HLH-2004 for untreated hemophagocytic lymphohistiocytosis (HLH)

Regimen in use at

Regimen

Study	Evidence
Henter et al. 2007 (HLH-2004)	Non-randomized

Initial therapy

• Start allogeneic stem cell transplant (SCT) donor search
• Dexamethasone (Decadron) in a tapering schedule as follows:
  • Weeks 1 & 2: dexamethasone 10 mg/m2 (route not specified) once per day
  • Weeks 3 & 4: dexamethasone 5 mg/m2 (route not specified) once per day
  • Weeks 5 & 6: dexamethasone 2.5 mg/m2 (route not specified) once per day
  • Week 7: dexamethasone 1.25 mg/m2 (route not specified) once per day
  • Week 8: "taper then discontinue"
• Etoposide (Vepesid) as follows:
  • Weeks 1 & 2: etoposide 150 mg/m2 IV twice per week
  • Weeks 3 to 8: etoposide 150 mg/m2 IV once per week
• Cyclosporine A 3 mg/kg/dose by mouth twice per day (total dose per day is 6 mg/kg), if normal kidney function. Then, titrate doses with goal of levels around 200 mcg/L (monoclonal, trough level). It was not clear from the paper whether this is modified or non-modified cyclosporine.
• Intrathecal therapy to "start only if progressive neurological symptoms or if an abnormal CSF has not improved," maximum of 4 doses, as follows:
  • Weeks 3 to 6: Methotrexate (MTX) (dosed by age as listed below) IT once per week. Methotrexate doses by age:
    • less than 1 year old: 6 mg each dose
    • 1 to 2 years old: 8 mg each dose
    • 2 to 3 years old: 10 mg each dose
    • greater than 3 years old: 12 mg each dose
  • Weeks 3 to 6: Prednisolone IT once per week. Prednisolone doses by age:
    • less than 1 year old: 4 mg each dose
    • 1 to 2 years old: 6 mg each dose
    • 2 to 3 years old: 8 mg each dose
    • greater than 3 years old: 10 mg each dose

Supportive medications:

• Prophylactic cotrimoxazole (5 mg/kg of trimethoprim equivalent), three times weekly, start on week 1 and treat onwards
• An oral antimycotic from weeks 1 to 9
• IvIG 0.5 g/kg IV once every 4 weeks
• "Gastroprotection suggested" for weeks 1 to 9

8-week course; patients with resolved, non-familial, non-genetically verified disease stopped therapy. Patients with familial, genetically verified, persistent, or reactivation/relapsed disease continued to continuation therapy, until an allogeneic HCT could be performed, as follows:

Continuation therapy

Starts during week 9.

• Dexamethasone (Decadron) 10 mg/m2 (route not specified) once per day for three days, every two weeks (on even weeks)
• Etoposide (Vepesid) 150 mg/m2 IV once every two weeks (on odd weeks)
• Cyclosporine A by mouth twice per day, aiming for trough blood levels of 200 mcg/L (not clear from the paper whether this is modified or non-modified)
• Proceed with allogeneic stem cell transplant (SCT) as soon as an acceptable donor is found, such as:
  • HLA-idential record donor
  • Matched unrelated donor
  • Mismatched unrelated donor
  • Family haploidentical donor

Continuous

References

1. Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007 Feb;48(2):124-31. link to full article at ResearchGate link to original article contains verified protocol link to study protocol PubMed