SEVERE hyperinflammation remains a fatal complication following CAR T-cell therapy, driving high mortality across clinical cohorts. A retrospective single-center study examining 301 adult patients treated with commercial CD19- or BCMA-directed chimeric antigen receptor products identified immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, termed IEC-HS, in 14 individuals, representing an overall incidence of 4.7%. The complication developed across multiple hematologic malignancies, including multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, and B-cell acute lymphoblastic leukemia. Onset occurred at a median of ten days following cell infusion, emerging either during ongoing cytokine release syndrome or shortly after its resolution. Preceding cytokine release syndrome was documented in every affected patient, confirming its role as a universal clinical precursor.
Baseline evaluation prior to lymphodepletion revealed consistent warning signs. All patients exhibited markedly elevated serum ferritin, alongside frequent elevations in lactate dehydrogenase, baseline thrombocytopenia, and anemia. In addition, 57% of affected patients presented with high tumor burden at the time of conditioning chemotherapy. Following CAR T-cell therapy, patients developing the hyperinflammatory syndrome demonstrated profound cellular proliferation, with a median peak expansion of 54,806 CAR T-cell copies per milliliter. Clinical presentation was defined by severe hyperferritinemia, hypofibrinogenemia, grade four cytopenias, and hepatic dysfunction in 86% of cases. Infectious complications arose in 79% of patients, comprising severe bacterial bloodstream infections, cytomegalovirus reactivation, and invasive fungal infections, including pulmonary aspergillosis and mucormycosis.
Management required aggressive immunosuppression, primarily combining systemic dexamethasone and the interleukin-1 receptor antagonist anakinra in 86% of cases. Refractory presentations prompted the administration of intravenous immunoglobulin, tocilizumab, ruxolitinib, siltuximab, emapalumab, or etoposide. Although the inflammatory syndrome resolved in half of the patients within a median of seven days, overall mortality reached 79%, with active toxicity accounting for most fatalities. Consequently, one-year overall survival dropped to 31% in patients with the syndrome compared to 69% in unaffected individuals. Notably, surviving patients more frequently had underlying multiple myeloma and higher baseline ferritin. These findings highlight that dynamic ferritin tracking and immediate intervention are critical when managing life-threatening toxicities during CAR T-cell therapy.
Reference
Shaforostova I et al. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis Following CAR T-Cell Therapy: Results of a Real-World Study. Cancers. 2026;18(10):1594.
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