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Rejeski, K.* ; Blumenberg, V.* ; Iacoboni, G.* ; Lopez-Corral, L.* ; Kharboutli, S.* ; Hernani, R.* ; Petrera, A. ; Müller, N.* ; Hildebrand, F.* ; Frölich, L.* ; Karschnia, P.* ; Schmidt, C.* ; Cordas Dos Santos, D.M.* ; Piñana, J.L.* ; Müller, F.* ; Martin, A.A.* ; Dreyling, M.* ; von Bergwelt-Baildon, M.* ; Barba, P.* ; Subklewe, M.* ; Bücklein, V.*

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 7:e858 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cytokine Release Syndrome; Escherichia-coli; Cell Therapy; Fluoroquinolone Resistance; Procalcitonin; Biomarkers; Toxicity; Outcomes; Sepsis; Impact
ISSN (print) / ISBN 2572-9241
e-ISSN 2572-9241
Zeitschrift Hemasphere
Quellenangaben Band: 7, Heft: 4, Seiten: , Artikelnummer: e858 Supplement: ,
Verlag Wolters Kluwer Health
Verlagsort Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) CF Metabolomics & Proteomics (CF-MPC)
Förderungen Else Kroner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP)
School of Oncology of the German Cancer Consortium (DKTK)
Bavarian Center for Cancer Research (BZKF)
Else-Kroner-Fresenius Stiftung
Wilhelm-Sander Stiftung
Bavarian Elite Graduate Training Network
DFG
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Gilead Research Scholar Program