A 22-year-old woman with persistent fever for one month was admitted to our center on November 20, 2020. She was heavily treated with antibiotics before admission. Otherwise, the patient was previously considered healthy. Her routine work-up showed cytopenia in three lineages, hepatic insufficiency, increased levels of serum ferritin, elevated levels of soluble CD25 (sCD25), hepatomegaly, splenomegaly, and hemophagocytosis in the bone marrow. According to the HLH-2004 criteria, the patient was diagnosed with hemophagocytic lymphohistiocytosis. Further analysis of the underlying triggers revealed EBV infection, and there was no evidence of underlying immunodeficiency. Peripheral lymphocytes were sorted by flow cytometry, and quantitative polymerase chain reaction was performed on the sorted cells. The patient was confirmed to have EBV-HLH involving the NK cell lineage. After two cycles of L-DEP chemotherapy, the patient achieved complete remission of HLH. She underwent an HLA-identical sibling allo-HSCT using a VP16 + TBI/Cy conditioning regimen. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A (CsA), a short course of methotrexate, and mycophenolate mofetil. Both white blood cell (WBC) and platelet (PLT) engraftment occurred 11 days after allo-HSCT. EBV-DNA levels in the patient's peripheral blood mononuclear cells (PBMCs) and plasma were monitored regularly and remained negative.
The EBV-DNA level in the patient's PBMCs rose to 5.8x102 copies/mL 43 days after transplantation, whereas the EBV-DNA level in the patient's plasma remained negative (<5.0x102 copies/mL). To eliminate EBV, the dosage of CsA was gradually tapered. The EBV-DNA level in the patient's plasma and PBMCs rose to 9.9x102 copies/mL and 4.9x103 copies/mL, respectively, 53 days after transplantation. The patient developed intermittent fever and nausea without superficial lymph node enlargement. Further analysis demonstrated that EBV infection mainly involves the B cell lineage, without evident clonal B cell populations. Rituximab was administered intravenously at a dosage of 375 mg/m2. However, the EBV-DNA levels in PBMCs and plasma continued to rise, and EBV infection mainly involved the NK cell lineage, which indicated recurrence of the primary disease. Chimerism status was monitored regularly using polymerase chain reaction amplification of short tandem repeats, and the patient remained in complete donor chimerism.
The patient's condition developed rapidly, presenting with high fever, nausea, hepatic insufficiency, cytopenia of two lineages, and elevated levels of ferritin and sCD25, 60 days after the procedure. We administered ruxolitinib (a selective inhibitor of Janus kinase 1 and 2) 10 mg twice daily to control the hyperinflammatory state, followed by donor lymphocyte infusion (DLI) 67 days after transplantation. After DLI, significant improvements in clinical and laboratory manifestations were observed; however, EBV-DNA levels in the patient's PBMCs and plasma remained positive.
The patient showed signs of HLH recurrence again 81 days after transplantation and received two cycles of the DEP regimen in combination with DLI. However, the patient still experienced another episode of HLH recurrence during chemotherapy. The EBV-DNA level in the patient's PBMCs was 6.1x103 copies/mL 101 days after transplantation, whereas the EBV-DNA level in the patient's plasma was 4.3x104 copies/mL. As a last resort, sintilimab (a PD-1 monoclonal antibody; Suchow Xinda Biotechnology Co. Ltd., Suchow, China) was administered intravenously at a dose of 2 mg/kg on day 104. The patient's fever, cytopenia, elevated liver enzymes, and increased serum ferritin and sCD25 levels returned to normal ranges. EBV-DNA levels in the patient's PBMCs and plasma tested negative soon after sintilimab injection. An additional cycle of sintilimab was administered intravenously on day 118. The changes in EBV-DNA load throughout the treatment are shown in Figure 1. Changes in WBC and PLT counts and ferritin, sCD25, and alanine aminotransferase levels are shown in Figure 2.
The patient experienced occasional skin rashes, gastrointestinal infections, and pneumonia during follow-up, which were all controllable with anti-GVHD and anti-infective drugs. EBV-DNA levels in the PBMCs and plasma were monitored regularly and remained negative. Eight months after transplantation, the patient developed severe pneumonia, and blood culture confirmed Escherichia coli infection. Unfortunately, the patient discontinued treatment for financial reasons and eventually died.