AnnaCarin Horne1, Tatiana von Bahr Greenwood1, Samuel C C Chiang1, Marie Meeths1, Caroline Björklund1, Maria Ekelund1, Peter Erensjö1, Stefan Berg1, Stefan Hagelberg1, Yenan T Bryceson1, Ulf Andersson1, Jan-Inge Henter1. 1. The study was supported by grants from the Swedish Children's Cancer Foundation, Swedish Cancer Foundation, Swedish Research Council, Cancer and Allergy Foundation of Sweden, and Region Stockholm (ALF-project) to JIH; and from the Swedish Children's Cancer Foundation, Swedish Cancer Foundation, Swedish Research Council, and Swedish Foundation for Strategic Research to YTB. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data, or in writing the manuscript. A.C. Horne, MD, PhD, M. Meeths, MD, PhD, Childhood Cancer Research Unit, and Pediatric Rheumatology Unit, Department of Women's and Children's Health, Karolinska Institutet, and Theme of Children's Health, Karolinska University Hospital, Stockholm; T. von Bahr Greenwood, MD, J.I. Henter, Professor, MD, PhD, Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Theme of Children's Health, Karolinska University Hospital, Stockholm; S.C. Chiang, PhD, Y.T. Bryceson, PhD, Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, and Karolinska University Hospital Huddinge, Stockholm; C. Björklund, MD, Department of Pediatric Hematology and Oncology, Umeå University Hospital, Umeå; M. Ekelund, MD, Department of Pediatrics, Ryhov County Hospital, Jönköping, and Department of Women's and Children's Health, Uppsala University, Uppsala; P. Erensjö, MD, Department of Pediatrics, Falun Hospital, Falun; S. Berg, MD, PhD, Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg; S. Hagelberg, MD, PhD, U. Andersson, Professor, MD, PhD, Pediatric Rheumatology Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, and Theme of Children's Health, Karolinska University Hospital, Stockholm, Sweden. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. A.C. Horne, Department of Women's and Children's Health, Karolinska Institutet, Tomtebodavägen 18A, SE-171 77 Stockholm, Sweden. Email: annacarin.horne@sll.se. Accepted for publication February 2, 2021.
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/m2 once weekly), added to conventional MAS-HLH treatment that was considered insufficient. The mean accumulated etoposide dose was 671 mg/m2 (range 300-1050 mg/m2) as compared to 1500 mg/m2 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 × 109/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.
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/m2 once weekly), added to conventional MAS-HLH treatment that was considered insufficient. The mean accumulated etoposide dose was 671 mg/m2 (range 300-1050 mg/m2) as compared to 1500 mg/m2 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 × 109/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.
Authors: Karin Palmblad; Hanna Schierbeck; Erik Sundberg; Anna-Carin Horne; Helena Erlandsson Harris; Jan-Inge Henter; Ulf Andersson Journal: Mol Med Date: 2021-05-11 Impact factor: 6.354