L-DEP Is an Effective Treatment for Adult and Adolescent Patients with Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis

Epstein-Barr virus-associated hemophagocytic lymphohistocytosis (EBV-HLH) is the most frequent subtype of secondary HLH with infectious triggers. In addition to meet the HLH-2004 diagnostic criteria, the diagnosis of EBV-HLH requires the evidence of EBV infection and exclusion of primary HLH and lymphoma-associated HLH. The prognosis of EBV-HLH is generally dismal. To assess the efficacy of current treatment protocols in adult and adolescent patients with EBV-HLH, we retrospectively analyzed 171 HLH patients presented at our institution from March 2009 to April 2016. Of those, 133 patients were EBV-HLH; 35 patients were lymphoma-associated HLH; 3 of 68 patients who underwent genetic test were diagnosed with primary HLH including one with homozygous mutation in UNC13D, one with homozygous mutation in RAB27A, and one with hemizygous mutation in SH2D1A. The rest of the 68 patients exhibited various levels of genetic defects. Of the 133 EBV-HLH patients, 91 male and 42 female cases (2.2:1) were aged between 14 - 77 years with a median age of 26 years. EBV-DNA load on admission was at a median of 6.6 × 10⁵ copies/ml (range: from 5.0 × 10³ - 7.8 × 10⁹ copies/ml). One-year mortality rate for them was 66.4%. One hundred and twelve cases were initially treated by HLH-94 or HLH-2004 regimen. Of those, 52 cases (46.4%) had response including 22 cases (19.6%) of complete response (CR) and 30 cases (26.8%) of partial response (PR). Six patients received L-DEP regimen as initial treatment, of which 5 cases had response consisting 3 cases of CR and 2 cases of PR. The overall response rate (ORR) was 83.3%. The rest 15 patients received initial treatment without etoposide, 5 patients (33.3%) achieving PR and 10 patients (66.7%) showing no response. Sixty-nine refractory or relapsed cases received DEP or L-DEP regimen, ORR of which was 79.7%. For those cases, 26 cases received DEP regimen, of which 17 cases (65.4%) had response including 5 cases of CR and 12 cases of PR. Forty-three patients received L-DEP as salvage therapy, of which 38 cases (88.4%) had response including 13 cases of CR (30.2%) and 25 cases of PR (58.1%). Compared to DEP treatment, who received L-DEP had a higher effective rate (65.4% versus 88.4%, p=0.031). Of 133 EBV-HLH patients, only 36 patients received allogeneic hematopoietic stem cell transplantation, the survival rate was 61.1%. In conclusion, EBV-HLH is a fatal disease. Our results indicate DEP or L-DEP is an effective salvage therapy. Additionally, L-DEP may be a more effective therapy than HLH-94/2004 regimen to be used as an initial treatment. Finally, allogeneic hematopoietic stem cell transplantation is an effective approach for the treatment of EBV-HLH.