Hemophagocytic Lymphohistiocytosis After CAR T-Cell Therapy: A Systematic Review and Meta-Analysis

Chimeric Antigen Receptor T-cell Immunotherapy represents a breakthrough in treating relapsed/refractory hematologic malignancies, yet immune-related adverse events, particularly hemophagocytic lymphohistiocytosis (HLH), also known as immune effector cell-associated HLH-like syndrome (IEC-HS), are rapid-progressing and life-threatening. This systematic review and meta-analysis searched PubMed, Embase, and Cochrane CENTRAL up to August 20, 2025. Nineteen studies were analyzed using a random-effects model, covering 2780 patients, 47 HLH cases, and 20 HLH-related deaths. The pooled incidence of HLH was 1.6% at a median follow-up of 12.9 months, with an associated HLH mortality of 0.7%. The incidence of HLH differed markedly by disease entity (p = 0.0008), highest in B-cell acute lymphoblastic leukemia (B-ALL: 6.9%). CAR T-cell product was also a significant determinant (p = 0.0036), with tisagenlecleucel (Tisa-cel) showing the highest incidence (4.3%). Subgroup analyses confirmed that Tisa-cel had a significantly higher HLH incidence than axicabtagene ciloleucel (Axi-cel) in large B-cell lymphoma (2.4% vs. 0.6%, p = 0.038), and ciltacabtagene autoleucel (Cilta-cel) had a higher incidence than idecabtagene vicleucel (Ide-cel) in multiple myeloma (2.6% vs. 0.7%, p = 0.022). Higher-grade cytokine release syndrome (CRS) was positively correlated with HLH incidence, particularly in MM. Overall HLH incidence was significantly positively correlated with mortality. In conclusion, HLH risk after CAR T-cell therapy is primarily driven by underlying disease type and specific CAR T-cell product, with additional contribution from severe CRS. Enhanced surveillance and early intervention are strongly recommended for high-risk groups, particularly B-ALL patients and recipients of Tisa-cel or Cilta-cel.