CXCL9 and IL-18: potential biomarkers for efficacy evaluation in refractory hemophagocytic lymphohistiocytosis treated with RED (ruxolitinib, emapalumab and dexamethasone)

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory disorder characterized by excessive cytokine release. More than 30% of HLH cases are refractory to frontline therapy. Unfortunately, there is no universally accepted second-line regimen, and about 30% of patients fail to respond to current salvage treatments. Moreover, evidence guiding alternative therapies and the optimal timing for switching to new treatments in refractory patients is limited. This study retrospectively analyzed the efficacy and safety of the RED regimen (ruxolitinib, emapalumab, and dexamethasone) in 15 refractory HLH patients who had failed at least two previous salvage therapies. Overall, eight (53.3%) patients achieved partial remission, and four of those eight proceeded to hematopoietic stem cell transplantation (HSCT). Notably, pre-RED levels of C-X-C motif chemokine 9 (CXCL9) and interleukin-18 (IL-18) were significantly higher in patients who later responded to RED, suggesting that these biomarkers may predict a better response. We also observed that, for eight partial-remission patients, hemoglobin, fibrinogen, aspartate aminotransferase, calcium, and CXCL9 levels tracked well with early therapeutic responses (one to two weeks). No grade 3 or higher adverse effects were linked to the RED regimen. This comprehensive investigation of the RED approach in HLH, although small in sample size, supports the possibility that RED can serve as an effective and relatively safe salvage therapy for refractory HLH.