Confirmed efficacy of etoposide and dexamethasone in HLH treatment: Long term results of the cooperative HLH-2004 study

Elisabet Bergsten, AnnaCarin Horne, Maurizio Aricó, Itziar Astigarraga, R. Maarten Egeler, Alexandra H. Filipovich, Eiichi Ishii, Gritta Janka, Stephan Ladisch, Kai Lehmberg, Kenneth L. McClain, Milen Minkov, Scott Montgomery, Vasanta Nanduri, Diego Rosso and Jan-Inge Henter

Key points

  • Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P=.06)

  • HLH-2004 may possibly be improved by risk group stratification, less therapy reduction weeks 7-8 for verified FHL patients, and earlier HSCT


Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% CI, 48-60%), systemic therapy included etoposide, dexamethasone and, from week nine, cyclosporine A (CSA). HSCT was indicated in patients with familial/genetic, relapsing, or severe and persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. During 2004-2011, 369 children aged <18-years fulfilled the HLH-2004 inclusion criteria (5/8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At a median follow-up of 5.2 years, 230/369 (62%) patients were alive (5-year pSu 61%, 56-67%). The 5-year pSu in children with (n=168) and without (n=201) family history/genetically verified FHL was 59% (52-67%) and 64% (57-71%), respectively [familial occurrence (n=47): 58% (45-75%)]. Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was non-significantly reduced from 27% to 19% (P=.064 adjusted for age and gender). Time from start of therapy to HSCT was shorter compared to HLH-94 (P=.020 adjusted for age and gender) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% [verified FHL 70% (63-78%)]. Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.

  • Submitted June 5, 2017.
  • Accepted September 5, 2017.