Overview of the treatment protocols. (A) HLH-94 and (B) HLH-2004. (A) Both HLH-94 and HLH-2004 consist of an initial therapy of 8 weeks, with immunosuppressive and cytotoxic agents, and continuation therapy thereafter, for patients with familial, relapsing, or severe and persistent, aiming at a HSCT as soon as an acceptable donor is available. In both HLH-94 and HLH-2004, daily dexamethasone (Dexa) (10 mg/m2 per day weeks 1-2; 5 mg/m2 per day weeks 3-4; 2.5 mg/m2 per day weeks 5-6; 1.25 mg/m2 per day week 7, and tapering during week 8), and etoposide (VP-16) (150 mg/m2, twice weekly weeks 1-2, then once weekly) is administrated during the initial therapy. The continuation therapy for both HLH-2004 and HLH-94 consists of Dexa every second week (10 mg/m2 per day for 3 days), VP-16 (150 mg/m2) every second week, and CSA (aiming at 200 µg/L trough value). For patients with progressive neurological symptoms during the first 2 weeks, or if an abnormal cerebrospinal fluid value at onset has not improved after 2 weeks, intrathecal (I.T.) treatment is recommended (up to 4 doses, weeks 3, 4, 5, 6). In the HLH-94 protocol, I.T. MTX (doses by age: <1 year, 6 mg; 1-2 years, 8 mg; 2-3 years, 10 mg; >3 years, 12 mg each dose) is recommended. (B) In HLH-2004, CSA (aiming at 200 µg/L trough value) is administered already upfront during the initial therapy, a modification from HLH-94 where CSA is not administered until the continuation therapy. It is recommended to start CSA with 6 mg/kg daily orally (divide in 2 daily doses), if normal kidney function. Moreover, in the HLH-2004 protocol, in addition to I.T. MTX, I.T. prednisolone (doses by age: <1 year, 4 mg; 1-2 years, 6 mg; 2-3 years, 8 mg; >3 years, 10 mg each dose) is recommended. In HLH-2004, the total treatment period is reduced to 40 weeks as compared with 52 weeks in HLH-94. Reprinted from Henter et al12 (A) and Henter et al11 (B) with permission. BMT, bone marrow transplantation.
