How I treat HLH-like toxicities after immune effector cell therapy

ABSTRACT: Breakthroughs in cancer immunotherapy have redefined patient care, ushering in a new era of therapeutic modalities, chimeric antigen receptor T cells (CAR-T), and bispecific T-cell engagers, among others. Hemophagocytic lymphohistiocytosis (HLH)-like toxicities triggered by these immunotherapies 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 article, we highlight our collective approach in managing 2 recognized CAR-associated HLH-like toxicity syndromes, CRS-MOD and IEC-HS, and provide an overview of the current treatment landscape.