How I Treat HLH-Like Toxicities Following Immune Effector Cell Therapy

Breakthroughs in cancer immunotherapy have redefined patient care, ushering in a new era of therapeutic modalities including checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and bispecific T-cell engagers, amongst others. However, their distinct toxicity profiles have required clinicians across all specialties to rapidly adopt an immunologic perspective in management. Among them, therapy related hemophagocytic lymphohistiocytosis (HLH)-like toxicities are increasingly recognized as part of a broader category of hyperinflammatory syndromes. The recently defined Immune effector cell-associated HLH-like syndrome (IEC-HS), characterized by hallmark clinical and biochemical features of secondary HLH, is both clinically and temporally distinct from cytokine release syndrome (CRS), typically emerging as CRS subsides or after it has resolved. In contrast, in CRS with multiorgan dysfunction (CRS-MOD), HLH-like manifestations often appear with worsening CRS and progress through standard CRS-directed therapy. Importantly, CRS-MOD is to be differentiated from the acute hyperferritinemia and transient organ toxicities seen with CRS, which often responds to standard CRS management. Clinically differentiating these HLH-like syndromes remains challenging; however, their shared pathophysiology has contributed to an evolving landscape of therapeutic strategies. Given the association of HLH-like toxicities with poor outcomes, enhanced recognition, comprehensive diagnostic approaches and early intervention strategies may improve outcomes-preserving the potential benefit of the therapies patients are receiving. In this "How I Treat," we highlight our collective approach in managing two recognized CAR-associated HLH-like toxicity syndromes, CRS-MOD and IEC-HS, and provide an overview of the current treatment landscape.