Extensive non-clonal CAR T-cell expansion causing fatal hyperinflammatory syndrome with immune effector cell-associated hemophagocytic lymphohistiocytosis, cytokine release syndrome, and neurotoxicity syndrome

Sep 29, 2026

Uploaded by Rowan

Case report describing a patient receiving cilta-cel for relapsed and refractory IgGk myeloma who developed massive, non-clonal CAR T-cell expansion with fatal hyperinflammatory syndrome. The clinical course showed overlapping features of cytokine release syndrome, immune effector-cell associated neurotoxicity syndrome, and IEC-HS, including cytopenias, hyperferritinemia-related markers, coagulopathy, transaminitis, and high HScore. Despite escalation with antibiotics, tocilizumab, dexamethasone, methylprednisolone, anakinra, and cyclophosphamide with re-lymphodepletion, the patient progressed to grade IV ICANS, with renal failure requiring dialysis and death on day 22 after infusion.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages5

Reading Time13 min

AccessFree to download

Case Report

Background and Clinical Rationale

Patient Characteristics and Disease Course

CAR T Administration and Early Complications

Diagnostic Findings and Treatment Escalation

Outcomes and Final Progression

CASE REPORT Extensive non-clonal CAR T-cell expansion causing fatal hyperinflammatory syndrome with immune effector cellassociated hemophagocytic lymphohistiocytosis, cytokine release syndrome, and neurotoxicity syndrome Chimeric antigen receptor T-cell (CART) therapy has become the standard of care for patients with relapsed and refractory (R/R) B-cell neoplasia. However, CART-triggered cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS), or immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) may lead to significant non-relapse mortality. IEC-HS is a serious toxicity, defined by pathological macrophage activation associated with IEC therapy, characterized by cytopenias, hyperferritinemia, coagulopathy, and transaminitis 1 Recently published real-world data on ciltacabtagene autoleucel (cilta-cel) report 5 cases of IEC-HS among 236 analyzed patients (2%) .2 Moreover, IEC-HS is observed not only following CART therapy itself but also in cases involving autologous stem cell boosts for IEC-associated hematotoxicity.3 The symptom complex cannot be easily distinguished from severe CRS; however, an essential element is its clinical and chronological independence, as it often occurs after CRS and is accompanied by hemophagocytosis in bone marrow or other tissues.1 Wereport a patient treated with cilta-cel for R/R myeloma who experienced massive, albeit non-clonal, CART expansion associated with severe hyperinflammatory syndrome characterized by overlapping features of CRS, ICANS, IEC-HS, leading to death 22 days after infusion. Samples and data were collected in accordance with the principles of the Declaration of Helsinki. Standardized sampling for CART phenotyping is approved by the Ethics Committee of the University of Tübingen, Germany. In accordance with local regulations, no formal ethics committee approval was required for this single case report. Written informed consent for further analyses and publication was obtained from the patient’s family. A 72-year-old male patient received cilta-cel in February 2024 for the treatment of refractory and rapidly progressive serological and morphological IgGk myeloma. The initial diagnosis was made in May 2015, and six prior treatment lines had been administered before cilta-cel. Due to a substantial serological and morphological progression, the patient was admitted to our center for leukapheresis and to plan cilta-cel therapy in October 2023. In contrast to the stable serological parameters, a CT scan carried out in December 2023 showed massive progression affecting the entire axial skeleton, significantly jeopardizing the patient’s physical stability. Extramedullary lesions were not observed. The last biopsy from July 2023 had shown an infiltration of 15-20% . According to these results, the CART therapy initially planned for December 2023 was postponed and radiotherapy was initiated to stabilize the osteolytic lesions. Before initiation of the therapy, the patient again showed significant serological progressive disease. His performance status was Eastern Cooperative Oncology Group grade 0. No cardiac disease was observed, and no comorbidities were known except for arterial hypertension. CAR T cells were administered on day 0 after lymphodepletion with fludarabine and cyclophosphamide (30 mg/ m2 and 300 mg/m2, day-5 to day-3) . On day +4, the patient developed a fever, suggesting an infection or grade ICRS. Antibiotic therapy was escalated to meropenem and linezolid and later supplemented with levofloxacin. However, none of the microbiological investigations, including blood cultures (days-3/+4/+6/+22), urine cultures (days-3/+4/+6/+14) and viremia testing (days +1/+8/+16) identified a causative pathogen. Given the patient’s cardiopulmonary stability and the fact that fever was the only initial symptom of CRS, we decided not to administer pre-emptivetocilizumab, consistent with the guideline

FAQs

What toxicity constellation was reported in this case?

The case describes fatal hyperinflammatory syndrome with overlapping features of CRS, ICANS, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS).

How was infection evaluated when fever occurred early?

Microbiological investigations, including blood and urine cultures and viremia testing, did not identify a causative pathogen.

What treatments were used after deterioration on day +7?

Treatment was initiated with tocilizumab and dexamethasone, followed by escalation to methylprednisolone and anakinra when IEC-HS and ICANS markers worsened.

Sep 29, 2026

Uploaded by Rowan