Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol

Abstract

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. Forty-nine 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.

Figure 1

Overview of the HLH-94 treatment protocol. BMT: Patients with familial or persistent disease were recommended to go to HSCT as soon as an acceptable donor was available, preferably when the disease was nonactive. The patients without familial or persistent disease were recommended to stop therapy after the initial therapy, and restart in case of reactivation. Dexa: Daily dexamethasone (10 mg/m² for 2 weeks followed by 5 mg/m² for 2 weeks, 2.5 mg/m² for 2 weeks, 1.25 mg/m² for 1 week, and 1 week of tapering; pulses were 3 days, 10 mg/m² daily). VP-16: Etoposide 150 mg/m² IV. IT therapy: Intrathecal methotrexate in patients with progressive neurological symptoms and/or persisting abnormal cerebrospinal fluid findings. CSA: Cyclosporin A aiming at blood levels of 200 μg/L (trough value).

Figure 2

Kaplan-Meier survival curves. (A) All eligible study patients treated with HLH-94 (n=249). (B) All patients with an affected sibling (n=60). (C) All patients who received transplants (n=124). (D) Survival related to HLH disease activity at HSCT (nonactive disease: black line; active disease: grey line; the time in both panels C and D is shown as the time from HSCT).

Figure 3

Cause and time of deaths occurring in patients who did not receive transplantation within the first year of treatment (n=64). The majority of patients died with or from active HLH (▒). The causes of death in 4 patients who did not have active HLH at death (■) were: fatal bleeding following liver biopsy (n=1, 7th week); septicemia where HLH status at death is not known (n=1, 2nd week), and cause of death not stated (n=2, 1st and 38th weeks). One patient who died with or from active HLH is not represented in the graph, since the exact death date is missing.