Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for > 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ؎ 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ؎ 8%; tendency to increased survival (P ‫؍‬ .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ؎ 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Fortynine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P ‫؍‬ .011), and less often had CNS disease (P < .001) or hepatomegaly (P ‫؍‬ .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects. (Blood. 2011;118(17):4577-4584)

SummaryHaemophagocytic lymphohistiocytosis (HLH) may cause meningoencephalitis and significant neurological sequelae. We examined the relationship between neurological symptoms and cerebrospinal fluid (CSF) at diagnosis, and long‐term outcome, in all children enroled in the HLH‐94‐study prior to July 1, 2003, for whom information on CSF at diagnosis was available (n = 193). Patients were divided into four groups: (i) normal CSF (cells/protein) and no neurological symptoms (n = 71); (ii) normal CSF but neurological symptoms (n = 21); (iii) abnormal CSF but no symptoms (n = 50); and (iv) abnormal CSF with neurological symptoms (n = 51). At diagnosis, neurological symptoms were reported in 72/193 (37%) (seizures = 23); abnormal CSF in 101/193 (52%), and either or both in 122/193 (63%). Altogether 16/107 (15%) survivors had neurological sequelae at follow‐up (median 5·3 years). Multivariate hazard ratios (HR) for mortality were 0·98 [95% confidence interval (CI) = 0·42–2·31], 1·52 (0·82–2·82) and 2·05 (1·13–3·72) for groups 2–4, compared with group 1. Moreover, sequelae were more frequent in group 4 (7/21, 33%) compared to groups 1–3 (9/86, 10%) (P = 0·015). Patients with abnormal CSF at diagnosis had significantly increased mortality [HR = 1·78 (95% CI = 1·08–2·92), P = 0·023]. Thus, a substantial proportion of HLH survivors suffer neurological sequelae, and children with abnormal CSF have increased risk of mortality and neurological sequelae. Prompt treatment of HLH at onset or relapse may reduce these complications.

There seem to be easily available clinical predictors of early mortality in HLH patients, which may help guide treatment decisions.