it. Sixty-nine (68%) had been tested for SARS-CoV-2 at least once, and 10 (14.5%) reported testing positive - including 6 UCD, 3 iMCD, and 1 HHV8+ MCD patients. The reported prevalence of SARS-CoV-2 infection in the US compares at 10.5%. Two of the 10 patients reported asymptomatic disease (both UCD), 7 reported mild disease (4 UCD, 1 iMCD, 1 HHV8+MCD), and 1 reported moderate disease requiring hospitalization but not a ventilator or intensive care (iMCD). This severity distribution suggests that these potentially immunocompromised patients experience a range of disease severity consistent with SARS-CoV-2 infection in the broader US population. The most commonly-reported symptoms included fevers/chills, headaches, and loss of taste or smell (N=7 each), as well as shortness of breath/difficulty breathing, muscle and body aches, and cough (N=5 each). Rarer symptoms were also noted among the iMCD patients, including discoloration of skin, lips, or nailbeds (N=1) and newfound confusion (N=2). Two of the 10 patients reported stopping siltuximab treatment during their COVID-19 diagnosis;both subsequently resumed treatment. No other treatment changes were reported. Of the 101 respondents, 87 (86%) had received at least 1 vaccine dose. Treatments, such as immunosuppressants and immunomodulators, were paused for 7 of these patients including, during the vaccination period;this was presumably done to increase the likelihood of a robust response to the vaccine. Fifty-one patients (59%) reported side effects to either dose 1 or 2. Side effects were generally mild, and none required hospitalization. Side effects were more commonly reported after dose 2, with the most common being arm pain (N=34), fatigue (N=30), and headache (N=26). Of those who reported not receiving the vaccine, 2 intend to receive it in the future, 5 reported being unsure about receiving it, and 7 do not intend to receive the vaccine. Common concerns include potential interaction with CD (N=9) and limited safety data (N=8). This study represents the first investigation into the experience of CD patients with SARS-CoV-2 testing, diagnosis, and vaccination. We did not observe a markedly increased inflammatory response to SARS-CoV-2 infection, and vaccination was well-tolerated. A limitation is self-selection survey bias;it is possible that those who chose to participate represent those who had a milder reaction in general. However, it is noteworthy that there were no reports of severe disease in this sample. The prevalence of confirmed SARS-CoV-2 infection in this cohort (14.5%) is marginally higher than reported in the US population (10.5%) but statistical comp risons were not performed given that this study does not provide a general epidemiological estimate. However, the distribution of symptoms and vaccine adverse effects in this sample were comparable to the general population. Though additional follow-up is planned for the future, these data are an important basis for understanding the interaction of SARS-CoV-2 and CD. Disclosures: Casper: EUSA Pharma: Consultancy. Fajgenbaum: Pfizer: Other: Study drug for clinical trial of sirolimus;N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’;EUSA Pharma: Research Funding. OffLabel Disclosure: Our makes reference to the following: “Interleukin-6 (IL-6) is central to the pathogenesis of CD, and increased IL-6 often accompanies severe COVID-19 cases;inhibition of IL-6 with monoclonal antibodies has been shown to be effective therapy for both CD and severe COVID-19.” Inhibition of IL-6 with monoclonal antibodies for use in COVID-19 is off-label.

COVID-19 acute respiratory distress syndrome: A simulation study of the effects of combination therapy with tocilizumab and siltuximab.

AIMS: To assess the potential of interleukin-6 (IL-6) signalling blockade in the lung to treat SARS-CoV-2 infection via model-based simulation by exploring soluble IL-6 receptor (sIL-6R) sequestration by tocilizumab (TCZ) and IL-6 sequestration by siltuximab (SIL). METHODS: Literature values of IL-6, IL-6 antagonist SIL, sIL-6R, IL-6R antagonist TCZ and their respective binding constants were used to develop a model to predict the impact of treatment on IL-6 signalling. Models were used to generate simulated bronchoalveolar lavage fluid concentrations for normal subjects, subjects at risk of developing acute respiratory distress syndrome (ARDS), and subjects with ARDS under 4 conditions: without treatment; treatment with TCZ; treatment with SIL; and treatment with TCZ + SIL. RESULTS: With TCZ intervention, IL-6 levels are unaffected and sIL-6R is reduced somewhat below the Normal case. IL-6:sIL-6R complex only slightly decreased relative to the no-intervention case. With SIL intervention, sIL-6R levels are unaffected and IL-6 is greatly reduced below the Normal case. IL-6:sIL-6R complex is greatly decreased relative to the no-intervention case. With TCZ + SIL intervention, IL-6 and sIL-6R levels are reduced below the Normal case and achieve suppression equivalent to monotherapy results for their respective targets. IL-6:sIL-6R complex reduction is predicted to be greater than that achieved with monotherapy. This reflects sequestration of both components of the complex and the nonlinear binding equilibrium. CONCLUSION: Coadministration of both IL-6 and IL-6R sequestering products such as SIL and TCZ may be necessary to effectively treat COVID-19 patients who have or are at risk of developing ARDS.

Experience with the use of siltuximab in patients with SARS-CoV-2 infection.

OBJECTIVE: The study aims to describe characteristics and clinical outcome of patients with SARS-CoV-2 infection that received siltuximab according to a protocol that aimed to early block the activity of IL-6 to avoid the progression of the inflammatory flare. METHODS: Retrospective review of the first 31 patients with SARS-CoV-2 treated with siltuximab, in Hospital Clinic of Barcelona or Hospital Universitario Salamanca, from March to April 2020 with positive polymerase-chain reaction (PCR) from a nasopharyngeal swab. RESULTS: The cohort included 31 cases that received siltuximab with a median (IQR) age of 62 (56-71) and 71% were males. The most frequent comorbidity was hypertension (48%). The median dose of siltuximab was 800 mg ranging between 785 and 900 mg. 7 patients received siltuximab as a salvage therapy after one dose of tocilizumab. At the end of the study, a total of 26 (83.9) patients had been discharged alive and the mortality rate was 16.1% but only 1 out of 24 that received siltuximab as a first line option (4%). CONCLUSIONS: Siltuximab is a well-tolerated alternative to tocilizumab when administered as a first line option in patients with COVID-19 pneumonia within the first 10 days from symptoms onset and high C-reactive protein.

The role of IL-6 and IL-6 blockade in COVID-19.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. AREAS COVERED: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. EXPERT OPINION: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.

Overview on the use of IL-6 agents in the treatment of patients with cytokine release syndrome (CRS) and pneumonitis related to COVID-19 disease.

INTRODUCTION: A novel coronavirus pneumonia (COVID-19) has caused significant life loss and healthcare burden globally. COVID-19 is known to cause a cytokine release syndrome (CRS) like response, and interleukin-6 (IL-6) is one of the cytokines involved. Clinicians are using IL-6 inhibitors to CRS, and researchers are investigating the use of IL-6 inhibitors, namely tocilizumab, sarilumab, siltuximab, in COVID-19 management. AREAS COVERED: In this article, we will discuss the pharmacology of these three inhibitors and summarize available clinical data via literature search on PubMed with keywords of tocilizumab, sarilumab, siltuximab, and COVID-19. While awaiting more data from randomized clinical trials on these drugs, observational studies and clinical reports have demonstrated IL-6 inhibitors showed some benefits in improving clinical outcome and a well-tolerated safety profile. EXPERT OPINION: There is a role for suppressing the immune response with IL-6 inhibitors that will continue to require investigation. These agents are available and have demonstrated a mild safety profile. There may be advantages to a targeted approach to suppressing the hyperinflammatory state of the disease. Timing, the long-term effects, and what cocktail of medications demonstrates the strongest outcomes are all important considerations as IL-6 inhibitors continue to be evaluated in this global pandemic.

Role of monoclonal antibody drugs in the treatment of COVID-19.

Currently clinicians all around the world are experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical presentation of this pathology includes fever, dry cough, fatigue and acute respiratory distress syndrome that can lead to death infected patients. Current studies on coronavirus disease 2019 (COVID-19) continue to highlight the urgent need for an effective therapy. Numerous therapeutic strategies have been used until now but, to date, there is no specific effective treatment for SARS-CoV-2 infection. Elevated inflammatory cytokines have been reported in patients with COVID-19. Evidence suggests that elevated cytokine levels, reflecting a hyperinflammatory response secondary to SARS-CoV-2 infection, are responsible for multi-organ damage in patients with COVID-19. For these reason, numerous randomized clinical trials are currently underway to explore the effectiveness of biopharmaceutical drugs, such as, interleukin-1 blockers, interleukin-6 inhibitors, Janus kinase inhibitors, in COVID-19. The aim of the present paper is to briefly summarize the pathogenetic rationale and the state of the art of therapeutic strategy blocking hyperinflammation.

Outlook of IL-6 signaling blockade for COVID-19 pneumonia.

In this review article, it is highlighted the implications of pleiotropic functions of interleukin-6 (IL-6) for one of the therapeutic options targeting for COVID-19. Moreover, it is discussed how real-world data and trials with IL-6 signaling blockade will be crucial in informing the development of new treatment for COVID-19 pneumonia. Given physiological roles of IL-6 in inflammatory conditions and the data from real world, IL-6 signal inhibitors, along with standard of care (SOC) treatment, might provide efficacy, offering the potential to treat COVID-19 in hospitalized populations more effectively than current SOC alone. Therefore, on-going and planned randomized placebo-controlled studies in combination with SOC and other therapeutics to assess safety and efficacy of IL-6 signal inhibitors in hospitalized patients with severe COVID-19 pneumonia will be warranted to address the high unmet need and burden of disease in this severely ill population.

Interleukin-6 Blocking vs. JAK-STAT Inhibition for Prevention of Lung Injury in Patients with COVID-19.

The severe respiratory insufficiency observed during COVID-19 infection may not be directly related to a cytopathogenic effect induced by the virus itself, but to an exaggerated and inappropriate immune response. In an effort to reduce the severity of organ dysfunction, including respiratory insufficiency, monoclonal antibodies (Mabs) that block the interleukin-6 receptor, such as tocilizumab, sarilumab, and siltuximab, are under investigation for the treatment of COVID-19. However, blocking of just one of the many cytokines involved in the inflammatory reaction may not slow down the magnitude of the process. Since timing is important, the immune deficiency induced by IL6 blockade at the late immunodeficiency phase of sepsis that follows the initial inflammatory response may be detrimental. Finally, monitoring the degree and duration of IL6 blockade may be challenging because of the long half-life of Mabs (2-3 weeks). Pro- and anti-inflammatory cytokines act through a common JAK-STAT signaling pathway, which can be inhibited by JAK-STAT inhibitors. Ruxolitinib, a tyrosine kinase inhibitor selective for JAK1, 2, blocks many pro- and anti-inflammatory cytokines including IL6. Ruxolitinib has favorable pharmacodynamics and an acceptable safety profile. The short half-life (4-6 h) of the drug offers the opportunity for ideal monitoring of the degree and duration of cytokine blocking, simply by the adjusting dose and duration of therapy. From a theoretical point of view, the balanced control of cytokine blockade throughout the course of the septic process should be the cornerstone of modern management. According to this hypothesis, maximization of blocking should be attempted at the phase of hyper-inflammation for preventing severe organ damage, while pro-inflammatory blockade should be minimized at the late phase of immunoparalysis for prevention of secondary infections. Based on the above considerations, we consider that the efficacy and safety of this drug deserves testing in the context of a controlled randomized trial.

Treatment of severely ill COVID-19 patients with anti-interleukin drugs (COV-AID): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome. TRIAL DESIGN: A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study. PARTICIPANTS: Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded. INTERVENTION AND COMPARATOR: Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization. MAIN OUTCOMES: The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized. RANDOMISATION: Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab. TRIAL STATUS: COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 1st, 2020 (ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.