Distribution of Infectious Complications Following CLL1 CAR-T Cell Therapy for R/R AML: A Single-Center Experience

Introduction

The CLL1-targeted chimeric antigen receptor T (CAR-T) cell therapy offers a novel therapeutic approach for refractory or relapsed acute myeloid leukemia (R/R AML).The targeted elimination of tumor cells by CLL1 CAR-T therapy also induces cytotoxic effects on neutrophils, leading to a severe granulocytopenia, thereby significantly increasing the risk of infectious complications during CAR-T therapy. The study aims to offer guidance in predicting and managing infectious complications in patients with R/R AML following CLL1 CAR-T cell therapy, thereby enhancing patient prognosis and reducing mortality associated with infections.

Methods

From January 2021 to December 2023, a total of 51 patients with R/R AML were enrolled and received infusion of CLL1 CAR-T cells. The CAR-T cell preparation process was conducted at the laboratory of Department of Hematology at Tianjin First Central Hospital. All patients underwent lymphodepletion chemotherapy using the FC regimen, consisting of fludarabine and cyclophosphamide. The patients with a substantial tumor burden were additionally administered decitabine or cytarabine. Acyclovir prophylaxis and compound sulfamethoxazol were initiated prior to FC regimen application until 3-6 months post CAR-T cell infusion. Infection onset was defined as the day of the first clinical diagnosis or microbiologic return, regardless of mode of onset. The infections that occurred within the 30-day period prior to and 28-day period following CAR-T cell infusion were accurately documented, while patient data was analyzed up until 28 days after CAR-T cell infusion or until follow-up failure, disease recurrence, or death.

Results

A total of 51 patients had a median of 4 (range: 1-13) previous lines of therapy. The median dose of infused CLL1 CAR-T cells was 1.25 (0.20-3.00)×10⁶/kg. The pre-lymphodepletion median neutrophil count was 0.72 (0.00-7.15) ×10⁹/L, lymphocyte count was 0.70 (0.04-10.14) ×10⁹/L, and IgG level was 492 (179-1020) mg/dl. Out of 51 patients with R/R AML, 26 (51.0%) had a history of infection within the 30 days preceding lymphodepletion.

Within the period of 0 to 28 days following CART cell infusion, a total of 46 infection events were observed in 63% (32/51) of patients. Of the 32 patients with early infection, 21 (65.6%) experienced a single infection event, while 11 (34.4%) experienced multiple infection events (2 events, n=8; 3 events, n=3), with a median infection time of 9 days (range: 2-24), which was delayed by 4 days compared to the median time for CRS response. In the absence of mild infections, moderate infections accounted for 41% (n=13) of the early infection events, severe infections accounted for 44% (n=14), and life-threatening infections accounted for 15% (n=5).

The most frequently observed infection sites included respiratory tract infections (n=21), bloodstream infections (n=6), and skin and soft tissue infections (n=3). Bacterial infections accounted for the highest proportion among all infectious pathogens, with a cumulative incidence of 56.9% (95% CI: 50.4%-61.3%) within a 28-day period. Among the identified pathogens, there were 25 cases of Gram-negative bacteria, while Gram-positive bacteria were detected in four cases. Within a period of 28 days, the cumulative infection rates for fungi and viruses were 15.6% (95% CI: 11.7%-19.1%) and 11.7% (95% CI: 9.3%-14.8%), respectively. Univariate analysis and logistic multivariate analysis confirmed that pre-lymphodepletion neutrophil level (OR=3.785, 95%CI: 0.8605-20.34) and incidence of CRS (OR=4.141, 95%CI: 0.8840-24.99) independently served as prognostic factors for heightened infection risk.

This study also reported the efficacy and adverse events of CAR-T cell therapy. The findings will be detailed in subsequent sections.

Conclusions

In this study, we observed a heightened risk of infection within the initial 28 days following CLL1 CAR-T cell therapy, with bacterial and fungal infections being the predominant events. The pre-lymphodepletion neutrophil level and severity of CRS were identified as independent prognostic factors associated with an increased susceptibility to infection. However, this study was conducted at a single center with a limited sample size; therefore, further large-scale or multi-center studies are warranted to comprehensively evaluate the infectious complications associated with CLL1 CAR-T cell therapy in the future.

No relevant conflicts of interest to declare.