The HLH-94 study resulted in a remarkably improved outcome with a 5-year probability of survival (pSu) of 54% (±6%). HLH-2004 was initiated with the aim to improve survival further, and reduce pre-SCT mortality and neurological sequelae.
HLH-2004 was based on HLH-94, with eight weeks initial treatment followed by a continuation phase, both including etoposide and dexamethasone. As compared with HLH-94, three treatment changes were made: 1) Due to high mortality weeks 1-8, treatment was intensified by administrating cyclosporine A (CSA) upfront, aimed at increasing immunosuppression without inducing additional myelotoxicity. Notably, CSA had been reported to inhibit production of interferon (IFN)-gamma, and to be beneficial in initial HLH treatment. 2) To reduce time to SCT, it was recommended that SCT be performed as soon as an acceptable donor was available. 3) Given their beneficial systemic effect, corticosteroids were added to the intrathecal (IT) methotrexate (MTX) treatment recommended for a subset of patients.
TIMELINE OF TRIAL:
The study started January 1, 2004, and closed for enrollment of new patients on December 31, 2011. Cut-off for data entry was March 31, 2016.
Altogether, 368 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, 230/368 (62%) patients were alive (5-year pSu 62%, 57-67%). The 5-year pSu in children with (n=167) and without (n=201) family history/genetically verified FHL was 59% and 64%, respectively. Biallelic mutations were identified in 157 patients with 5-year pSu 61%,
Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was reduced from 27% to 19% (P=.064 adjusted for age and gender). 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.