Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation

Primary hemophagocytic lymphohistiocytosis (pHLH) is a life -threatening hyperin fl ammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X -linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5 -year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% fi rst -line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other fi rst -line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (con fi dence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving fi rst -line etoposide. Compared with the HLH-2004 study, both pre HSCT and post-HSCT survival of patients receiving fi rst -line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced -toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential bene fi t of newborn screening. This contemporary standard -of -care study of patients with pHLH reveals that fi rst -line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes.