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, Jan-Inge Henter

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.