Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management.

Introduction

Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of patients with hematological malignancies. It has shown remarkable success in achieving long-term complete response for certain hematological malignancies. [ 1 ] Currently, seven CAR-T therapy products have been approved by the U.S. Food and Drug Administration (FDA). Along with the clinical application of CAR-T therapy, common toxic and side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have received extensive attention, and management and treatment strategies have been formulated. [ 2 – 5 ] However, as a serious complication, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) has not received sufficient attention and corresponding toxicity management strategies.

IEC-HS is a rare but potentially fatal disease manifested as excessive immune system activation and a high-inflammatory state after receiving CAR-T therapy. At present, the pathogenesis of IEC-HS is unclear; there are many diagnostic criteria, and it is difficult to distinguish from reported CRS (especially high-grade CRS), which leads to huge differences in the incidence of IEC-HS and different treatment methods for IEC-HS.

Due to the high fatality rate [ 6 , 7 ] and diverse clinical manifestations of IEC-HS, its early recognition, accurate diagnosis, risk identification, and effective treatment are of great significance for improving patient survival rates. Therefore, we will conduct a retrospective review of the related pathogenesis, diagnostic criteria, incidence rate, and treatment options of IEC-HS. At the same time, we will also discuss how to distinguish severe CRS from IEC-HS in the literature and summarize the high-risk factors of IEC-HS.

Pathogenesis of IEC-HS

The pathogenesis of IEC-HS is not completely clear, and there are different viewpoints. Most researchers attribute secondary hemophagocytic lymphohistiocytosis (sHLH) pathogenesis to cytotoxic T lymphocyte (CTL) and natural killer (NK) cell dysfunction, particularly defective perforin-mediated apoptosis of antigen-presenting cells, which drives sustained lymphocyte activation, inflammatory cytokine storms, and macrophage hyperactivation. [ 8 – 10 ]

In the context of CAR-T therapy, IEC-HS is closely linked to the unbridled expansion of CTLs (including CAR-T cells) and acute NK cell lymphopenia. The latter impairs the inhibition of T-cell hyperactivation, contributing to uncontrolled inflammation. [ 11 – 15 ] In parallel, evidence also indicates that innate immune overactivation through persistent toll-like receptor (TLR) signaling may represent an alternative pathway, [ 8 , 16 ] with murine models demonstrating TLR agonist-induced hemophagocytic lymphohistiocytosis (HLH)-like manifestations. [ 17 ]

A critical feature distinguishing IEC-HS is its distinct cytokine profile, which is dominated by IFN-γ, TNF-α, and IL-1β, rather than IL-6. This cytokine milieu perpetuates a pathological feedback loop involving macrophage activation and hemophagocytosis. [ 8 , 16 , 18 , 19 ] Moreover, CAR-T cells further exacerbate this process through contact-dependent CD40–CD40L interactions with macrophages. [ 15 ]

As for the differences between primary hemophagocytic lymphohistiocytosis (pHLH) and IEC-HS, Wang et al [ 15 ] summarized that although both exhibit similar hyperinflammatory features, their pathogenic origins are distinct. pHLH results from inherited defects in CTL and NK cell function, causing intrinsic failure of cytotoxic regulation. In contrast, IEC-HS is an acquired, therapy-related syndrome that, as discussed above, arises from cytokine-driven inflammation secondary to excessive activation of CAR-T and other effector T cells. Therefore, pHLH represents a genetic immune dysregulation, whereas IEC-HS reflects a secondary, treatment-induced cytokine storm. [ 15 ]

Diagnostic criteria for IEC-HS

Current diagnostic criteria for IEC-HS

Currently, the diagnosis of IEC-HS lacks a harmonized diagnostic standard. The existing common diagnostic criteria include the HLH-94, [ 20 ] the HLH-2004, [ 21 ] the H-score, [ 22 ] the diagnostic criteria proposed by Neelapu et al , [ 23 ] the diagnostic criteria proposed by Shah et al , [ 24 ] and the diagnostic criteria recently proposed by the American Society of Transplantation and Cellular Therapy (ASTCT) [Table 1 ].

It is worth mentioning that the ASTCT standard does not specify any numerical thresholds for serum ferritin concentration. However, in the article, based on previous studies, ASTCT consensus has proposed reference values for serum ferritin concentration by target: for CD19 CAR-T treatment, it is >10,000 ng/mL; [ 25 ] for CD22 CAR-T treatment, it is >100,000 ng/mL; [ 18 ] and for B-cell maturation antigen (BCMA) CAR-T treatment, it increases at a rate of ≥100 μg·L –1 ·h –1 within 24 h. [ 26 ]

Modified and expanded diagnostic criteria

In clinical practice, several studies have applied modified versions of existing diagnostic criteria to improve sensitivity in CAR-T-treated patients. For instance, the diagnostic criteria have been modified based on the standard proposed by Neelapu et al [ 23 ] : For patients with CRS, whether active or regressive, the peak ferritin level should be ≥10,000 ng/mL, and at least two of the following conditions must be present: nephrotoxicity, hepatotoxicity, hypoxia, coagulation disorders, and/or hemophagocytosis in bone marrow aspiration/biopsy. [ 27 ] Furthermore, diagnostic criteria modified based on the criteria proposed by Neelapu et al [ 23 ] and Shah et al [ 24 ] have also been proposed: For CRS patients, the peak ferritin should be ≥100,000 ng/mL, and at least two of the following conditions must be met: liver transaminase level ≥ grade 3 or bilirubin ≥ grade 3, pulmonary manifestations ≥ grade 3 (e.g., edema or hypoxia), renal insufficiency ≥ grade 3, coagulation disorders, and hemophagocytosis in the bone marrow. [ 18 ]

Grading system for IEC-HS severity

To assess the severity of the disease and select appropriate treatment options, ASTCT consensus has introduced the grading of IEC-HS for the first time [Table 2 ]. [ 19 ] This classification provides a structured framework for clinical assessment and standardizes severity reporting across institutions.

Cytokine profiles associated with IEC-HS

Many cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin-13 (IL-13), interleukin-15 (IL-15), interleukin-16 (IL-16), interleukin-18 (IL-18), interleukin-18 binding protein (IL-18BP), interleukin-33 (IL-33), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein-1 alpha (MIP-1α), etc., can often be detected in the bodies of IEC-HS patients. [ 8 , 18 , 28 – 31 ] These cytokine patterns reflect sustained macrophage and T-cell activation and provide a biological basis for cytokine-based diagnostic exploration.

Key cytokines with diagnostic implications

IFN-γ plays an important role in the pathophysiology of HLH. [ 30 ] Some studies have found that overproduction of IFN-γ is responsible for the emergence of hematologic symptoms in HLH, but its role in the emergence of inflammatory symptoms in HLH may not be as pronounced as that of promoting the emergence of hematologic symptoms. [ 32 ]

TNF-α is elevated in many inflammatory processes, so excessive production of it may lead to the appearance of non-specific inflammation. At the same time, TNF-α may be involved in the activation of macrophages. [ 33 ]

IL-18 is considered to play a central role in the pathogenesis of HLH. However, studies have found that an increase in IL-18 alone is not sufficient to cause the onset of HLH. Patients with IL-18-related HLH-prone diseases can remain in a non-HLH state for a long time unless they encounter an infection trigger factor. [ 34 – 38 ] HLH infection trigger factors (such as Epstein–Barr virus) can induce host cells or immune cells to upregulate the expression of IL-10 and can even encode homologs of viral IL-10. [ 39 , 40 ]

IL-10 is an important negative immune regulatory factor in the body, mainly produced by activated monocytes/macrophages, regulatory T cells (Tregs), and Th cells. It exerts an anti-inflammatory effect by inhibiting the release of pro-inflammatory mediators, antigen presentation, and phagocytosis. Therefore, the high expression of IL-10 in HLH patients may be a compensatory increase. [ 41 ] However, it should be noted that some studies have pointed out that when IL-10 and IL-18 increase together, they will drive the occurrence of HLH. [ 42 ]

IL-2 is produced by T cells and stimulates CTLs and Tregs. [ 30 ] When IL-2 is excessively consumed by CD8 + T cells, the number of Tregs will decrease, thereby causing the appearance and circulation of HLH inflammatory symptoms. [ 32 ]

Clinical utility and limitations of cytokine measurements

The detection of cytokines can assist in the diagnosis of IEC-HS and the judgment of the disease course. However, due to the limitations of current detection technologies, the real-time performance of cytokine detection results is poor, and the progression of IEC-HS is rapid, so clinical practicability is not ideal. However, with the development of detection technologies, it will be feasible to use cytokine detection to assist in diagnosis in the future.

Furthermore, it is worth mentioning that by detecting cytokine levels and through the ratio between specific cytokines, different HLH subtypes can be distinguished. [ 41 ]

Predictive models for IEC-HS development

Given the dangerous condition of IEC-HS, poor prognosis, and high mortality rate, we all expect to be able to predict the occurrence of IEC-HS in advance. Fortunately, some scholars have proposed some prediction models for IEC-HS.

Lichtenstein et al [ 18 ] used the IFN-γ level on the second day of CRS and the baseline bone marrow T: NK cell ratio to predict the risk of IEC-HS in CRS patients. Zu et al [ 43 ] used the fibrinogen level on the third day of CRS and the lactate dehydrogenase (LDH) level on the sixth day of CRS to predict the risk of IEC-HS in CRS patients. Although the accuracy, sensitivity, and specificity of the two are almost the same, considering the timeliness of cytokine detection and the fact that the IFN-γ levels of high-grade CRS and IEC-HS are not much different, the latter prediction model may have more practical application value.

Distinguishing severe CRS and IEC-HS in the literature

Reported severe CRS and IEC-HS overlap in many aspects, such as clinical presentation and laboratory test results. In clinical practice, it has become a challenge to accurately differentiate between these two conditions and provide appropriate treatment measures. Data-driven analyses have delineated diagnostic discriminators between severe reported CRS and IEC-HS [Figure 1 ], enabling timely targeted therapies. Nevertheless, accurate differentiation demands rigorous clinical expertise and nuanced disease comprehension.

Distinguishing by onset time

Numerous scholars have found a sequential relationship between reported CRS and IEC-HS in terms of time of onset. [ 11 , 18 , 19 , 24 , 44 , 45 ] More specifically, the onset of IEC-HS is usually later than that of CRS. In addition, CRS symptoms generally resolved or subsided before the onset of IEC-HS. Consequently, it has been observed by some scholars that the median onset of IEC-HS tends to be 14 days after CAR-T infusion, [ 11 , 18 , 24 ] compared to a median onset of CRS of 5–8 days after CAR-T infusion. [ 18 , 45 ]

Distinguishing by laboratory indicators

Despite the overlap between reported CRS and IEC-HS in many laboratory indices, it has been found that ferritin, LDH, and aspartate aminotransferase (AST) levels in patients with IEC-HS were significantly higher than those in patients with severe CRS by continuous monitoring of serum parameters, and that the time of appearance of the peaks was coincidental with the time of onset of IEC-HS. Moreover, the decline rate of C-reactive protein (CRP) in IEC-HS patients is significantly lower than that in patients with severe CRS. [ 43 ]

Ferritin rises rapidly in both IEC-HS patients and patients with severe CRS. However, the level in patients with severe CRS immediately declines, while the level in IEC-HS patients continues to rise from the 9th to the 12th day after the onset of CRS. Nevertheless, both IEC-HS patients and CRS patients maintained equally high levels in the later stages of treatment. [ 43 ] In addition, it was found that the peak value of ferritin in patients with IEC-HS is significantly higher than that in CRS patients without IEC-HS ( P <0.0001). [ 18 ]

LDH and AST only slightly increase in patients with severe CRS, while there is a significant peak in IEC-HS patients. In the later stage of treatment, both LDH and AST return to the normal range. [ 43 ]

The CRP in both patients with reported severe CRS and IEC-HS rises rapidly and reaches a peak 3–5 days after the onset of CRS. After that, patients with severe CRS can rapidly decline to the normal range, but the decline rate in IEC-HS patients is slower. [ 43 ]

Distinguishing by cytokines

Although there is a high degree of overlap in the cytokine profiles of patients with severe CRS and IEC-HS in the literature, a few cytokines still show differences under continuous detection and dynamic observation.

The rate of IFN-γ elevation is similar in patients with reported severe CRS and IEC-HS. However, the peak of IFN-γ in patients with IEC-HS lasts for many days, whereas in patients with severe CRS, IFN-γ subsides rapidly after reaching its peak. [ 18 , 43 ]

The levels of IFN-γ, granzyme B, IL-12, IL-1α, IL-1β, IL-1 receptor, IL-10, IL-33, and CD40 ligand (CD40L) are significantly increased during the active stage of IEC-HS, while they are similar between mild and severe CRS and are all lower than the level of IEC-HS. [ 43 ]

In terms of chemokines, IEC-HS is associated with elevated levels of most chemokines (such as CCL2, CCL11, CCL20, CXCL1, and CXCL10). In contrast, CRS patients mainly show an increase in the level of CCL5. [ 43 ]

Regarding growth factors, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are significantly increased in IEC-HS patients. [ 43 ]

Incidence of IEC-HS

As the diagnostic criteria for IEC-HS are not unified and more and more CAR-T cells targeting different antigens are being developed, the incidence of IEC-HS varies greatly in different studies [Figure 2 ].

We have found that the reported incidence of IEC-HS in some databases is relatively low. Current clinical practice frequently categorizes IEC-HS patients as high-grade CRS cases due to substantial diagnostic overlap. These patients manifest typical CRS biomarkers including markedly elevated ferritin, CRP, and soluble interleukin-2 receptor (sIL-2R) levels, alongside clinical presentations that mirror conventional CRS patterns. This diagnostic conflation likely contributes to both the underrecognition of IEC-HS as a distinct entity and its consequent underrepresentation in epidemiological data. [ 46 ]

An article analyzing data from the FDA Adverse Event Reporting System (FAERS) from January 1, 2017 to December 31, 2021 found a 2.7% incidence of IEC-HS. [ 6 ] Meanwhile, another analysis of FAERS data through March 3, 2022, found an overall incidence of IEC-HS of about 2% (ranging from 1.6% to 2.8%, 1.7% for Axi-Cel, 1.6% for Brexu-Cel, 2.5% for Tisa-Cel, and 2.8% for Liso-Cel). [ 7 ] Moreover, a study of the data in the Vizient clinical database from 2017 to 2021 found that the incidence of IEC-HS was 1.27%. [ 7 ] Additionally, a survey of 114 centers in 24 countries in the European Society for Blood and Marrow Transplantation (EBMT) found that the estimated incidence of IEC-HS was 3.48%. [ 47 ]

In comparison to the data in databases, with the gradual academic focus and attention on IEC-HS, many new diagnostic criteria in addition to the HLH-2004 criteria continue to be developed. We found that the incidence of IEC-HS in some studies with new explicit diagnostic criteria was much higher than the incidence in earlier databases. This may indicate that the real incidence of IEC-HS is not as low as previously perceived.

Differential incidence of IEC-HS under different diagnostic criteria

Criteria proposed by Neelapu et al [ 23 ] and criteria proposed by Shah et al [ 24 ]

The diagnostic criteria proposed by Shah et al [ 24 ] , being a modified version derived from Neelapu et al [ 23 ] ’s original framework, are analyzed in conjunction with their progenitor system. This combined discussion encompasses both the Neelapu-based criteria and their Shah adaptation, the latter constituting a systematic revision through parameter reconfiguration. A synthesis of available data shows comparable incidence rates across both classification systems when applied to identical clinical populations, lending support to this analytical approach.

In an article targeting CD19 and adopting the criteria proposed by Shah et al [ 24 ] , the incidence of IEC-HS was 14.8% (4/27). [ 45 ] Besides, in one of the two studies mentioned earlier, targeting CD19 and adopting the modified criteria based on the criteria proposed by Neelapu et al [ 23 ] , the incidence of IEC-HS was 14.1% (26/185). [ 27 ] It should be noted, however, that the research objects in that article were children and young people.

In the study by Shah et al [ 24 ] , the incidence of IEC-HS targeting CD22 with their own proposed criteria was 32.8% (19/58). [ 24 ] Meanwhile, in the other study mentioned earlier, targeting CD22 and adopting the criteria modified by combining the criteria proposed by Neelapu et al [ 23 ] and Shah et al [ 24 ] , the incidence of IEC-HS was 35.6% (21/59). [ 18 ]

For BCMA target, a study using the criteria proposed by Neelapu et al [ 48 ] reported an incidence of IEC-HS was 20.2% (20/99).

Criteria proposed by ASTCT

As the diagnostic criteria proposed by ASTCT were only put forward in 2023, there are currently relatively few research articles using the criteria proposed by ASTCT. In an article targeting CD22 and adopting the criteria proposed by ASTCT, the incidence of IEC-HS was 19% (3/16). [ 49 ]

It can be seen that when targeting CD22, the incidence of IEC-HS using the criteria proposed by ASTCT is lower than that using the criteria proposed by Neelapu et al [ 23 ] and Shah et al [ 24 ] . This also indicates that the incidence of IEC-HS is different under different diagnostic criteria.

Differential incidence of IEC-HS after treatment with different targets

CD19

In an article where diagnostic criteria were not specified and CD19 was used as a target, the incidence of IEC-HS was 12.8% (5/39). [ 50 ] In addition to this, the incidence of IEC-HS after CD19-targeted therapy was in the range of 14.1–14.8% using a variety of criteria delineated to those proposed by Neelapu et al [ 23 ] and Shah et al [ 24 ] as described above. [ 27 , 45 ]

CD22

As mentioned above, in the study by Shah et al [ 24 ] in which CD22 was the target and the criteria proposed by Shah et al [ 24 ] were used, the incidence of IEC-HS was 32.8% (19/58). [ 24 ] In an additional study targeting CD22, using a combination of the criteria proposed by Neelapu et al [ 23 ] and the criteria proposed by Shah et al [ 24 ] with modifications, the incidence of IEC-HS was 35.6% (21/59). [ 18 ] Moreover, in an article targeting CD22 and adopting the criteria proposed by ASTCT, the incidence of IEC-HS was 19% (3/16). [ 49 ]

BCMA

As mentioned earlier, in an article targeting BCMA and adopting the criteria proposed by Neelapu et al [ 23 ] , the incidence of IEC-HS was 20.2% (20/99). [ 48 ]

It can be found that the incidence rates after treatment with different targets are different, even when the same criteria are used. The highest incidence of IEC-HS was observed after treatment with the CD22 target, and some scholars have hypothesized that this may be related to the expression of CD22 by dendritic cells in some cases, [ 18 ] although there is no clear reason as to why the incidence rate is highest with the CD22 target.

Incidence varies by product

As of now, the FDA has approved seven CAR-T therapy products for marketing. By reviewing relevant studies and product instructions, it becomes evident that the incidence rates vary among these products [Figure 3 ]. [ 51 – 58 ]

High-risk factors for IEC-HS

IEC-HS represents a clinical syndrome characterized by dismal prognosis and multifactorial pathogenesis. The identification and systematic characterization of its risk factors carries critical clinical significance, enabling early detection, preventive interventions, and timely therapeutic management. By establishing comprehensive risk stratification models through multivariate analysis, clinicians can leverage evidence-based prognostic tools to optimize patient survival outcomes and quality of life.

ASTCT consensus points out that factors that may affect the development of IEC-HS include patient characteristics, disease-specific factors, and immune effector cell-related (IEC-related) factors. Patient characteristics involve baseline inflammation level, immunosuppressive state, cytopenia, and genetic susceptibility; disease-specific factors include disease burden, tumor cell proliferation kinetics, and immune resistance mechanisms; and IEC-related factors cover antigen targets, the construction of CAR-T cells, the selection of costimulatory molecules, T cell selection, and cell dose. [ 19 ] However, it should be specifically noted that there is currently no direct evidence to support whether some of the factors mentioned above are high-risk factors for the development of IEC-HS.

Patient characteristics

Individual differences play a key role in the occurrence of IEC-HS. A series of patient characteristics, such as inflammation level at baseline, and NK cell counts, may significantly affect an individual’s susceptibility to IEC-HS. Specifically, those with a baseline pro-inflammatory state and low NK cell counts are considered to be at high risk of developing IEC-HS [Figure 4 ]. These characteristics suggest that in clinical practice, we need to conduct more detailed monitoring and management of these specific patient groups to timely identify and intervene, which may reduce the incidence and severity of IEC-HS.

Baseline inflammation

It was demonstrated that the baseline pro-inflammatory state is an important risk factor for patients to experience toxic events after receiving CAR-T therapy. Patients with the highest risk of severe toxicity after CAR-T therapy can be identified through the baseline pro-inflammatory state. [ 59 ] Further research has found that among patients with high-grade CRS, compared to those without IEC-HS, patients who progress to IEC-HS have significantly higher levels of inflammatory markers (such as CRP) in the blood before CAR-T cell infusion ( P = 0.0494), [ 27 ] which emphasizes the potential role of inflammatory markers in predicting the risk of IEC-HS. Additionally, because IL-6 can inhibit the effector differentiation of CD8 + T cells and the release of IFN-γ, [ 60 ] some scholars believe that using tocilizumab (anti-IL-6 receptor) to treat CRS cannot prevent the occurrence of IEC-HS. Instead, it may lead to more tumor cell pyroptosis and pathological inflammasome activation due to amplified cytotoxicity, creating a pro-inflammatory state and facilitating the development of IEC-HS. [ 61 ] All of the above illustrate that the baseline pro-inflammatory state is a high-risk factor for the development of IEC-HS.

Low NK cell counts

It has been observed that the number of NK cells tends to be lower in patients with secondary HLH. [ 12 , 62 ] As a subtype of secondary HLH, patients with IEC-HS have also shown reduced numbers of NK cells. [ 18 ] Research has indicated that before CAR-T treatment, patients who subsequently experienced IEC-HS exhibited a significantly higher T cells to NK cells ratio (T: NK) in their bone marrow compared to those who did not develop IEC-HS. Subsequent observations have demonstrated that post-CAR-T therapy, the T: NK ratio, as well as the ratio of CAR-T cells to NK cells (CAR-T: NK), in the bone marrow of patients with IEC-HS, remained persistently elevated relative to patients without IEC-HS. [ 18 ]

NK cells play a role analogous to that of a rheostat in regulating the immune response of T cells. Studies have already found that NK cells can inhibit the overactivation of CD8 + T cells, which may lead to an over-enhancement of CD8 + T cell-mediated immune responses when NK cells are functionally inhibited or their numbers are depleted. [ 13 , 14 ] In addition, it has been found that patients who developed IEC-HS had NK cell reduction before infusion, and it was more severe when CAR-T expansion peaked, and remained even on day 28 post-infusion. [ 18 ] As a result of the expansion of CAR-T cells and the reduction of NK cells in the body, the cellular immune response is in a state of over-activation, in which a large number of cytokines are released, macrophages are abnormally activated, and a positive feedback loop is formed, which may exacerbate the imbalance in the immune response. If this state of over-activation is not properly controlled, it may eventually lead to the development of IEC-HS. In summary, low NK cell counts are one of the high-risk factors of IEC-HS.

Disease-specific factors

Existing research evidence shows that there is a significant correlation between disease burden and the occurrence of IEC-HS. Patients with acute lymphoblastic leukemia (ALL) as the primary disease and those who have experienced high-grade CRS are considered to have a higher risk of developing IEC-HS [Figure 4 ]. This association emphasizes the importance of carefully evaluating the patient’s underlying disease state and the severity of CRS before implementing CAR-T therapy. This evaluation can not only help doctors more accurately predict the risk of IEC-HS but also guide the adoption of corresponding preventive measures, thereby possibly reducing the occurrence of IEC-HS and improving the treatment outcome of patients.

It has been observed that CAR-T cell expansion will be more pronounced under high disease burden than under low disease burden ( P <0.001). [ 63 ] A reasonable theory for this phenomenon is that higher CD19 antigen load in patients with higher disease burden drives CAR-T cell proliferation. [ 27 ] In turn, the massive expansion of CAR-T cells leads to a cellular immune response in a state of hyperactivation, which ultimately leads to the development of IEC-HS, which may be the reason why high disease burden becomes a high-risk factor for the development of IEC-HS.

B-ALL

There was a study that found that patients who developed IEC-HS had a high ALL burden before CAR-T therapy, both in bone marrow ( P = 0.002) and in peripheral blood before infusion ( P = 0.011). [ 45 ] Not only that, in another study that looked at children and young adults, it was found that all (26/26) of the patients who developed IEC-HS had a high B-ALL burden. In addition, it was also found that patients with high-grade CRS who developed IEC-HS had a significantly higher bone marrow disease burden than patients with high-grade CRS who did not develop IEC-HS ( P = 0.0005). [ 27 ]

Aside from the above studies, according to the incidence of marketed products [Figure 3 ], the incidence of IEC-HS in ALL patients treated with Tisagenlecleucel is much higher than that in patients with diffuse large B-cell lymphoma and follicular lymphoma (FL) treated with the same product. The incidence of IEC-HS in ALL patients treated with Tisagenlecleucel and Brexucabtagene autoleucel is higher than the incidence in patients treated with all products except ALL. All these suggest that a high burden of B-ALL disease is a high-risk factor for the occurrence of IEC-HS.

High-grade CRS

Compared with patients with low-grade CRS, patients with high-grade CRS often exhibit consistent clinical, laboratory, and biomarker characteristics with IEC-HS (such as the same cytokine profile, elevated ferritin, decreased fibrinogen). [ 64 , 65 ] In addition, patients with high-grade CRS usually meet the diagnostic criteria for IEC-HS. [ 66 ] All these suggest that high-grade CRS is a high-risk factor for the occurrence of IEC-HS.

At the same time, it has also been found that high-grade CRS is associated with the development of IEC-HS. The incidence of IEC-HS in patients with high-grade CRS in the study was 57.5% (23/40), compared with a 3.9% (3/77) incidence of IEC-HS in patients with low-grade CRS (Fisher exact odds ratio, 33.4; 95% cumulative incidence (CI): 8.9–110.4; P <0.0001), which also suggests that high-grade CRS is a high-risk factor of developing IEC-HS. [ 27 ]

IEC-related factors

When delving into the risk factors of IEC-HS, we recognize that IEC play a crucial role in the development of the disease. Factors strongly associated with IECs include the selection of antigenic targets, the type of co-stimulatory molecules, the T cell selection process, the dosage setting of CAR-T cells, the risk of over-expansion of CAR-T cells, and TET2 gene mutation [Figure 4 ]. By considering these factors together, we can more fully understand their role in the pathogenesis of IEC-HS and develop strategies accordingly to improve the safety and efficacy of CAR-T therapy. This integrated approach is critical for optimizing treatment regimens and reducing the risk of potential complications.

Target

We have detailed the incidence of the different targets in the “Incidence of IEC-HS” section. As we have observed, under the same diagnostic criteria, the incidence of IEC-HS after CAR-T cell therapy targeting CD22 is the highest, suggesting that CAR-T cell therapy targeting CD22 may be one of the high-risk factors for the occurrence of IEC-HS. Although some scholars speculate that the reason for the highest incidence of the CD22 target may be related to the expression of CD22 by dendritic cells in some cases, [ 18 ] there is currently no definite reason.

Costimulatory molecule

As a crucial component of CAR-T cells, different products have different costimulatory molecules. Currently, the two common costimulatory molecules are CD28 and tumor necrosis factor receptor superfamily, member 9 (4-1BB) [Figure 3 ]. It has been found that CAR-T cells expanded faster and more efficiently with CD28 as a stimulatory molecule, but with limited persistence; CAR-T cells expanded more slowly but with longer persistence with 4-1BB as a co-stimulatory molecule. [ 67 , 68 ] For this reason, using CD28 as a co-stimulatory molecule is more inclined to induce hematologic toxic effects, [ 69 ] while using 4-1BB as a stimulatory molecule is more prone to long-term and delayed hematologic toxicity (e.g., B-cell aplasia). [ 6 ] A study on the reported hematological toxicity in FAERS found that the incidence of IEC-HS in Axicabtagene ciloleucel with CD28 as the costimulatory molecule (lower limit of the reporting odds ratio 95% confidence interval [ROR 0.25 ] = 22.77, lower bound of the information component 95% confidence interval [IC 0.25 ] = 4.42) is higher than that in Tisagenlecleucel with 4-1BB as the costimulatory molecule (ROR 0.25 = 14.97, IC 0.25 = 3.82), [ 6 ] suggesting that using CD28 as a costimulatory molecule is one of the high-risk factors for the occurrence of IEC-HS.

T cell selection

Research has found that after CD4/CD8 T cell selection (TCS) during CAR-T cell manufacturing, under the condition of the same CAR-T cell dose (1 × 10 6 /kg), the incidence of IEC-HS in patients infused with CAR-T cells after T cell selection (71.4%, 5/7) is much higher than that in patients without T cell selection (16.7%, 3/18) ( P = 0.017). Not only that, at all CAR-T cell doses, the incidence of IEC-HS was higher in CD4/8-TCS patients (55.2%, 16/29) than in patients without TCS (14.3%, 3/21) throughout the trial ( P = 0.0039). [ 24 ] Besides, another study has revealed that compared with non-TCS patients, TCS leads to higher in vivo CAR-T cell expansion. [ 18 ] Over-expansion of CAR-T cells is also one of the high-risk factors for IEC-HS, which may explain why TCS is a high-risk factor for the development of IEC-HS.

CAR-T cell dose

In the study by Shah et al [ 24 ] , when TCS was not performed and the CAR-T cell dose was increased from 3 × 10 5 /kg to 1 × 10 6 /kg, the incidence of IEC-HS increased from 0 to 16.7%. After TCS was performed and the high dose (1 × 10 6 /kg) was reduced (to 3 × 10 5 /kg), the incidence of IEC-HS decreased from 71.4% to 44.0%. It can be found that regardless of whether TCS is performed or not, a higher CAR-T cell dose can lead to a higher incidence of IEC-HS, suggesting that high CAR-T dose setting may be a high-risk factor for the occurrence of IEC-HS.

In addition, one study found a 75% incidence of grade ≥3 CRS in patients treated with a high CAR-T cell dose (2 × 10 6 /kg, 68 mL), compared to 27% and 22% in patients treated with a low cell dose (1 × 10 6 /kg, 68 mL and 40 mL), respectively. [ 70 ] Furthermore, a KarMMa study found that the incidence of high-level CRS was 0, 6% (4/70), and 6% (3/54) at CAR-T cell doses of 150 × 10 6 , 300 × 10 6 , and 450 × 10 6 , respectively, [ 71 ] suggesting that a high CAR-T cell dose may lead to high-grade CRS and thus become a high-risk factor of IEC-HS. Moreover, this KarMMa study also found that the higher the CAR-T cell dose, the higher the median value during CAR-T cell expansion. [ 71 ] Excessive expansion of CAR-T cells is also one of the high-risk factors of IEC-HS. The above two explanations may be the reasons why a high CAR-T cell dose is a high-risk factor for the occurrence of IEC-HS.

Excessive expansion of CAR-T cells

As mentioned earlier, many scholars have found that the median onset time of IEC-HS is generally on the 14th day after infusion. [ 11 , 18 , 24 ] Interestingly, it has been found that the peak of CAR-T cell expansion occurs within 14 ± 7 days after infusion, [ 24 , 61 , 72 ] which seems to imply a certain relationship between the excessive expansion of CAR-T cells and IEC-HS. This is indeed the case. T cells, especially CD8 + T cells, are considered to be the key driving factor in the pathophysiology of HLH. [ 73 ] The extensive expansion of CAR-T cells causes the cellular immune response to be in an over-activated state, ultimately leading to the occurrence of IEC-HS. In addition to this, it has also been observed that over-expansion of CAR-T cells is a characteristic of the occurrence of HLH in mouse models and in humans. [ 11 ] Therefore, excessive expansion of CAR-T cells is also a high-risk factor for the occurrence of IEC-HS.

TET2 gene mutation

Although there is currently no direct research evidence indicating that gene mutation is a high-risk factor for patients developing IEC-HS, there are already studies exploring the role of TET2 gene mutation in CRS. Given the high degree of similarity in pathophysiologic mechanisms and clinical manifestations between IEC-HS and severe CRS, and the fact that IEC-HS is often misdiagnosed as high-grade CRS in clinical practice, it is largely justified to generalize the results of the studies on gene mutations in CRS to the consideration of IEC-HS. Such generalization may help us to better understand the pathogenesis of IEC-HS and provide guidance for future research and clinical practice.

A study found that in a patient with chronic lymphocytic leukemia (CLL) treated with CAR-T targeting CD19, the patient was diagnosed with CRS after the first infusion. Afterward, the presence of a mutation in the TET2 gene in the CAR-T cells from the second infusion performed triggered a second high-level CRS in the patient as well as a large clonal expansion of the CAR-T cells. [ 74 ] Meanwhile, another study found that when targeting BCMA-targeted CAR-T for the treatment of patients with multiple myeloma (MM), a patient presenting with a TET2 gene mutation accompanied by human herpesvirus type 7 (HHV7) infection developed a first severe CRS on day 9 post-infusion, a second severe CRS on day 20 post-infusion, and a marked re-expansion of CAR-T cells on day 22 post-infusion, which lasted for 18 days before dying of liver failure and hepatic encephalopathy. [ 75 ]

TET2 dysfunction may produce potent CAR-T cells and simultaneously promote the development of memory CAR-T cells, thereby triggering an effective anti-tumor response. However, because TET2 may control the production of human T cell subset-specific cytokines in an antigen-receptor-dependent and/or co-stimulatory signaling-independent manner, the elevated cytotoxic activity of TET2 -knockout CAR-T cells, together with the increased expression of granzyme B and perforin, may have contributed to the development of severe CRS or even IEC-HS. [ 74 ]

In addition to the above, the patients with TET2 gene mutation mentioned above were associated with over-expansion of CAR-T cells and the occurrence of high-grade CRS, both of which are themselves high-risk factors for the development of IEC-HS. In summary, despite the current lack of evidence, we believe that TET2 gene mutation may be a high-risk factor of IEC-HS.

Management of IEC-HS

Conventional therapeutic agents

In the management of IEC-HS, a large number of patients are still receiving conventional treatment strategies based on earlier regimens. It is important to note that the “conventional therapeutic agents” referred to here are those included in the HLH-94 and HLH-2004 regimens, which have been widely adopted for the management of HLH in the past. The following discussion focuses on the use of two traditional agents, corticosteroids and etoposide, in the management of IEC-HS.

Corticosteroids

Corticosteroids are widely recommended for the management of IEC-HS despite the fact that there are no systematic evaluations of the efficacy of corticosteroids in the management of IEC-HS. With the exception of patients with low-grade IEC-HS, most patients are treated with corticosteroids. This recommendation reflects the trust placed in clinical practice in the anti-inflammatory and immunosuppressive effects of corticosteroids, even in the absence of direct evidence supporting their efficacy in IEC-HS. [ 76 ]

The recommendation for using corticosteroids is based on the following points. First, systemic corticosteroids are the preferred initial treatment agents in various HLH management regimens. [ 77 , 78 ] Second, corticosteroids are often combined with other agents (such as etoposide, anakinra) to manage pHLH and sHLH. Studies have shown that according to the HLH-94 regimen, the overall three-year survival rate of corticosteroids combined with etoposide management reached 55%, [ 79 ] and the overall five-year survival rate of the HLH-2004 regimen was 62%. [ 80 ] Finally, corticosteroids also show effectiveness in preventing and managing other toxicities related to CAR-T cell therapy. For example, early use of corticosteroid intervention can significantly reduce the incidence of grade 3 and above CRS and neurological adverse reactions, reducing from 12% and 29% to 2% and 17%, respectively. [ 81 ] Another study found that no grade 3 or above CRS occurred in patients after early use of corticosteroid intervention, and 68% (27/40) of patients did not experience CRS or neurological adverse reactions within 72 h after infusion. [ 82 ]

However, there are currently differing academic opinions on whether corticosteroids affect the efficacy of CAR-T therapy. Some studies have shown that the use of corticosteroids does not have a negative impact on the effect of CAR-T treatment, [ 81 , 83 ] whereas in contrast, it has been suggested that early and prolonged use of high-dose corticosteroids is associated with early progression and death in patients with large B-cell lymphoma. [ 84 ] Overall, further research is needed to determine whether corticosteroids have an impact on CAR-T cell therapy efficacy.

Etoposide

Etoposide, as an important component of the HLH-94 and HLH-2004 regimens, has been used in the management of pHLH and sHLH. [ 80 , 85 , 86 ] Regarding the specific use of etoposide, the HLH Steering Committee of the Histiocyte Society has issued official recommendations. [ 87 ]

It was found that etoposide has the ability to selectively eliminate activated T-cells (non-activated T-cells such as memory T-cells are not affected). [ 88 ] In addition, after adding etoposide to patients with macrophage activation syndrome (MAS)-HLH on the basis of conventional anti-inflammatory treatment, it was found that inflammatory cytokines such as IFN-γ decreased significantly. [ 89 ]

Currently, there is a lack of research on the effectiveness of etoposide in the management of IEC-HS. It should be noted that since etoposide has the effect of eliminating activated T cells, using etoposide to manage IEC-HS may lead to the elimination of CAR-T cells. [ 19 ] Moreover, there is currently no research on the impact of etoposide on the efficacy of CAR-T cell therapy. For these reasons, etoposide is only recommended as the last-line treatment method or for preventing high-grade IEC-HS in the management of IEC-HS. [ 19 , 90 ]

New therapeutic agents

With the breakthrough progress of CAR-T therapy, IEC-HS has begun to receive extensive attention from the academic community. In order to effectively manage this serious complication, researchers have started to explore new therapies suitable for IEC-HS. These emerging treatment strategies mainly focus on the targeted management of cytokines, including the use of tocilizumab (a blocker of IL-6 receptor), anakinra (a blocker of IL-1 receptor), and emapalumab (a blocker of IFN-γ). Beyond that, inhibitors targeting Janus Kinase 1/Janus Kinase 2 (JAK1/JAK2), such as ruxolitinib, have also become a method for the management of IEC-HS. The following text will further discuss the role of these agents in the management of IEC-HS.

Tocilizumab

Tocilizumab is a recombinant humanized monoclonal antibody targeting the IL-6 receptor and has been approved by the FDA for the management of CRS caused by CAR-T treatment. By binding to soluble and membrane-bound IL-6 receptors, it effectively blocks IL-6-mediated signal transduction. [ 91 ] There are studies that have found that early prophylactic use of tolizumab can reduce the incidence of severe CRS [ 92 , 93 ] and shorten the duration of CRS. [ 94 ] Considering the overlap in pathogenesis and clinical manifestations between IEC-HS and CRS, tocilizumab may be used to manage IEC-HS. In fact, anti-IL-6 therapy was used to treat patients with suspected IEC-HS in the regimen proposed by Neelapu et al [ 23 ] .

However, the ASTCT consensus recently does not encourage the use of tocilizumab or other IL-6 blockers to manage IEC-HS in patients without manifestations of CRS. [ 19 ] This recommendation may be based on several reasons. First, existing research data shows that there is no significant difference in IL-6 levels between patients with and without IEC-HS when tocilizumab is used. In addition, most patients who develop IEC-HS still progress despite previous treatment with tocilizumab to manage CRS. [ 18 ] Second, there is currently a lack of strong data to support the efficacy of tocilizumab in the management of IEC-HS. Beyond that, there is also a divergence in the academic community on the efficacy of tocilizumab in the management of sHLH. One study believes that its efficacy is limited and may increase the risk of infectious complications, [ 95 ] while another small sample study shows that 88.9% (8/9) of patients experienced response after using tocilizumab. [ 96 ] All in all, the effectiveness and safety of tocilizumab in the management of IEC-HS need further research.

Anakinra

Anakinra is an IL-1 receptor antagonist that can block the activity of IL-1α and IL-1β. [ 97 ] In the management of sHLH, anakinra shows relatively good effects. A study found that the CI of response at 30 days of sHLH patients treated with anakinra combined with high-dose steroids reached 83.3%, the CI of relapse at 1 year was 0%, and the overall survival at 1 year reached 77.8%. [ 98 ] Moreover, in another treatment of 44 pediatric sHLH patients, after using anakinra for management, the overall survival rate of children was 73%, and starting to use anakinra early (hospitalization ≤5 days) can reduce the mortality rate. [ 99 ]

As for the management of IEC-HS, although there is a lack of experimental data on the use of anakinra, the use of anakinra in IEC-HS is supported, considering that IL-1β is significantly elevated in patients with IEC-HS. [ 18 , 24 ] Additionally, the good therapeutic effect of anakinra in sHLH also makes the recent ASTCT regimen recommend using it as a first-line treatment agent. [ 19 ]

As for the impact of anakinra on the efficacy of CAR-T cell therapy, it is currently unknown. However, ASTCT consensus expects its impact to be very small. [ 19 ]

Ruxolitinib

Ruxolitinib is an inhibitor of JAK1 and JAK2. Ruxolitinib can block the JAK/STAT (Signal transducer and activator of transcription) signal transduction pathway by inhibiting JAK1 and JAK2, resulting in the simultaneous inhibition of many pro-inflammatory cytokines, including IFN-γ, IL-2, and IL-6. [ 100 ]

Ruxolitinib has been used by some scholars to treat pHLH and sHLH. A review published in 2021 summarized the cases of HLH treated with ruxolitinib. [ 28 ] In this review, a study involving 34 pediatric and adult patients demonstrated that the overall response rate (ORR) of ruxolitinib in the treatment of pHLH and sHLH reached 73.5% (25/34), of which the complete response rate (CRR) was 14.7% (5/34) and the partial response rate (PRR) was 58.8% (20/34). [ 101 ] In addition, another study on 36 adults with lymphoma-related sHLH found that the ORR of ruxolitinib treatment was 83.3% (30/36), the CRR was 27.8% (10/36), and the PRR was 55.6% (20/36). [ 102 ] Furthermore, in a prospective study conducted in 2022, the ORR of ruxolitinib monotherapy was 69.2% (36/52), and the CRR was 42.3% (22/52). [ 103 ]

In terms of the management of IEC-HS, the efficacy of ruxolitinib still needs the support of prospective experimental evidence. However, due to its mechanism of action and good performance in the treatment of sHLH, ruxolitinib has been recommended by ASTCT consensus as a second-line treatment agent for IEC-HS. [ 19 ]

Emapalumab

IFN-γ plays a central role in the pathogenesis of HLH. [ 73 , 104 ] Given this, targeted therapy strategies against IFN-γ are particularly crucial and may provide a new treatment approach for effective intervention in HLH. By neutralizing the activity of IFN-γ, anti-IFN-γ therapy is expected to reduce the high inflammatory response associated with HLH and thereby improve the clinical symptoms and prognosis of patients.

Emapalumab is an IFN-γ blocker and has been approved by the FDA for the treatment of refractory or relapsed pHLH. In a study of 34 pediatric pHLH patients treated with emapalumab, 63% of patients who had previously received conventional treatment and 65% of patients who had not received conventional treatment experienced a response after receiving emapalumab treatment. [ 105 ] Although the FDA only approves emapalumab for the treatment of pHLH, more and more scholars are beginning to use it for the treatment of sHLH. In a study treating MAS with emapalumab, 92.9% (13/14) of patients achieved a response by the eighth week, and all patients were alive at the end of follow-up. [ 106 ]

Studies have shown that the level of IFN-γ in IEC-HS patients is significantly higher than that in patients without IEC-HS. This finding supports the potential effectiveness of using emapalumab in the treatment of IEC-HS. Emapalumab may help reduce disease symptoms by neutralizing IFN-γ, thus providing a new treatment option for IEC-HS patients. [ 11 , 18 ] In fact, some scholars have successfully cured a case of IEC-HS patient by using emapalumab combined with anakinra and corticosteroids. [ 107 ] At present, ASTCT consensus has recommended emapalumab as a third-line treatment agent for IEC-HS (used in combination with corticosteroids and anakinra). [ 19 ]

IL-18 BP

A study has shown that in patients with sHLH, a significant increase in free IL-18 levels can be observed, which is 4.6 times higher than that in the control group ( P <0.001). [ 108 ] Correspondingly, in IEC-HS, scholars have also observed a significant increase in IL-18, [ 18 , 61 ] and the level of free IL-18 is significantly higher than that in patients with only CRS ( P = 0.01). [ 61 ] The significant increase in IL-18 levels may be related to multiple factors. In IEC-HS patients, although the levels of total IL-18 and its binding protein IL-18 BP will both increase, due to the death of a large number of tumor cells and the action of various high-risk factors, it may lead to a large amount of release of IL-18, exceeding the regulatory ability of IL-18 BP. [ 61 ] In general, IL-18 is a potential target for the treatment of IEC-HS.

Regarding the targeted treatment of IL-18, the most recognized agent currently is rhIL-18BP tadekinig-α. [ 109 ] However, there is currently a lack of research data on its efficacy and safety in the treatment of IEC-HS. However, it should also be noted that a phase I trial exploring the utility of this agent in salvage treatment for severe CRS and IEC-HS has been registered (No. NCT05306080 ).

Existing treatment regimens

In clinical practice, both conventional therapeutic agents and new therapeutic agents have shown certain effects on the treatment of IEC-HS. However, there is currently no unified standard for issues such as the optimal combination of these agents, the optimal timing of treatment, and dose selection, which need to be determined according to the specific treatment regimen for IEC-HS.

Currently, for the treatment of IEC-HS, clinicians can refer to multiple regimens, including the HLH-94 regimen, the HLH-2004 regimen, the regimen proposed by Neelapu et al , [ 25 ] and the recommended regimens formulated by the Society for Immunotherapy of Cancer (SITC), the American Society of Clinical Oncology (ASCO), the joint guideline of the EBMT and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association (EHA), and the ASTCT [Table 3 ]. These regimens provide a guiding framework to help clinicians make treatment decisions and select the most appropriate treatment strategy. Through the guidance of these regimens, clinicians can treat patients more accurately to achieve the best treatment effect.

HLH-94 and HLH-2004

The HLH-94 regimen [ 20 , 79 , 80 ] and HLH-2004 regimen [Table 3 ], [ 21 , 80 ] as widely used treatment regimens for HLH, have been proven to have a good prognosis (71% of patients achieve permanent response or can survive until transplantation). [ 110 ] Although HLH-94 and HLH-2004 are mainly applicable to primary HLH and are targeted at pediatric patients, they are not explicitly recommended for the treatment of IEC-HS, and there is a lack of research data on their effectiveness in the treatment of IEC-HS. However, some centers still use them as treatment regimens for IEC-HS. [ 47 ] In 2019, in an expert consensus of the “Adult HLH” working group of the Histiocyte Society, a strong consensus was mentioned that new immunotherapies may induce cytokine storms similar to HLH and require specific treatment. [ 111 ] This also suggests that although the HLH-94 and HLH-2004 regimens have a better effect in treating some HLH, they may be less effective in the treatment of IEC-HS.

The regimen proposed by Neelapu et al [ 23 ]

Neelapu et al [ 23 ] from the MD Anderson Institute have proposed a new regimen for the treatment of patients with IEC-HS [Table 3 ]. [ 23 ] This regimen first treats patients with suspected IEC-HS according to the treatment of CRS, using anti-IL-6 treatment and corticosteroid treatment for grade ≥3 organ toxicities. And if the patient does not improve within 48 hours, etoposide is used for additional treatment. At the same time, intrathecal injection of cytarabine or cytarabine combined with hydrocortisone is performed for patients with related neurological symptoms. [ 23 ] However, it should be noted that currently there is a lack of direct evidence to support the use of etoposide and cytarabine in the treatment of IEC-HS.

SITC regimen

The SITC published the “Clinical Practice Guideline on Immune Effector Cell-Related Adverse Events” in 2020 [Table 3 ]. [ 90 ] This guideline provides recommendations for the management of HLH/MAS-like manifestations associated with IEC therapy. For patients with suspected IEC-HS, it recommends management following CRS treatment principles, with IL-6 blockade as the first-line therapy. Tocilizumab is suggested as the primary agent, and corticosteroids can be added if there is no improvement after one dose. For late-onset or tocilizumab-refractory cases, anakinra and corticosteroids may be considered. In severe or refractory cases, etoposide may serve as a last resort. Supportive therapy with cryoprecipitate is advised for hypofibrinogenemia, with close monitoring. The SITC guideline provides qualitative recommendations without specific drug dosages, emphasizing individualized management based on clinical response.

ASCO regimen

The ASCO proposed a new regimen for the treatment of IEC-HS in a 2021 guideline on the treatment of immune-related adverse events after CAR-T therapy [Table 3 ]. [ 112 ] The new regimen has many similarities to the treatment regimen proposed by Neelapu et al [ 23 ] . However, the new regimen stipulates prerequisites for the use of corticosteroids (the patient’s condition worsens or is unstable). At the same time, it is proposed that for patients with fibrinogen levels lower than 150 mg/dL, fibrinogen replacement therapy should be considered. In addition, the use of anakinra is also proposed. [ 112 ]

EBMT–JACIE–EHA regimen

The EBMT–JACIE–EHA guideline (2021) provides a stepwise approach for the management of IEC-HS, emphasizing early evaluation and escalation according to clinical response [Table 3 ]. [ 113 ] The regimen recommends initial treatment with corticosteroids and IL-1 blockade using anakinra. If no improvement is observed within 24–48 h, intensified corticosteroid therapy is advised, and anakinra should be continued. In cases of persistent deterioration or increased serum ferritin, etoposide may be introduced. For patients with concomitant neurotoxicity, intrathecal administration of cytarabine or methotrexate can be considered. This regimen highlights the importance of dynamic reassessment and combination of immunosuppressive and cytokine-targeted therapies to effectively control hyperinflammatory responses in IEC-HS.

ASTCT regimen

The ASTCT consensus released a recommended treatment regimen for IEC-HS in 2023 [Table 3 ]. [ 19 ] In this regimen, anakinra is recommended as a first-line treatment agent, which can be combined with corticosteroids or used as monotherapy. For patients with grade 2 IEC-HS, treatment can start with a lower dose of two agents or a higher dose of a single agent. Second-line treatment suggests increasing the dose of anakinra and adding corticosteroids if corticosteroids were not applied in the first-line treatment. If the patient’s condition deteriorates rapidly, the treatment regimen mentions that ruxolitinib can be considered. Third-line treatment includes continuous use of anakinra and corticosteroids. At the same time, depending on the specific situation of the patient, ruxolitinib may need to be added, or etoposide can be selected for CAR-T therapy-related lymphocytosis, or emapalumab can be used for cases with elevated IFN-γ levels. [ 19 ] However, it should be noted that the treatment regimen recommendations proposed by ASTCT are based on expert opinions, and the specific effectiveness and reliability still need further prospective studies.

Discussion

Challenges and optimization needs of diagnostic criteria

IEC-HS has a variety of non-specific indicators and symptoms, which make the diagnostic process complex and challenging. Due to the lack of clear and specific diagnostic criteria, currently, various diagnostic methods used to address this difficulty are listed in Table 1 . The existence of these criteria reflects the continuous exploration and efforts of the academic community on how to more effectively identify and diagnose IEC-HS.

A survey targeting the EBMT found that the HLH-2004 criteria are currently the most widely used diagnostic criteria. [ 47 ] However, this standard was originally designed for pediatric HLH patients, and certain indicators such as the threshold of ferritin concentration may not have the same clinical relevance in adult patients. [ 114 ] Besides, both the HLH-2004 criteria and the H-score are proposed based on primary and secondary HLH and do not take into account the concept of CAR-T related IEC-HS. Therefore, when establishing corresponding indicators, the characteristics of this group are not fully incorporated. Additionally, empirical evidence indicates that applying both HLH-2004 criteria and H-score for IEC-HS diagnosis in relapsed/refractory large B-cell lymphoma patients post CAR-T therapy demonstrates compromised diagnostic accuracy, carrying significant risks of false-negative and false-positive classifications. [ 115 ] Moreover, in the study of relapsed/refractory B-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (r/r B-ALL/LBL), researchers found that due to the disease itself, the baseline characteristics of refractory patients before infusion meet most of the criteria in the HLH-2004 criteria (such as cytopenia, fever, and splenomegaly). [ 18 ] While the documented limitations of HLH-2004 criteria and H-score for IEC-HS diagnosis substantiate their suboptimal utility in this specific context, it remains imperative to acknowledge their established diagnostic robustness in classical HLH presentations. Contemporary evidence confirms these frameworks retain high reliability when applied to critically ill patients meeting conventional HLH criteria, notwithstanding their constrained performance in CAR-T therapy-associated IEC-HS scenarios. [ 116 , 117 ]

The criteria proposed by Neelapu et al [ 23 ] have an important prerequisite that the patient has CRS. Although some scholars reported that all IEC-HS patients in their studies had or had experienced CRS, and considered IEC-HS as a variant of CRS, [ 18 , 45 ] more and more scholars believe that secondary HLH, including IEC-HS and CRS, are different entities. [ 118 , 119 ] At the same time, some scholars found that not all IEC-HS patients had or had experienced CRS. [ 18 ] For the above reasons, the criteria proposed by Neelapu et al [ 23 ] also need to be further optimized.

The criteria proposed by Shah et al [ 24 ] are modifications based on the criteria proposed by Neelapu et al . [ 23 ] This modification is to adapt to their research, that is, to diagnose IEC-HS that occurs after CAR-T therapy targeting the CD22 target. However, there is currently no clear report showing the utility of the criteria proposed by Shah et al [ 24 ] in diagnosing IEC-HS in CAR-T therapy for other targets. This indicates that the criteria proposed by Shah et al [ 24 ] may be effective in specific situations. Moreover, given that their scope of application may be limited, these criteria may need further optimization and adjustment in the future to improve their applicability and accuracy in different situations. In addition, other diagnostic criteria in the text are only applicable to their research, so there are also problems of applicability and accuracy.

The diagnostic criteria recently proposed by the ASTCT are different from previous diagnostic criteria in many aspects, showing their unique advantages and characteristics. First of all, when defining the diagnostic threshold, this standard pays more attention to individualization and sets more specific thresholds for various diagnostic indicators based on the patient’s baseline data. Second, compared with the criteria previously proposed by a single center or research group, such as the H-score, the criteria of Neelapu et al [ 23 ] and Shah et al [ 24 ] , the ASTCT criteria are formulated by many experts in the field, which increases the universality and applicability of them. When diagnosing IEC-HS, the ASTCT criteria no longer adopt the strict quantification and unified judgment methods commonly found in many previous diagnostic criteria (for example, meeting more than five of the eight items), but comprehensively consider a variety of clinical manifestations (including “the most common” and “other possible” symptoms), combine individualized indicator thresholds, and finally refer to the professional judgment of doctors, such as “rapid increase in ferritin” and other situations to make a diagnosis. But whether such diagnostic methods can provide higher accuracy, specificity, sensitivity, and ease of use still needs more research to support and validate them.

To improve the accuracy and consistency of the diagnosis of IEC-HS, future research needs to focus on the development of more standardized and precise diagnostic criteria. On the one hand, new criteria should be able to synthesize clinical symptoms, laboratory test results, and relevant biomarkers for early and accurate recognition of IEC-HS. On the other hand, in addition, the new diagnostic criteria should be validated through large-scale multicenter studies to ensure their generalizability and reliability in different clinical settings.

Standardized diagnostic criteria are essential for clinical practice, enhancing diagnostic precision while mitigating risks of misdiagnosis and underdiagnosis. Beyond their immediate clinical utility, these criteria critically inform therapeutic decisions, enable objective efficacy evaluations, and ensure methodological rigor in research. Furthermore, harmonized diagnostic frameworks facilitate cross-study comparability and data synthesis, establishing the necessary foundation for elucidating IEC-HS pathogenesis and advancing novel therapeutic approaches. Consequently, future research must prioritize diagnostic criterion optimization to achieve earlier detection, targeted management, and ultimately improved survival and quality of life for affected patients.

Limitations of summary of high-risk factors

In this review, we have summarized the current understanding of high-risk factors for the occurrence of IEC-HS in the academic community. However, these summarized risk factors have limitations due to the relative newness of research in this field and variable diagnostic criteria.

First, the diagnostic criteria for IEC-HS have not been unified at present, which leads to a large difference in the reported incidence in different studies. For example, the HLH-2004 criteria were formulated without considering CAR-T treatment-related complications, and some of its indicators may not be applicable to adult patients. Beyond that, although some diagnostic criteria, such as the criteria proposed by Shah et a l, have been applied in specific target research, their universality and accuracy still need to be further verified. This inconsistency in diagnostic criteria poses a challenge in identifying high-risk factors for IEC-HS.

Second, current research mostly focuses on the impact of a single high-risk factor on the occurrence of IEC-HS, while there are few studies on the complexity of the combined action of multiple factors. The occurrence of IEC-HS may be the result of the interaction of multiple factors, including the baseline characteristics of patients, disease burden, and specific factors of CAR-T treatment. Therefore, single-factor research may not be able to fully reveal all the high-risk factors for the occurrence of IEC-HS.

Third, due to the relatively low incidence of IEC-HS compared to the most common CRS and ICANS after CAR-T treatment and the diverse clinical manifestations, the sample size of related studies is limited, which may affect the accurate identification and evaluation of high-risk factors. Additionally, there may be differences in the definition and evaluation methods of high-risk factors in different studies, which also brings difficulties to the summary and comparison of high-risk factors.

It is worth noting that as microbiomics is increasingly emphasized, its impact on the efficacy and adverse effects of CAR-T therapy has been observed. It has been observed that Bifidobacterium and Leuconostoc are enriched in patients with MM with high-grade CRS. [ 120 ] High-grade CRS, which is one of the high-risk factors, further mediates the development of IEC-HS. However, due to the lack of direct evidence, we did not categorize the related genera as a high-risk factor for IEC-HS.

Despite identifying potential IEC-HS risk factors through current research, these findings remain constrained by methodological limitations. Future investigations should prioritize: (1) Diagnostic criterion refinement: Augmenting discriminatory capacity through optimized sensitivity/specificity thresholds to enable precise clinical phenotyping. (2) Cohort expansion: Enhancing statistical robustness and generalizability via scaled multicenter cohorts. (3) Multifactorial pathogenesis decoding: Elucidating synergistic interactions among risk variables through systems biology approaches. (4) Prospective validation frameworks. Implementing longitudinal designs for real-time risk factor verification and therapeutic intervention assessment.

Collectively, these strategic directions will catalyze the development of evidence-based management paradigms, ultimately advancing patient-centric outcomes.

Existing challenges and optimization strategies of treatment methods

Although the current treatment strategies for IEC-HS have made certain progress, there are still many challenges and limitations, and further optimization and innovation are urgently needed.

On the one hand, the efficacy and safety of existing therapeutic agents still need to be verified through large-scale clinical trials. For example, although corticosteroids have shown short-term efficacy in some cases, it is still a question whether their long-term use will suppress the activity of CAR-T cells and affect their anti-tumor effect. For another example, as a chemotherapy agent, although etoposide is widely used in the HLH-94 and HLH-2004 regimens, its clearance effect on CAR-T cells may lead to a narrowing of the treatment window.

On the other hand, novel therapeutic agents such as tocilizumab, anakinra, ruxolitinib, and emapalumab, although theoretically having the advantages of being highly targeted and having fewer side effects, there is still a lack of sufficient clinical data to support their effectiveness and safety in the treatment of IEC-HS. In addition, the optimal dosage, timing of use, and combination regimen of these drugs with other treatments need to be clarified by further studies.

In addition, most of the existing treatment regimens are based on expert opinions and clinical experience and lack unified treatment guidelines and standardized processes. This leads to treatment decisions relying to a certain extent on the subjective judgment of doctors, which may affect the consistency and effectiveness of treatment.

Future treatment paradigm refinement should prioritize: (1) Therapeutic validation: rigorously assessing novel and repurposed agents through controlled trials to establish evidence-based safety/efficacy profiles. (2) Protocol standardization: developing consensus guidelines with risk-adapted algorithms to ensure therapeutic consistency. (3) Precision therapy implementation: integrating genomic biomarkers, disease burden metrics, and immune profiling for personalized treatment optimization. (4) Preemptive intervention: establishing real-time surveillance protocols for high-risk signatures to enable early disease interception. (5) Longitudinal outcome mapping: instituting structured follow-up frameworks to quantify survival trajectories and treatment durability. Collectively, these initiatives will catalyze the transition toward mechanism-targeted therapies while minimizing iatrogenic risk.

Therapeutic refinement through continuous innovation is expected to yield enhanced efficacy and safety profiles for IEC-HS management, ultimately improving patient survival and quality of life. Concurrently, such advances will substantiate the safety framework of CAR-T cell therapies while validating their therapeutic effectiveness, thereby accelerating the evolution of precision immunotherapy in oncology.

In conclusions, this review synthesizes IEC-HS pathogenesis, diagnostic criteria, epidemiological patterns, and therapeutic regimens, critically analyzing key differentiators from CRS and validated high-risk predictors. We underscore the imperative for standardized diagnostics and delineate limitations in current treatment paradigms. By advancing mechanistic research, refining diagnostic precision, and developing targeted therapies with optimized safety profiles, we anticipate significant enhancements in CAR-T therapy safety—ultimately translating to improved survival trajectories and quality of life for patients.

Conflicts of interest

None.

Footnotes

Yixuan Zhang, Jilong Yang, and Huiqi Xin contributed equally to this work.

How to cite this article: Zhang YX, Yang JL, Xin HQ, Ai KX, Yang MS, Li YH, He YJ. Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management. Chin Med J 2026;139:1464–1483. doi: 10.1097/CM9.0000000000004066

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