High Risk of Early Mortality in Adult Patients with Acquired Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition in which dysregulation of innate immune effectors including natural killer (NK) cells and macrophages leads to destruction of hematopoietic elements. HLH is most frequently reported in association with malignancies or viral infections, with heritable deficiencies in cytotoxicity pathways predisposing children (and rarely adults) to HLH. Criteria for diagnosing HLH include: histological evidence of hemophagocytosis, two or more cytopenias, hyperferritinemia, hypofibrinogenemia or hypertriglyceridemia, elevated soluble IL-2R, decreased in vitro NK cell function, fever, and splenomegaly. Patients meeting >=5 of these criteria are diagnosed with HLH.

Source: We identified 19 consecutive adult patients (53% male; median age 43y, range 16-83) admitted to Stanford Hospital with clinical suspicion for HLH and histological evidence of hemophagocytosis between 1997 and 2009; 2 patients were excluded from analysis due to incomplete data. Of the remaining 17 patients, 11 (65%) met criteria for a diagnosis of HLH.

At presentation, all patients were anemic with a median Hgb concentration of 8.6 g/dL. Leukopenia was present in 8/11 (73%) with a median WBC count of 2 K/uL. Thrombocytopenia was present in 10/11 (91%) patients with a median Plt count of 30 K/uL. In 6 patients not meeting HLH criteria, median hematologic findings were Hgb 8.6 g/dL, WBC 2.6 K/uL, and Plts 126 K/uL. All patients demonstrated marked elevations of ferritin, median 3915 ng/dL (range 1039 – 29,700). Triglycerides were elevated in 7/10 (70%) for whom data were available, median 296 mg/dL (range 204 – 1,506). Fibrinogen was decreased in 3/13 (23%). Soluble IL-2 receptor level was above normal limits in all patients in whom it was measured (range 796 – 17,378 U/mL), but met the >2,400 U/mL criteria in only 3/6 (50%). In vitro NK function was diminished in 2/5 (40%) patients tested. Fever and splenomegaly were found in 94% and 59% of patients, respectively. Of 11 patients meeting HLH criteria, 5 had associated malignancies (DLBCL, NK cell leukemia, T cell lymphoma, AML, and Kaposi sarcoma) and 4 had concomitant viral infections (2 EBV, 1 EBV/B19, and 1 HIV-1/HHV-8). Three patients had isolated viral infections (all EBV), while 3 had idiopathic HLH. Amongst 6 patients not meeting HLH diagnostic criteria, 2 (33%) had an associated malignancy (SLL and NK cell lymphoma), 1 had an isolated EBV infection, and 3 had idiopathic disease. At a median follow-up of 16 months for surviving patients, the case fatality rate amongst those with established HLH diagnoses was 55%, with all deaths occurring within 2 months from diagnosis. Five patients were treated according the HLH-94/04 protocol combining dexamethasone, cyclosporine and etoposide. Two patients died within 2 months of initiating treatment, and 3 remain alive (survival to date ranges 4-31 months). The longest surviving patient underwent allogeneic HCT. A patient who presented with AML-associated HLH underwent induction chemotherapy then proceeded to allogeneic HCT and remains alive 9 months after diagnosis. Amongst 6 patients not meeting HLH criteria, the case fatality rate was 67% with a median survival of 2.3 months. None of these patients were treated with the HLH-94/04 protocol; however, 2 were treated with cyclosporine and remain alive 16 and 24 months after diagnosis.

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Of the HLH diagnostic criteria, multiple cytopenias, hyperferritinemia, and hypertriglyceridemia were sensitive measures, whereas hypofibrinogenemia, markedly elevated sIL-2R, and decreased in vitro NK cell function were found in fewer than half of patients. At our institution, EBV-associated HLH predominates (7/17 cases, 41%). Most of the malignancy-associated HLH we have seen also occurred in the context of EBV infection. The case fatality rate amongst all patients with histologic evidence of hemophagocytosis, including those not meeting HLH criteria, is high. In most patients, treatment according to HLH-94/04 may be appropriate and likely improves survival. In our experience with the HLH-94/04 protocol, 60% of patients remain alive. Until sufficient evidence emerges that this treatment strategy leads to durable remissions in the majority of patients, allogeneic HCT should remain a consideration for most patients.

No relevant conflicts of interest to declare.