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

Abstract

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% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, fromweek 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n 5 168) and without (n 5 201) family history/ genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n547], 58%[45%-75%]).Comparing with historical data (HLH-94), usingHLH- 94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P5.064 adjusted for age and sex). Time from start of therapy toHSCTwas shorter compared with HLH-94 (P 5 .020 adjusted for age and sex) 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.