PEG-aspargase and DEP regimen combination therapy for refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis

Abstract

Background: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is the most frequent subtype of secondary HLH triggered by infections. Previous studies have shown that ~30 % or more of patients with EBV-HLH do not respond to standard therapy. This study investigated the efficacy and safety profile of a modified DEP regimen in combination with PEG-aspargase (L-DEP) as a salvage therapy for refractory EBV-HLH.

Methods: In this study from October 2014 to October 2015, 28 patients with refractory EBV-HLH received a L-DEP regimen at the Beijing Friendship Hospital, Capital Medical University. Treatment efficacy and adverse events were evaluated at 2 and 4 weeks after L-DEP treatment.

Results: Median EBV-DNA concentrations before and 2 weeks after receiving the L-DEP regimen were 9.6 × 10(5) (1.5 × 10(4) - 1 × 10(9)) copies/mL and 2.2 × 10(5) (3.8 × 10(2) - 1.2 × 10(7)) copies/mL, respectively; the post-treatment values were significantly lower than that of the pretreatment (P = 0.048). Nine of the 28 study patients achieved complete response (CR) and 15 partial response (PR), resulting in an overall response rate of 85.7 % (CR+PR). Four patients who did not achieve response died within 4 weeks of receiving L-DEP. Thirteen of the 24 patients who achieved partial or complete response received subsequent allogenic hematopoietic stem cell transplantation (allo-HSCT). Ten of these 13 patients survived until 1 March 2016. The major adverse effects of the L-DEP regimen were high serum amylase concentrations, abnormal liver function, and coagulation disorders.

Conclusions: This study suggests that L-DEP is a safe and effective salvage therapy prior to allo-HSCT for refractory EBV-HLH and increases the possibility of such patients receiving allo-HSCT. A prospective multicenter large-scale clinical trial that aims to validate the L-DEP regimen for refractory EBV-HLH is currently underway (ClinicalTrails.gov Identifier: NCT02631109).

Keywords: Epstein–Barr virus; Hemophagocytic lymphohistiocytosis; PEG-aspargase.

Figures

Fig. 1

Protocol for L-DEP regimen

Fig. 2

Changes in white blood cell counts (WBC) (a), platelet counts (b), alanine aminotransferase (ALT) concentrations (c), aspartate aminotransferase (AST) concentrations (d), total bilirubin (TBiL) concentrations (e), lactate dehydrogenase concentrations (f), fibrinogen (Fbg) concentrations (g), ferritin concentrations (h), and soluble CD25 concentrations (i) at the time of initial diagnosis of EBV-HLH, before, and 2 and 4 weeks after the L-DEP regimen

Fig. 3

Survival of patients with refractory EBV-HLH (a). Relationship between the number of pretreatment EBV-DNA copies (1 × 105 copies/mL) and survival (b). Relationship between the number of pretreatment EBV-DNA copies (1 × 106 copies/mL) and survival (c). Relationship between declining multiples of EBV-DNA copies and survival after L-DEP regimen (d)