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

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.

Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies

“…Aside from established clinical risk factors as discussed above, a few studies assess the role of individual biomarkers for predicting infection risk. CRP peak tended to be higher on the day of diagnosis of CRS grade ≥2 versus infection in one study, 130 while an increase in CRP prior to fever onset was associated with infection in another 57 . A higher procalcitonin level within 48 h from fever was also associated with infection 131 .…”

“…More recently, the combination of a high CAR‐Hematotox score with a high procalcitonin (≥1.5 μg/L) on the day of first fever identified patients who went on to develop severe infections during the phase of coincident CRS 130 . Finally, important risk stratification tools from the transplant setting (both solid organ and HCT), including CMV immune monitoring should be studied in this population.…”

An International Survey on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR T-cell Therapy on Behalf of the EBMT and EHA

“…The survey results also underline that externally validated risk-stratification systems such as the CAR-HEMATOTOX score remain under-utilized. 14,19,[30][31][32] Interestingly, bone marrow studies were broadly performed before CAR-T infusion especially in high-risk candidates. A multitude of factors confer an increased risk profile for ICAHT, which can include prior hematopoietic cell transplantation, presence of bone marrow infiltration of the underlying malignancy, baseline cytopenias, and inflammatory state.…”

The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

“…Serial assessments of serum procalcitonin [PCT] may further help to rule out infections in the context of CRS (e.g. HT low patients with non‐elevated PCT at time of first fever) 59,60 . Second, the HT score could help to define patients that benefit from early and/or prophylactic G‐CSF use 39,40 and identify ultra high‐risk patients in whom collection of autologous CD34+ stem cells should be strongly considered before CAR T therapy 44 .…”