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

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

doi:10.1097/HS9.0000000000000858

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. 2023 Apr 5;7(4):e858. doi: 10.1097/HS9.0000000000000858. eCollection 2023 Apr.

Authors

Kai Rejeski^{1

2

3

4}, Viktoria Blumenberg^{1

2

3

4}, Gloria Iacoboni^{5

6}, Lucia Lopez-Corral^{7

8}, Soraya Kharboutli^{4

9}, Rafael Hernani¹⁰, Agnese Petrera¹¹, Niklas Müller¹, Friederike Hildebrand¹, Lisa Frölich^{1

3}, Philipp Karschnia¹², Christian Schmidt¹, David M Cordas Dos Santos^{1

3}, José Luis Piñana¹⁰, Fabian Müller^{4

9}, Ana Africa Martin^{7

8}, Martin Dreyling¹, Michael von Bergwelt-Baildon^{1

3

4}, Pere Barba^{5

6}, Marion Subklewe^{1

2

3

4}, Veit L Bücklein^{1

2

3

4}

Affiliations

¹ Department of Medicine III - Hematology/Oncology, University Hospital, LMU Munich, Germany.
² Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich, Germany.
³ German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg, Germany.
⁴ Bavarian Cancer Research Center (BZKF), Partner Sites Munich and Erlangen, Germany.
⁵ Department of Hematology, Vall d'Hebron Institute of Oncology (VHIO), University Hospital Vall d'Hebron, Barcelona, Spain.
⁶ Department of Medicine, Universitat Autònoma of Barcelona (UAB), Bellaterra, Spain.
⁷ Hematology Department, Hospital Clínico Universitario de Salamanca, IBSAL, CIBERONC, Salamanca, Spain.
⁸ Centro de Investigación del Cáncer-IBMCC, Salamanca, Spain.
⁹ Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Hospital Erlangen, Germany.
¹⁰ Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain.
¹¹ Metabolomics and Proteomics Core Facility, Helmholtz Zentrum Munich - German Research Center for Environmental Health, Munich, Germany.
¹² Department of Neurosurgery, University Hospital, LMU Munich, Germany.

Abstract

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 CRS^only 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 [AUC_ROC] = 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 (AUC_ROC = 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.