Background
Prospective international single-arm cohort (HLH-2004). N=369, age ≤18 yr, primary (familial) HLH receiving HLH-2004 induction. pHLH driven by cytotoxic-lymphocyte defects (PRF1, UNC13D, STX11, STXBP2, RAB27A) → uncontrolled macrophage activation; untreated median survival <2 mo. Builds on HLH-94 (etoposide + dexamethasone) by adding cyclosporine A to induction and intrathecal MTX for CNS disease.
Interventions and follow up
Treatment: HLH-2004 induction — dexamethasone 10 mg/m²/day wk 1-2 then taper, etoposide 150 mg/m² twice weekly wk 1-2 then weekly wk 3-8, cyclosporine A (start wk 1, target 200 ng/mL), + intrathecal MTX + hydrocortisone for CNS disease; continuation therapy bridging to allo-HCT
Primary endpoint: Probability of survival at 6 mo (descriptive)
mFollow up: Median 2.7 yr
Primary endpoint: Probability of survival at 6 mo (descriptive)
mFollow up: Median 2.7 yr
Results
5-yr survival (transplanted): 66%
5-yr survival (non-transplanted): 8%
Response by wk 8 (hematologic improvement): ~64%
Median time to response: ~6 wk
CNS involvement at diagnosis: 40%; intrathecal MTX improved CNS response
5-yr survival (non-transplanted): 8%
Response by wk 8 (hematologic improvement): ~64%
Median time to response: ~6 wk
CNS involvement at diagnosis: 40%; intrathecal MTX improved CNS response
Adverse events
Hematologic: severe cytopenias (etoposide-expected)
Infections: major cause of morbidity/mortality during immunosuppression
Secondary malignancy: etoposide-associated AML/MDS risk — low but real in long-term survivors
Organ toxicity: cyclosporine nephro-/neurotoxicity; multi-agent hepatotoxicity
Early mortality (induction): ~18%, often from uncontrolled HLH or infection
Infections: major cause of morbidity/mortality during immunosuppression
Secondary malignancy: etoposide-associated AML/MDS risk — low but real in long-term survivors
Organ toxicity: cyclosporine nephro-/neurotoxicity; multi-agent hepatotoxicity
Early mortality (induction): ~18%, often from uncontrolled HLH or infection
Conclusions
HLH-2004 induction/continuation achieved hematologic response in ~64% with 5-yr survival of 66% in transplanted patients, establishing the protocol as the global standard for primary HLH and a bridge to curative allo-HCT.
Key Limitations
Single-arm, no randomized comparison to HLH-94; adding cyclosporine to induction did not clearly improve early survival. Heterogeneous (primary + secondary HLH) enrollment in the broader cohort; high early induction mortality; outcomes confounded by allo-HCT eligibility/access.
Clinical Context
Etoposide + dexamethasone backbone (HLH-94/2004) remains the standard induction for primary HLH per HLH Society/histiocytosis consensus, bridging to allo-HCT for cure. Front-line CSA in induction has been deprioritized; emerging agents (emapalumab, ruxolitinib) address refractory disease.