Gastrointestinal Infections and Gastrointestinal Bleeding in CAR-T Cell Recipients are Underrated but Severe Adverse Events: A Real-World Study

Introduction

In recent years, Chimeric Antigen Receptor T-cell (CAR-T) therapy has shown lasting efficacy in treating patients with hematologic malignancies. However, multi-system toxic reactions associated with CAR-T therapy have been frequently reported, with gastrointestinal adverse events (GAEs) being particularly significant. Previous clinical trials and real-world studies have reported some common GAEs such as nausea, diarrhea, vomiting, and constipation. Nevertheless, restrictive inclusion criteria and selective populations might have led to an underestimation of some rare but severe toxicities. To better manage the treatment of CAR-T recipients and reduce the risk of serious toxicity, a systematic safety evaluation of CAR-T-related GAEs is necessary.

Research Background and Sources

The authors of this paper include Zhiqiang Song, Yang Wang, Ping Liu, Yuke Geng, Na Liu, Jie Chen, and Jianmin Yang, among others. They are affiliated with the Hematology Institute of Changhai Hospital of the Second Military Medical University in Shanghai, China. The article, titled “(Chimeric Antigen Receptor T-cell recipients: a real-world study)” was published in the journal Cancer Gene Therapy on March 28, 2024.

Research Objectives and Methods

Data Sources and Study Design

This study extracted report data from the FDA Adverse Event Reporting System (FAERS) from January 2017 to December 2021 for retrospective post-marketing adverse event analysis of CAR-T-related GAEs. Reports containing CAR-T-related brand names or generic names were selected, and ultimately, 1,518 reports of CAR-T-related GAEs were confirmed out of 105,087,611 reports. All datasets can be accessed through the FDA website https://www.fda.gov/regulatory-information/freedom-information.

Statistical Analysis

Different proportion analysis methods such as Reporting Odds Ratio (ROR) and Information Component (IC) were used to detect GAEs under all CAR-T products. Statistical shrinkage transformation was processed, and further analysis was conducted using relative statistical formulas. Signal detection was performed when drug-related AE records exceeded three cases. Signals were deemed significant if the lower limit of the 95% confidence interval for ROR (ROR025) was greater than 1 or the lower limit of the 95% confidence interval for IC (IC025) was above 0. The mortality rate was calculated based on the number of reported deaths and the total number of corresponding GAEs. Statistical analysis was conducted using SAS and R software.

Study Results

Descriptive Analysis

Between 2017 and 2021, 1,518 reports of CAR-T-related GAEs were confirmed in the FAERS database. Among them, 58.83% (n=893) were related to tisagenlecleucel, 37.02% (n=562) to axi-cel, 1.65% (n=25) to liso-cel, and 2.50% (n=38) to kte-x19. Reports of GAEs in CAR-T recipients increased over time, reaching a peak in 2020 (n=471) but slightly declining in 2021. The vast majority of these reports came from the United States (n=1154, 76.02%), and the mortality rate related to GAEs in CAR-T recipients was 35.57%.

CAR-T Related GAEs

Based on version 24.0 of the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs), 91 types of GAEs related to CAR-T therapy were confirmed. Among the 1,518 GAE reports, 23 GAEs showed a higher over-reporting signal, with 11 GAEs (156 cases, 10.28%) related to gastrointestinal infections (GIs), such as Clostridium difficile colitis (n=44, 2.90%, ROR=5.55), enterovirus infection (n=23, 1.52%, ROR=20.02), and mycoses caused by fungi (n=15, 0.99%, ROR=3.09). The overall fatality rate of GI-related adverse events was 29.49%, with mycoses leading to an exceptionally high fatality rate of 60%. Additionally, four over-reported GAEs were related to hemorrhage, with gastrointestinal bleeding mortality reaching 73.17%.

Differences in GAEs across Different CAR-T Products

Specific analysis indicated significant differences among various CAR-T products. For example, axi-cel was associated with a higher risk of GAEs such as nausea, diarrhea, dysphagia, and abdominal pain. Most GAEs peaked within 10 days after CAR-T cell infusion. Furthermore, higher hazards were common in patient groups with a high tumor burden or extensive previous treatment regimens.

Characteristics of Fatal GAEs

The study focused on the top ten GAEs with the most death reports, and explored the correlation between CRS (Cytokine Release Syndrome) and GAEs. It was found that lower CRS might reduce the risk of CAR-T-related GAEs, thus lowering the associated mortality rate. Early prevention of severe GAEs is especially suitable for patients with a high tumor burden or as preparation for transplantation.

Safety Analysis

Safety analysis indicated that maintaining CAR-T cell doses between 0.2×10^6 to 5×10^6 cells/kg can effectively reduce the risk of death from GAEs, consistent with FDA-approved dosages.

Conclusion and Significance

This study, for the first time, comprehensively reveals the spectrum of CAR-T-related GAEs in a real-world context. Gastrointestinal toxic reactions caused by CD19-targeted CAR-T therapy have been underestimated, yet pose severe problems among CAR-T recipients. By gaining a deeper understanding of GAEs in a real-world context, treatment choices can be better guided, and the management of this revolutionary therapy can be improved. As the application of CAR-T therapy continues to increase in the future, these research results will help clinicians to early warn of these rare but fatal GAEs, thereby reducing the risk of severe toxicities.