Use of the Anti-CD20 Antibody Rituximab In the Treatment of Epstein-Barr Virus-Induced Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare complication of Epstein Barr virus (EBV) infection that is characterized by the proliferation of EBV-infected B cells and the exuberant activation of T lymphocytes and macrophages. Current therapeutic approaches aim to curtail EBV-induced immune cell activation through the use of chemotherapy and/or immunosuppressive medications. The anti-CD20 antibody Rituximab targets EBV-infected B cells and reduces disease burden in individuals with EBV-associated post transplantation lymphoproliferative disorders. Its safety and efficacy in patients with EBV-HLH remain unknown.

To gather information regarding experience with the use of Rituximab in the treatment of EBV-HLH, questionnaires were distributed to members of the Histiocyte Society who stated they had administered this medication to one or more patients. Retrospective clinical and laboratory data were gathered and analyzed for this report.

Here we describe 41 patients with EBV-HLH who received treatment with Rituximab. The cohort consists of 29 boys and 12 girls, ranging in age from 1 to 44 years (median 6.5 years). All patients met criteria for HLH according to HLH-2004 guidelines. A causal link to EBV was established in all patients based on positivity by monospot (n=9), EBV serology (n=27), EBV PCR (n=40) or a combination of these methods. Among the 37 patients for whom genetic data were available, 16 (43%) harbored germline mutations in HLH-associated genes, including PRF1 (n=2), SH2D1A (n=8), XIAP/BIRC4 (n=2), UNC13D (n=3) and STXBP2 (n=1). On average, patients received a total of 3 infusions of Rituximab (range 1 to 10) at a dose of 375 mg/M2. The first dose of Rituximab was administered within 1 month from the date of HLH diagnosis in most patients, and it was always given in conjunction with other medications, including chemotherapy (n=37), steroids (n=40), cyclosporine (n=33), immunoglobulin (n=33) and/or anti-viral medications (n=24). Rituximab administration was associated with reversible immediate side effects in 8 patients (fever, n=7; chills, n=2; allergic reaction, n=5; hypotension, n=2). Nine patients experienced later side effects, including transaminitis (n=1), neutropenia (n=4) and hypogammaglobulinemia (n=4); although in 1 patient the reduced immunoglobulin levels may have been secondary to this patient's underlying SH2D1A mutation. In 22 of 23 (96%) patients for whom serial data are available, administration of Rituximab led to a significant reduction in EBV load, and in 18 of 24 (75%) patients, a reduction in ferritin levels was observed. For 21 of 39 (53%) patients, Rituximab ameliorated the clinical and laboratory features of HLH with a median time to improvement of 14 days (range 2–100 days).

Rituximab is a well-tolerated medication with minimal side effects, even when administered to patients with HLH. Based on our data that Rituximab reduces viral load, diminishes inflammation and improves clinical status, we support its incorporation into future HLH therapeutic trials for patients whose disease is precipitated by EBV infection.

No relevant conflicts of interest to declare.