Loading
Rarely after CAR T-cell therapy the immune system stays switched on after cytokine release syndrome has settled, and starts damaging the blood, liver and clotting (IEC-HS). It shows as very high ferritin, falling blood counts, low clotting proteins and liver test changes. It is treated with anakinra and steroids, adding other drugs if it worsens, while infection and relapse are ruled out.
ASTCT 2023 named and defined IEC-HS: a hyperinflammatory syndrome with features of macrophage activation or HLH, attributable to immune effector cell therapy, with new or worsening cytopenias, hyperferritinaemia, coagulopathy with hypofibrinogenaemia and/or transaminitis. It usually follows CRS and appears as CRS resolves; it is a diagnosis of exclusion, and a substantially raised (more than twice the upper limit or baseline) or rapidly rising ferritin is a prerequisite. Fever is deliberately not a criterion, to keep it distinct from CRS. Grading (Table 2) follows CTCAE 'immune system disorder, other', grade 1 to 5.
Treatment (expert opinion, Figure 3 and Table 3): start before life-threatening complications with anakinra (adults 100 to 200 mg subcutaneous or intravenous every 6 to 12 hours) with or without corticosteroids (adults dexamethasone 10 to 40 mg daily), allowing about 48 hours to judge effect before adding agents; ruxolitinib second line, dose-reduced with azoles or renal impairment; for refractory life-threatening disease, etoposide 50 to 100 mg/m2 once (not HLH-94 induction doses), or emapalumab where IFN-gamma is high (debated). Tocilizumab is discouraged for IEC-HS without CRS. Supportive: daily blood count, PT/PTT and fibrinogen, daily renal and liver tests, fibrinogen replacement, transfusion, cautious G-CSF, infectious disease input and prophylaxis matched to the immunosuppression. SITC 2020 (LE: 4): cryoprecipitate for delayed hypofibrinogenaemia, anakinra and steroids for late tocilizumab-refractory HLH/MAS-like toxicity, etoposide only as a last resort.
Why: This is a different illness from the early fever and needs different treatment.
“We ultimately define IEC-HS as the development of a pathological and biochemical hyperinflammatory syndrome that 1) manifests with features of macrophage activation/HLH, 2) is attributable to IEC therapy, and 3) is associated with progression or new onset of cytopenias, hyperferritinemia, coagulopathy with hypofibrinogenemia and/or transaminitis.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: IEC-HS usually starts as the first inflammation is settling; calling severe CRS by this name would change treatment wrongly.
“Hence, it is imperative to distinguish suspected IEC-HS from CRS recurrence or a prolonged severe CRS, to pursue treatment options and monitoring accordingly.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: A normal ferritin makes this syndrome very unlikely.
“Nonetheless, given the high negative predictive value of a normal ferritin, substantial elevations in ferritin are a prerequisite to a diagnosis of IEC-HS and normal ferritin values with ongoing inflammation should prompt considerations of alternative etiologies.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: Infection and relapse can look the same and need quite different treatment.
“Expediency should be given to excluding the most common and dangerous concurrent diagnoses, including infection and/or progressive malignancy.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: Patients can deteriorate quickly, and bleeding risk rises as fibrinogen falls.
“Daily monitoring of complete blood cell count with differential, coagulation parameters (PT/PTT) and fibrinogen are recommended for patients with IEC-HS.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: Low fibrinogen out of proportion to other clotting tests is a hallmark and causes delayed, severe bleeding.
“Delayed coagulopathy may possibly be one hallmark of delayed onset HLH/MAS-like toxicity, typically hypofibrinogenemia disproportionately worse than changes in PT/PTT, which requires close follow-up and replacement with cryoprecipitate”
Why: Early treatment may stop it progressing; piling on drugs too fast adds infection risk.
“Therapy should generally be initiated with corticosteroids +/− anakinra prior to development of life-threatening complications and, if possible, a time interval to evaluate for efficacy (e.g., 48 hours) should elapse before additional agents are added to avoid cumulative toxicity of multiple immunosuppressive agents.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: There is no evidence it works in HLH-like illness, and most patients have already had it for CRS.
“Additionally, despite established efficacy in CRS, use of tocilizumab or other IL-6 blocking agents (e.g., siltuximab) for IEC-HS, without CRS manifestations, was specifically discouraged due to lack of evidence for efficacy in any HLH-related context, and since most patients will have already received tocilizumab prior to the onset of IEC-HS.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: Ruxolitinib blocks several inflammatory signals at once; its levels rise with poor kidney function and some antifungals.
“As ruxolitinib levels increase with renal dysfunction and with concurrent CYP3A4 inhibitors, including antifungal agents (i.e., azoles), appropriate dose reductions must be made.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: Etoposide kills activated T cells, including the CAR T cells, so it is kept for when the patient's life takes priority.
“Etoposide should only be administered to patients experiencing late-onset, tocilizumab-refractory HLH/MAS-like symptoms after CAR T cell therapy as a last resort”
Why: Each added immunosuppressant raises the risk of fungal, viral and Pneumocystis infection.
“As the risk of infection in patients with IEC-HS incrementally increases with additive use of immunosuppression, infectious disease consultation is strongly encouraged—particularly with clinical deterioration.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Why: Long immunosuppression causes infections, but stopping too fast can let the syndrome return.
“Nonetheless, given the deleterious impact of immunosuppression, including risk of infection—when clinical and laboratory parameters have stabilized, gradually tapering therapy is encouraged while monitoring for recrudescence of symptoms.”
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
The ASTCT 2023 consensus is the only document that defines, grades and sets out treatment for IEC-HS as a named syndrome, and is the best available source; its treatment advice is expert opinion, stated by the panel as not evidence-based. SITC 2020, written before the term existed, agrees on the shape: cryoprecipitate for disproportionate hypofibrinogenaemia, anakinra and steroids for late tocilizumab-refractory HLH/MAS-like toxicity, and etoposide only as a last resort (all LE: 4). The two differ in emphasis on etoposide: SITC limits it to a last resort; ASTCT also places it after first- and second-line therapy but gives a moderate single dose (50 to 100 mg/m2, possibly weekly) and advises against HLH-94 induction dosing. EBMT/JACIE 2019 says only that delayed macrophage activation syndrome is managed with standard approaches. The ASTCT 2026 update to the consensus grading, which includes IEC-HS, was read only as its abstract.
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023 · SITC, Journal for ImmunoTherapy of Cancer 2020 · EBMT and JACIE, Haematologica 2020 · American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2026
Where it differs: Considers the anti-interferon-gamma antibody emapalumab for life-threatening IEC-HS, especially with documented IFN-gamma elevation, at the package-insert dose.
Evidence: Evidence is from a small paediatric primary HLH cohort; the panel calls adult use extrapolative and notes cost and urgent procurement may be prohibitive. No consensus was reached.
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Where it differs: For constructs carrying a targetable safety switch (for example truncated EGFR, targeted by cetuximab), turning the CAR T cells off is considered before etoposide in rapidly progressive disease.
Evidence: Expert opinion; applies only to constructs that carry such a switch, which commercial products in the sources do not describe.
American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023
Where it differs: Frames late HLH/MAS-like toxicity within the CRS algorithm, considering third-line CRS agents such as anakinra and steroids, rather than as a separate syndrome with its own grading.
Evidence: LE: 4.
Where it differs: States that delayed macrophage activation syndrome and CRS are managed with standard approaches, without a specific algorithm.
Evidence: Ungraded best practice recommendation.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Treatment recommendations for IEC-HS “Due to lack of prospective clinical trials for IEC-HS and limited literature on treatment approaches for HLH-like manifestations following CAR T cells—the following treatment recommendations are derived from expert opinion, rely on available evidence from CRS/IEC-HS cohorts and previous evidence with treatment of pHLH and sHLH, and warrant prospective studies.” | expert opinion, not evidence-based | American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2023 |
| Cryoprecipitate for delayed hypofibrinogenaemia | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Anakinra and steroids for late, tocilizumab-refractory HLH/MAS-like pathology “For treatment of late-onset, HLH/MAS-like pathology, which may be tocilzumab-refractory, third-line CRS agents such as anakinra and steroids may be considered (LE: 4).” | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Etoposide only as a last resort | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
Shares Infection screening, prophylaxis and immunoglobulin replacement around CAR T-cell therapy, CAR-T cell therapy and the tags protocol, cell-therapy, car-t.
Shares Methylprednisolone, Dexamethasone, Etoposide, CAR-T cell therapy and the tags protocol, cell-therapy, car-t.
Shares Infection screening, prophylaxis and immunoglobulin replacement around CAR T-cell therapy, CAR-T cell therapy and the tags protocol, cell-therapy, car-t.
Shares CAR-T cell therapy and the tags protocol, cell-therapy, car-t.
Shares ICANS after CAR T-cell therapy: ICE score, ASTCT grading, steroids and seizure management, Infection screening, prophylaxis and immunoglobulin replacement around CAR T-cell therapy, Cytokine release syndrome after CAR T-cell therapy: ASTCT grading, tocilizumab and steroids, Cytokine release syndrome (CRS) and the tags protocol, cell-therapy.
Shares Methylprednisolone, Society for Immunotherapy of Cancer and the tags protocol, acute-oncology.
Shares Methylprednisolone, Society for Immunotherapy of Cancer and the tags protocol, acute-oncology.
Shares Methylprednisolone, Society for Immunotherapy of Cancer and the tags protocol, acute-oncology.