Safety and efficacy of blinatumomab for EBV viremia and PTLD following allogeneic hematopoietic stem cell transplantation

Abstract

Abstract Background The incidence of Epstein-Barr virus (EBV) reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is 30%-60%. EBV-associated post-transplant lymphoproliferative disorder (PTLD) occurs in 1%-10% of allo-HSCT recipients leading to life-threatening complications. The development of effective anti-EBV therapies remains a significant challenge. Rituximab has been shown to target CD20+ B cells, yet remains ineffective against EBV-infected plasma cells, T cells, or NK cells. Blinatumomab is a CD19/CD3 bispecific antibody that engages T cells to lyse CD19-expressing cells. As infected B cells typically express CD19/CD20 and plasma cells express CD19, the use of blinatumomab as a therapeutic strategy is a potential area for further research. Furthermore, the potential of its T-cell activation to benefit patients with impaired EBV-specific immunity is a noteworthy consideration. However, clinical data on the use of blinatumomab for post-allo-HSCT EBV viremia and PTLD is limited. Methods We conducted a retrospective analysis of allo-HSCT patients treated with blinatumomab for EBV viremia and/or PTLD at Beijing Lu Daopei Hospital and Hebei Yan Da Lu Daopei Hospital between July 1, 2024, and August 1, 2025 (follow-up ended August 1, 2025). EBV viremia was defined as plasma EBV DNA ≥ 1000 copies/mL. Intracellular EBV DNA levels were quantified in flow-sorted cell populations: B cells (CD19+, CD20+, CD22+), NK cells (CD3-, CD56+), T cells (CD3+), and plasma cells (CD38+, CD138+). Peripheral blood clonality was assessed by flow cytometry. Lymphadenopathy was defined as lymph nodes >1.5 cm. Results Twelve patients (7 male, 5 female; median age 37 years [range 6-62]) were included. Diagnoses were acute myeloid leukemia (n=9), NK/T-cell lymphoma (n=1), anaplastic large cell lymphoma (n=1), and chronic myelomonocytic leukemia in blast crisis (n=1). Transplant types were unrelated donor (n=1) and haploidentical (n=11). The conditioning regimens were based on busulfan (n=10), TBI/TMLI (n=2). All patients received GVHD prophylaxis with anti-thymocyte globulin (ATG). The median time to EBV viremia post-HSCT was 39 days (range 23-274) and median interval from viremia onset to blinatumomab treatment of 8.5 days (range 3-13). At the initiation of blinatumomab treatment, the median plasma EBV DNA load was 7.2 × 10³ copies/mL (range 1.6×10³ - 7.5×10⁴); the median peak plasma EBV DNA level was 1.2 × 10⁴ copies/mL (range 3×10³ - 8.9×10⁵). EBV-infected cell types were identified as: B cells only (n=1), T cells and plasma cells (n=1), NK cells and B cells (n=1), T cells, B cells and plasma cells (n=1), B cells, NK cells and plasma cells (n=1), and T cells, B cells, NK cells and plasma cells (n=2) in 7 perform cell sorting patients. Median intracellular EBV DNA levels were: B cells: 1060 × 10⁴ copies/10⁶ cells (range 1.7-4700), T cells: 0.115 × 10⁴ copies/10⁶ cells (range 0-4300), NK cells: 0 × 10⁴ copies/10⁶ cells (range 0-20), plasma cells: 1200 × 10⁴ copies/10⁶ cells (range 0.2-8700). Peripheral blood monoclonal cells were detected in 6 patients: monoclonal B cells (n=2), monoclonal plasma cells (n=2), or both monoclonal B cells and plasma cells (n=2). Lymphadenopathy was present in 5 patients; one lymph node biopsy confirmed polymorphic PTLD. Prior interventions included rituximab (n=8, all ineffective), donor lymphocyte infusion (DLI, n=2), CD38 monoclonal antibody (n=1), or no preemptive therapy (n=3). The dosage of blinatumomab administered to patients was 9 µg/day for patients >45 kg or 5 µg/m²/day for patients <45 kg. The median treatment duration was 8.5 days (range 4-20). All patients achieved plasma EBV DNA clearance (median time 11 days, range 6-20) . Monoclonal cells resolved in all 6 patients. Lymphadenopathy resolved in all 5 patients. Cytokine release syndrome (CRS) occurred in 4 patients (all grade 1). No immune effector cell-associated neurotoxicity syndrome (ICANS). Four patients developed GVHD after blinatumomab cessation (median onset 8 days post-treatment, 5-46; all grade 1-2). The median CD4+ counts were 43/µL (0-597) and 160/µL (82-1489) before and after blinatumomab administration, respectively. All patients were alive at last follow-up. Conclusion Blinatumomab demonstrated high efficacy and an excellent safety profile for treating EBV viremia and/or PTLD following allo-HSCT. These encouraging results necessitate further investigation in larger cohorts.