Hemophagocytic lymphohistiocytosis: new grading classification and targeted therapies

Hemophagocytic lymphohistiocytosis (HLH), both primary/familial HLH and secondary HLH, is associated with multiorgan dysfunction caused by excessive immune activation and cytokine release. The high morbidity and mortality rates are in part due to diagnostic challenges leading to a delay in treatment initiation. The diagnosis, which uses the Histiocyte Society clinical criteria from 2004 and the HScore, remains challenging, with limited improvement in outcomes. No grading system is available for HLH. Although etoposide with dexamethasone remains the most frequently used first-line regimen, various new therapies are now being employed in the management of HLH. The interferon gamma inhibitor emapalumab, the Janus kinase signal transducer and activator of transcription pathway inhibitor ruxolitinib, and the interleukin 6 (IL-6) inhibitor tocilizumab have been trialed in HLH management, with additional treatment options being inhibition of IL-18 and tumor necrosis factor alpha. Here, we summarize current management options for HLH; we also propose a new grading system for HLH based on Common Terminology Criteria for Adverse Events version 5.0 as well as on known prognostic factors (eg, abnormal bilirubin and transaminase levels, elevated creatinine level, respiratory failure, neutropenia, hypertriglyceridemia, hypoalbuminemia, and coagulopathy), which could standardize the diagnosis and guide prompt and appropriate management.