A Respective Analysis of EBV DNA Status in T/NK Cell Lymphoma Associated-Hemophagocytic Lymphohistiocytosis

Background: To explore the clinical characteristics and prognostic implication of Epstein-Barr virus (EBV) DNA status in patients with T-cell or natural-killer cell lymphoma-associated hemophagocytic lymphohistiocytosis (T/NK-LAHLH).

Method: Patients who diagnosed with T/NK-LAHLH in the First Affiliated Hospital of Zhejiang University from January 2017 to August 2022 were included. Baseline characteristics were summarized and compared. Complete response (CR), partial response (PR) and no response (NR) were used to evaluate the 2-week efficacy of HLH treatment. Overall survival (OS) was estimated by Kaplan-Meier method and log-rank test. Cox proportional hazard model for potential factors were conducted.

Result: Eight-five T/NK-LAHLH patients were finally enrolled, with a median age of 52 (18-81) years. According to EBV DNA status, sixty-seven were classified as EBV DNA positive group and 18 were EBV DNA negative group. Patients in EBV DNA positive T/NK-LAHLH group displayed significantly lower PLT (P=0.003), and globulin level (P=0.033), higher IL-10 level (P=0.011) and longer activated partial thromboplastin time (APTT, P=0.034) than those of EBV DNA negative T/NK-LAHLH group at HLH diagnosed. For patients received the anti-HLH therapy only, the ORR was 33.9%, patients in the liposomal doxorubicin-etoposide-prednisolone (DEP) group and ruxolitinib combined with corticosteroid (Ru-D) group achieved relatively better efficacy, with ORR 56.3% and 64.3%, respectively. Whereas the ORR in the HLH-94 group was 23.1% and corticosteroid with or without intravenous immunoglobulins (GC±IVIG) regimen had no effect on T/NK-LAHLH, all patients showed no response to GC±IVIG regimen. The difference of ORR was significance among the four anti-HLH regimens (P<0.001). The median period of anti-HLH therapy was 5 days for patients who received anti-HLH therapy and then switched to anti-lymphoma chemotherapy, with ORR 78.3%. There was a significant difference in the efficacy and OS for whether converted to anti-lymphoma therapy within 2 weeks after receiving anti-HLH (P<0.001 and P=0.018, respectively). Patients who obtained HLH control within 2 weeks have a better OS (P<0.0001) than no response to therapy. EBV DNA-positive patients displayed significantly worse OS than EBV DNA-negative patients (P<0.0001). Furthermore, all 5 patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) were still alive during the follow-up period and achieved significantly prolonged survival (P=0.013) than those who did not. By multivariate analysis, EBV DNA positive, advanced age, prolonged APTT, elevated fibrinogen level and no response to HLH treatment were independent risk factors of OS.

Conclusion: EBV infection, along with coagulation abnormalities, advanced age and no response to HLH therapy were independent prognostic factors for patients with T/NK-LAHLH. Early diagnosis and appropriate chemotherapy plus HSCT are essential to achieve improved outcomes in T/NK-LAHLH patients.

Keywords ：hemophagocytic lymphohistiocytosis, T/NK cell lymphoma, EBV, HSCT, treatment, prognosis