Procalcitonin as a biomarker for predicting bacterial infection in chimeric antigen receptor T‐cell therapy recipients

Abstract

Background It is unknown whether serum procalcitonin (PCT) concentration monitoring can differentiate between bacterial infection or cytokine release syndrome (CRS) when chimeric antigen receptor T‐cell (CAR‐T) recipients present with a constellation of signs and symptoms that may represent both complications. Objective The objective of the study was to assess the utility of serum PCT concentrations as a biomarker of bacterial infection in CAR‐T recipients. Study design This single‐center, retrospective, medical record review evaluated patients prescribed CAR‐T therapy until death or 30 days after infusion. Logistic regression modeling determined the association between elevated serum PCT concentrations within 48 h of fever onset and microbiologically confirmed infection. Secondary outcomes included clinically suspected infection, CAR‐T toxicity rates, and broad‐spectrum antibiotic usage. Predictive performance of PCT was assessed by area under the receiver operating characteristic curve (AUC). Results The 98 included patients were a median age of 63 (IQR: 55–69) years old, 47 (48%) were male, and 87 (89%) were Caucasian. Baseline demographics and clinical characteristics were similar between patients with and without a bacterial infection. Serum PCT >0.4 ng/mL within 48 h of fever was significantly associated with a microbiologically confirmed bacterial infection (OR: 2.75 [95% CI: 1.02–7.39], p = 0.045). Median PCT values in patients with and without confirmed infections were 0.40 ng/mL (IQR: 0.26, 0.74) and 0.26 ng/mL (IQR: 0.13, 0.47), respectively. The AUC for PCT to predict bacterial infection was 0.62 (95% CI 0.48–0.76). All patients experienced CRS of some grade, with no difference in CRS severity based on elevated PCT. Broad‐spectrum antibiotics were used for a median of 45% and 23% of days in those with and without confirmed infection, respectively ( p = 0.075). Conclusion Elevated serum PCT concentrations above 0.4 ng/mL at time of first fever after CAR‐T infusion was significantly associated with confirmed bacterial infection. Furthermore, rigorous, prospective studies should validate our findings and evaluate serial PCT measurements to optimize antimicrobial use after CAR‐T therapy.

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

“…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 . Finally, cytokine levels, including higher levels of IL‐8 and IL‐1β, lower interferon‐γ, and a double peak of IL‐6 were associated with severe bacterial infections, 79 while cytokine levels did not differ between patients with and without infection in another study 46 .…”

“…57 A higher procalcitonin level within 48 h from fever was also associated with infection. 131 Finally, cytokine levels, including higher levels of IL-8 and IL-1β, lower interferon-γ, and a double peak of IL-6 were associated with severe bacterial infections, 79 while cytokine levels did not differ between patients with and without infection in another study. 46 In children receiving CD19 CAR-T cells for B-ALL and admitted to the ICU, interferon-γ and IL-1β could differentiate sepsis from CRS.…”

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 .…”

“…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 Finally, MCL patients with a HT score ≥4 were less likely to have a durable response to brexu-cel and represent a patient population of unmet clinical need.…”

Noninfectious causes of fever in hematologic malignancies. Are antibiotics still indicated?

“…Many such tools are already in widespread use, for example, proteomic tools or multiplex nucleic acid tests that can identify bacteria, and in some cases, antimicrobial resistance genes, directly from flagged blood culture bottles [56,57]. Multiplex molecular assays can also be applied directly to clinical specimens, including cerebrospinal fluid, respiratory specimens, or stool to detect pathogens [58][59][60][61]. An array of serologic, antigen-based, molecular, and other noninvasive tests can also facilitate the diagnosis of fungal infections, often from blood or other easily available clinical specimens [62].…”