Long‐Term Outcomes of a Stratified Treatment Regimen Based on Etoposide and Glucocorticoids in Children With Hemophagocytic Lymphohistiocytosis ( CCHG ‐ HLH ‐2018): A Multicenter, Single‐Arm Clinical Study

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome. The widely used HLH-1994/2004 protocols are primarily designed for primary HLH (pHLH). However, in Asia, particularly in China, secondary HLH (sHLH) is more prevalent, which may limit the efficacy of these protocols and increase treatment-related toxicity. To address this, we conducted a multicenter, prospective, single-arm clinical study to evaluate the CCHG-HLH-2018 protocol, a stratified treatment regimen based on glucocorticoids and etoposide, for pediatric HLH patients in China. A total of 286 patients from 20 centers were included, with a median follow-up of 64 months. Based on HLH-related indicators at onset, 64 patients (22.4%) were classified as low-risk group and 222 (77.6%) as high-risk group. The 5-year overall survival (OS) for all patients was 86.3% (95% CI, 81.7-89.8), with 96.9% (95% CI, 88.1-99.2) in low-risk group and 83.2% (95% CI, 77.6-87.5) in high-risk group (Holm-Bonferroni adjusted p = 0.006). The 5-year OS for pHLH patients was 72.9% (95% CI, 58.0-83.3), significantly lower than the 89.0% (95% CI, 84.3-92.4) for sHLH patients (Holm-Bonferroni adjusted p = 0.008). Among all patients, 54 (18.9%) achieved sustained remission without chemotherapy. No significant differences in OS and EFS were observed between high-risk patients receiving CSA-containing regimens and those receiving non-CSA regimens (p = 0.148, p = 0.107). However, exploratory subgroup analysis of idiopathic HLH patients suggested a trend toward improved survival with the CSA-containing regimen. The safety profile of the CCHG-HLH-2018 protocol was acceptable, with fewer adverse events in the low-risk group. Our findings suggest this stratified protocol is effective in reducing chemotherapy intensity for Chinese children with HLH. Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR1800017267.