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      Anti-BCMA-CAR-T-Zell-Therapie bei einem Patienten mit rezidiviertem und refraktärem Multiplen Myelom nach einer COVID-19-Infektion: ein Fallbericht

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          Abstract

          Hintergrund: Über das Risiko einer Virusinfektion mit dem schweren akuten Atemwegssyndrom Coronavirus 2 (SARS-CoV-2) bei Krebspatienten, von denen viele immungeschwächt und damit anfälliger für eine Vielzahl von Infektionen sind, ist sehr wenig bekannt. Als Vorsichtsmaßnahme haben viele klinische Studien während der ersten Welle der weltweiten Pandemie des neuartigen Coronavirus (COVID-19) die Aufnahme von Patienten pausiert. In diesem Fallbericht beschreiben wir die erfolgreiche Behandlung eines Patienten mit rezidiviertem und refraktärem Multiplem Myelom (MM), der unmittelbar nach der klinischen Genesung von COVID-19 mit einer chimären Antigenrezeptor (CAR)-T-Zelltherapie mit Anti-B-Zellreifungsantigen (BCMA) behandelt wurde. Fallvorstellung: Der 57-jährige weiße männliche Patient war seit 4 Jahren an MM erkrankt und galt bei der Vorstellung zur CAR-T-Zelltherapie als pentarefraktär. Er hatte eine Immunsuppression in seiner medizinischen Vorgeschichte und er erhielt am Tag vor der COVID-19-Diagnose eine Dosis lymphdepletierender Chemotherapie (LDC). Dieser Patient konnte eine erhebliche Immunantwort gegen das SARS-CoV-2-Virus aufbauen, und antivirale Antikörper bleiben auch 2 Monate nach Erhalt einer Anti-BCMA-CAR-T-Zelltherapie noch nachweisbar. Die kürzliche SARS-CoV-2-Infektion bei diesem Patienten führte nicht zu einer Exazerbation des CAR-T-assoziierten Zytokin-Freisetzungssyndroms (CRS) und umgekehrt führte die CAR-T-Zelltherapie nicht zu Komplikationen im Zusammenhang mit COVID-19. Einen Monat nach der CAR-T-Zell-Infusion wurde bei dem Patienten ein unbestätigtes partielles Ansprechen nach den Kriterien der International Myeloma Working Group (IMWG) festgestellt. Schlussfolgerung: Unser Fall liefert einen wichtigen Kontext für die Wahl der Behandlung von MM-Patienten in Zeiten von COVID-19 sowie für die Frage, ob die CAR-T-Therapie auch bei Patienten verabreicht werden kann, die von COVID-19 genesen sind. Da die COVID-19-Pandemie weltweit anhält, ist eine umfangreiche Diskussion über die Entscheidung, ob mit der CAR-T-Zelltherapie fortgefahren werden soll, erforderlich, wobei die potenziellen Risiken und Vorteile der Therapie gegeneinander abgewogen werden müssen. Dieser Fall legt nahe, dass es möglich ist, die Anti-BCMA-CAR-T-Zelltherapie nach der Genesung von COVID-19 erfolgreich abzuschließen. Die Studie CRB-402 wurde am 6. September 2017 bei clinicaltrials.gov registriert (NCT03274219).

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          Most cited references15

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          COVID-19: consider cytokine storm syndromes and immunosuppression

          As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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            Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

            The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathological roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.
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              A serological assay to detect SARS-CoV-2 seroconversion in humans

              Here, we describe a serological enzyme-linked immunosorbent assay for the screening and identification of human SARS-CoV-2 seroconverters. This assay does not require the handling of infectious virus, can be adjusted to detect different antibody types in serum and plasma and is amenable to scaling. Serological assays are of critical importance to help define previous exposure to SARS-CoV-2 in populations, identify highly reactive human donors for convalescent plasma therapy and investigate correlates of protection.
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                Author and article information

                Journal
                KKO
                Kompass Onkologie
                S. Karger GmbH (Wilhelmstrasse 20A, P.O. Box · Postfach · Case postale, D–79095, Freiburg, Germany · Deutschland · Allemagne, Phone: +49 761 45 20 70, Fax: +49 761 4 52 07 14, information@karger.de )
                2296-5416
                2296-5386
                February 2022
                14 February 2022
                14 February 2022
                : 9
                : 1
                : 40-45
                Affiliations
                [1] aDepartment of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
                [2] bBristol-Myers Squibb, Princeton, New Jersey, USA
                [3] cbluebird bio, Cambridge, Massachusetts, USA
                Author notes
                Article
                kko-0009-0040
                10.1159/000522435
                9059054
                0e3b88b9-f8c2-4eeb-831f-f8ee4bc76f4e
                Copyright © 2022 by S. Karger AG, Basel

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                Page count
                Figures: 2, References: 15, Pages: 6
                Categories
                Erfahrung aus der Praxis

                covid-19,sars-cov-2,car-t-zelle,multiples myelom,fallbericht

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