Malignancy-associated HLH: mechanisms, diagnosis, and treatment of a severe hyperinflammatory syndrome

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by uncontrolled immune activation. While traditionally associated with genetic mutations affecting cytotoxic function, recent advances have highlighted the prevalence and significance of HLH in adults, particularly in hematologic malignancies. This review focuses on malignancy-associated HLH (M-HLH), a complex and challenging condition with a poor prognosis. The review explores four main subtypes of M-HLH: (1) HLH as the initial presentation of malignancy, (2) Chemotherapy Associated HLH, (3) Cytokine Release Syndrome (CRS) Associated HLH-like Syndrome, and (4) immune effector cell-associated HLH-like syndrome. Diagnosis is complicated by overlap with cancer symptoms and limitations of existing criteria. The Optimized HLH Inflammatory (OHI) index shows promise in early identification of hyperinflammation in new-onset hematologic malignancies. Treatment approaches must balance controlling hyperinflammation with addressing the underlying malignancy. Emerging therapies, including targeted agents like anakinra, ruxolitinib, and emapalumab, offer new management possibilities. This review examines the current understanding of M-HLH pathophysiology, diagnostic approaches, and treatment strategies for each subtype. It underscores the critical need for further research to unravel underlying mechanisms and establish evidence-based treatment protocols. Given the complexity of M-HLH, international collaborative efforts are essential to advance knowledge and improve patient outcomes.

Keywords: CRS; HLH; Hemophagocytic lymphohistiocytosis; OHI index; hyperinflammation; lymphoma.