Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL
Early fever after chimeric antigen receptor T-cell (CAR-T) therapy can reflect both an infection or cytokine release syndrome (CRS). Identifying early infections in the setting of CRS and neutropenia represents an unresolved clinical challenge. In this retrospective observational analysis, early fev...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-04-01
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| Series: | HemaSphere |
| Online Access: | http://journals.lww.com/10.1097/HS9.0000000000000858 |
| _version_ | 1827333838873821184 |
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| author | Kai Rejeski Viktoria Blumenberg Gloria Iacoboni Lucia Lopez-Corral Soraya Kharboutli Rafael Hernani Agnese Petrera Niklas Müller Friederike Hildebrand Lisa Frölich Philipp Karschnia Christian Schmidt David M. Cordas dos Santos José Luis Piñana Fabian Müller Ana Africa Martin Martin Dreyling Michael von Bergwelt-Baildon Pere Barba Marion Subklewe Veit L. Bücklein |
| author_facet | Kai Rejeski Viktoria Blumenberg Gloria Iacoboni Lucia Lopez-Corral Soraya Kharboutli Rafael Hernani Agnese Petrera Niklas Müller Friederike Hildebrand Lisa Frölich Philipp Karschnia Christian Schmidt David M. Cordas dos Santos José Luis Piñana Fabian Müller Ana Africa Martin Martin Dreyling Michael von Bergwelt-Baildon Pere Barba Marion Subklewe Veit L. Bücklein |
| author_sort | Kai Rejeski |
| collection | DOAJ |
| description | Early fever after chimeric antigen receptor T-cell (CAR-T) therapy can reflect both an infection or cytokine release syndrome (CRS). Identifying early infections in the setting of CRS and neutropenia represents an unresolved clinical challenge. In this retrospective observational analysis, early fever events (day 0–30) were characterized as infection versus CRS in 62 patients treated with standard-of-care CD19.CAR-T for relapsed/refractory B-cell non-Hodgkin lymphoma. Routine serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], procalcitonin [PCT]) were recorded daily. Exploratory plasma proteomics were performed longitudinally in 52 patients using a multiplex proximity extension assay (Olink proteomics). Compared with the CRSonly cohort, we noted increased event-day IL-6 (median 2243 versus 64 pg/mL, P = 0.03) and particularly high PCT levels (median 1.6 versus 0.3 µg/L, P < 0.0001) in the patients that developed severe infections. For PCT, an optimal discriminatory threshold of 1.5 µg/L was established (area under the receiver operating characteristic curve [AUCROC] = 0.78). Next, we incorporated day-of-fever PCT levels with the patient-individual CAR-HEMATOTOX score. In a multicenter validation cohort (n = 125), we confirmed the discriminatory capacity of this so-called HT10 score for early infections at first fever (AUCROC = 0.87, P < 0.0001, sens. 86%, spec. 86%). Additionally, Olink proteomics revealed pronounced immune dysregulation and endothelial dysfunction in patients with severe infections as evidenced by an increased ANGPT2/1 ratio and an altered CD40/CD40L-axis. In conclusion, the high discriminatory capacity of the HT10 score for infections highlights the advantage of dynamic risk assessment and supports the incorporation of PCT into routine inflammatory panels. Candidate markers from Olink proteomics may further refine risk-stratification. If validated prospectively, the score will enable risk-adapted decisions on antibiotic use. |
| first_indexed | 2024-03-07T17:37:22Z |
| format | Article |
| id | doaj.art-d2a6963187ae4c0caac9c8f274ced473 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-03-07T17:37:22Z |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-d2a6963187ae4c0caac9c8f274ced4732024-03-02T16:38:58ZengWileyHemaSphere2572-92412023-04-0174e85810.1097/HS9.0000000000000858202304000-00017Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHLKai Rejeski0Viktoria Blumenberg1Gloria Iacoboni2Lucia Lopez-Corral3Soraya Kharboutli4Rafael Hernani5Agnese Petrera6Niklas Müller7Friederike Hildebrand8Lisa Frölich9Philipp Karschnia10Christian Schmidt11David M. Cordas dos Santos12José Luis Piñana13Fabian Müller14Ana Africa Martin15Martin Dreyling16Michael von Bergwelt-Baildon17Pere Barba18Marion Subklewe19Veit L. Bücklein201 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany5 Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Barcelona, Spain7 Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain4 Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany10 Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain11 Metabolomics and Proteomics Core Facility, Helmholtz Zentrum Munich – German Research Center for Environmental Health, Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany12 Department of Neurosurgery, University Hospital, LMU Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany10 Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain4 Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany7 Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany5 Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Barcelona, Spain1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, Germany1 Department of Medicine III – Hematology/Oncology, University Hospital, LMU Munich, GermanyEarly fever after chimeric antigen receptor T-cell (CAR-T) therapy can reflect both an infection or cytokine release syndrome (CRS). Identifying early infections in the setting of CRS and neutropenia represents an unresolved clinical challenge. In this retrospective observational analysis, early fever events (day 0–30) were characterized as infection versus CRS in 62 patients treated with standard-of-care CD19.CAR-T for relapsed/refractory B-cell non-Hodgkin lymphoma. Routine serum inflammatory markers (C-reactive protein [CRP], interleukin-6 [IL-6], procalcitonin [PCT]) were recorded daily. Exploratory plasma proteomics were performed longitudinally in 52 patients using a multiplex proximity extension assay (Olink proteomics). Compared with the CRSonly cohort, we noted increased event-day IL-6 (median 2243 versus 64 pg/mL, P = 0.03) and particularly high PCT levels (median 1.6 versus 0.3 µg/L, P < 0.0001) in the patients that developed severe infections. For PCT, an optimal discriminatory threshold of 1.5 µg/L was established (area under the receiver operating characteristic curve [AUCROC] = 0.78). Next, we incorporated day-of-fever PCT levels with the patient-individual CAR-HEMATOTOX score. In a multicenter validation cohort (n = 125), we confirmed the discriminatory capacity of this so-called HT10 score for early infections at first fever (AUCROC = 0.87, P < 0.0001, sens. 86%, spec. 86%). Additionally, Olink proteomics revealed pronounced immune dysregulation and endothelial dysfunction in patients with severe infections as evidenced by an increased ANGPT2/1 ratio and an altered CD40/CD40L-axis. In conclusion, the high discriminatory capacity of the HT10 score for infections highlights the advantage of dynamic risk assessment and supports the incorporation of PCT into routine inflammatory panels. Candidate markers from Olink proteomics may further refine risk-stratification. If validated prospectively, the score will enable risk-adapted decisions on antibiotic use.http://journals.lww.com/10.1097/HS9.0000000000000858 |
| spellingShingle | Kai Rejeski Viktoria Blumenberg Gloria Iacoboni Lucia Lopez-Corral Soraya Kharboutli Rafael Hernani Agnese Petrera Niklas Müller Friederike Hildebrand Lisa Frölich Philipp Karschnia Christian Schmidt David M. Cordas dos Santos José Luis Piñana Fabian Müller Ana Africa Martin Martin Dreyling Michael von Bergwelt-Baildon Pere Barba Marion Subklewe Veit L. Bücklein Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL HemaSphere |
| title | Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL |
| title_full | Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL |
| title_fullStr | Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL |
| title_full_unstemmed | Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL |
| title_short | Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL |
| title_sort | identifying early infections in the setting of crs with routine and exploratory serum proteomics and the ht10 score following cd19 car t for relapsed refractory b nhl |
| url | http://journals.lww.com/10.1097/HS9.0000000000000858 |
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