Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome–Hemophagocytic Lymphohistiocytosis
AnnaCarin Horne, Tatiana von Bahr Greenwood, Samuel C. C. Chiang, Marie Meeths, Caroline Björklund, Maria Ekelund, Peter Erensjö, Stefan Berg, Stefan Hagelberg, Yenan T. Bryceson, Ulf Andersson, Jan‐Inge Henter
Abstract
Objective Macrophage activation syndrome (MAS) constitutes 1 subtype of the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH), and the term MAS-HLH was recently proposed for HLH with underlying autoimmune/autoinflammatory conditions. The mortality of MAS-HLH has been estimated at 5–10%. Here we report our experiences with moderately dosed etoposide in severe MAS-HLH; the objective was to effectively reduce severe hyperinflammatory activity with limited side effects. Methods In addition to conventional antiinflammatory treatment, moderately dosed etoposide was administered to 7 children affected by rapidly progressing MAS-HLH with central nervous system (n = 5) and/or pulmonary (n = 5) involvement. Three had underlying systemic juvenile idiopathic arthritis (sJIA), 2 had atypical sJIA (no arthritis at diagnosis), and 2 had systemic lupus erythematosus. We performed lymphocyte cytotoxicity analyses in all 7 and genetic analyses in 6. Results All children promptly responded to moderately dosed etoposide (50–100 mg/m 2 once weekly), added to conventional MAS-HLH treatment that was considered insufficient. The mean accumulated etoposide dose was 671 mg/m 2 (range 300–1050 mg/m 2 ) as compared to 1500 mg/m 2 recommended in the first 8 weeks of the HLH-94/HLH-2004 protocols. One child developed neutropenic fever and another neutropenic sepsis (neutrophils 0.3 × 10 9 /L at therapy onset). Five of 7 children had low percentages (< 5%) of circulating natural killer (NK) cells prior to or in association with diagnosis; NK cell activity was pathologically low in 2 of 5 children studied. Disease-causing variants in HLH-associated genes were not found. All children were alive at latest follow-up (2–9 yrs after onset); neurological symptoms had normalized in 4 of 5 affected children. Conclusion Moderately dosed etoposide may be beneficial in severe and/or refractory MAS-HLH.