In recent years, chimeric antigen receptor T-cell therapy, commonly known as CAR-T therapy, has revolutionized the field of oncology, offering hope for patients with refractory or relapsed hematologic malignancies. Despite its transformative potential, this groundbreaking immunotherapy is not without significant risks. New insights emerging from a comprehensive pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) now reveal that hematologic and lymphatic system adverse events (AEs) associated with CAR-T therapies are a critical, yet underappreciated, challenge that clinicians must confront.
The study, conducted by Zhang et al. and published in BMC Cancer in 2025, provides the most extensive evaluation to date of the hematologic and lymphatic toxicities linked to various CAR-T products, including tisa-cel, axi-cel, brexu-cel, liso-cel, ide-cel, and cilta-cel. By parsing through 1,600 individual case safety reports from August 2017 through December 2023, this analysis delineates the granular spectrum of adverse events that follow CAR-T infusion, shedding light on their incidence, timing, clinical severity, and impact on patient mortality.
CAR-T therapy harnesses the patient’s own immune cells, genetically engineering T lymphocytes to recognize and destroy cancer cells expressing specific antigens, most typically CD19 in B-cell malignancies. Although this mechanism delivers potent antitumor activity, it simultaneously disrupts normal hematopoietic and lymphoid homeostasis. The FAERS data indicate that such disturbances manifest rapidly, with a majority of hematologic complications emerging within 10 days post-infusion, highlighting an acute window of vulnerability.
Among the 25 hematologic and lymphatic AEs identified, several stood out both for their frequency and their profound clinical implications. Most notably, B-cell aplasia exhibited the highest Reporting Odds Ratio (ROR) and Information Component (IC) values, signaling a robust association across all CAR-T products examined. This on-target, off-tumor effect, while an indicator of therapeutic activity, results in prolonged immunodeficiency, predisposing patients to infectious complications that can complicate their treatment course.
Adjacent to B-cell aplasia in terms of significance were cytopenias of varying lineages—pancytopenia, anemia, febrile bone marrow aplasia, and hypofibrinogenemia—each representing facets of marrow suppression or dysregulation. The underlying pathophysiology is multifactorial, attributed to cytokine-mediated inflammation, marrow niche disruption, and collateral immune-mediated toxicity, cumulatively exacerbating patient frailty.
Crucially, the study’s employment of LASSO regression analysis uncovered fifteen adverse events within the hematologic and lymphatic spectrum that bore a statistically significant correlation with mortality. This subclass includes severe but less frequently reported conditions such as splenic hemorrhage and disseminated intravascular coagulation (DIC). These life-threatening events underscore an urgent need for vigilant monitoring and prompt intervention protocols tailored to CAR-T recipients.
The differential association observed with specific CAR-T products revealed that therapies targeting CD19 and those incorporating the CD28 costimulatory domain exhibited a higher propensity for hematologic and lymphatic toxicities. This correlation invites further exploration into how product design—such as antigen specificity and intracellular signaling motifs—influences both efficacy and safety profiles.
While CAR-T therapy often commands attention for its cytokine release syndrome and neurotoxicity, the spotlight on hematologic AEs offered by Zhang et al. shifts the paradigm, emphasizing complications that can persist beyond the acute phase and tangibly influence patient survival. This extended morbidity calls for a multidisciplinary approach encompassing hematologists, oncologists, immunologists, and critical care specialists.
Furthermore, this study raises compelling questions about the current standards for post-CAR-T monitoring. The early onset of cytopenias and coagulopathies suggests that existing surveillance frameworks may need refinement to enable earlier detection and preemptive management, thereby reducing mortality rates associated with these complications.
The formidable figures derived from the FAERS analysis paint a sobering picture: a 15.3% mortality rate tied directly to hematologic and lymphatic system adverse events. Considering the growing adoption of CAR-T therapies worldwide, these findings bear immense clinical significance, underscoring an imperative to integrate risk stratification and personalized supportive care into therapeutic protocols.
Clinicians and researchers alike must now grapple with balancing the undeniable therapeutic promise of CAR-T cells against an evolving toxicity landscape. Innovations aimed at modulating the immunologic milieu, protecting hematopoietic function, or engineering next-generation CAR-T cells with improved safety metrics are avenues of intense ongoing investigation.
Notably, the identification of splenic hemorrhage and disseminated intravascular coagulation as harbingers of mortality prompts the development of targeted guidelines for their recognition and management in patients undergoing CAR-T therapy. Prophylactic strategies and aggressive therapeutic interventions tailored to these rare but fatal complications may enhance overall patient outcomes.
Zhang et al.’s pharmacovigilance approach underscores the value of post-marketing surveillance databases like FAERS in advancing our understanding of real-world CAR-T therapy safety. While clinical trials provide controlled environments, these large-scale databases capture the heterogeneity of patient experiences, comorbidities, and treatment exposures reflective of standard clinical practice.
The study’s methodology—leveraging disproportionality analysis through ROR and IC values—offers a statistically rigorous means of teasing apart drug-event associations from background noise. Such analytical precision is pivotal in distinguishing genuine adverse event signals from coincidental occurrences, fostering actionable insights.
In conclusion, the complex interplay between CAR-T therapy’s potent antitumor efficacy and its disruptive impact on the hematologic and lymphatic systems necessitates heightened awareness and proactive clinical strategies. As CAR-T indications expand beyond hematologic malignancies into solid tumors and other domains, integrating safety data of this magnitude will be integral to maximizing therapeutic benefit while minimizing harm.
Ultimately, the findings reported by Zhang and colleagues offer a critical roadmap for clinicians, researchers, and drug developers navigating the evolving landscape of cellular immunotherapy, illuminating hidden risks and guiding safer deployment of these transformative cancer treatments.
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Subject of Research: Hematologic and lymphatic system adverse events associated with CAR-T therapy
Article Title: Hematologic and lymphatic disorders associated with chimeric antigen receptor T-cell therapy: a pharmacovigilance analysis of the FDA adverse event reporting system (FAERS) database
Article References: Zhang, Z., Zheng, J., Liang, Y. et al. Hematologic and lymphatic disorders associated with chimeric antigen receptor T-cell therapy: a pharmacovigilance analysis of the FDA adverse event reporting system (FAERS) database. BMC Cancer 25, 846 (2025). https://doi.org/10.1186/s12885-025-14227-4
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14227-4
Keywords: CAR-T therapy, hematologic adverse events, lymphatic disorders, pharmacovigilance, FDA FAERS, B-cell aplasia, cytopenia, splenic hemorrhage, disseminated intravascular coagulation, pancytopenia, mortality, immunotherapy toxicity, LASSO regression analysis
