Rituximab May be Not Suitable for Epstein Barr Virus-Induced Hemophagocytic Lymphohistiocytosis in Chinese

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. Epstein-Barr virus (EBV) is the most frequent infection associated with HLH. Some studies revealed that rituximab containing regimens is an effective treatment for EBV- HLH. But we didn’t make the similar observation in Chinese adult patients. This study was aim to describe the outcomes and tried to explain the possible causes.

Methods: We performed an investigation involving 46 EBV-HLH patients. Eleven of them received treatment with rituximab plus HLH-94 protocol. The other 35 patients were only treated with HLH-94 protocol. The EBV-DNA load and survive rate of patients were used to evaluated curative effective. We identified the lineage of EBV-infected cell by immunohistochemistry (ICH) in combination with in site hybridization (ISH) in Epstein-barr Virus Encoded Rnas (EBER) for cell type-specific markers.

Result: The eleven patients received 3 rituximab infusions on average (range 2-4) at a dosage of 375mg/m² every week. We found no significant difference in EBV-DNA load between the rituximab containing regimens group and conventional HLH-94 group at diagnosis (median load was 3.2×10⁵copies/ml vs 2.8×10⁵copies/ml) and 4 weeks after therapy (median load 6.4×10³copies/ml vs 5.5×10³copies/ml). The survive rates of the two groups on 2 months, 6 months and 12 months respectively were 45.5% vs 42.9%, 27.3% vs 28.6%, 18.2% vs 20.0%. The pathological examination of tissue biopsy in the patients from rituximab containing regimens group revealed that EBER was positive in all patients. We identified the lineage of EBV-infected cell by double staining——ICH in combination with ISH. Nine of them were CD3+/EBER+, and only two of them were CD20+/EBER+.

Conclusion: It suggested that rituximab may be not suitable for EBV-HLH patients in China. Most probably, EBV predominantly infects T cells in Chinese, which could explain the nonsuperiority of rituximab in Chinese adult EBV-HLH. It is necessary to make further research to demonstrate it.