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

ABSTRACT 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.