Pre-Emptive Rituximab Treatment for Epstein-Barr Virus (EBV) Reactivation After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): High Incidence of Infections and Delayed Immune Reconstitution
Authors: Petropoulou Anna D. , Porcher Raphael , de Latour Regis Peffault , Xhaard Alienor , Ribaud Patricia , Socie Gerard , Robin Marie 
Published: October 2019

Abstract
Abstract 2303

Aim:
Before pre-emptive treatment with Rituximab, the incidence of EBV-associated post-transplant lymphoproliferative disease (PTLD) was about 15 to 20% of patients (pts) following allogeneic HSCT with an 80% overall mortality. Rituximab (anti-CD20) in this context has dramatically decreased EBV-PTLD incidence. The aim of this single-center study was to evaluate the incidence on infections and on immune reconstitution following Rituximab for EBV reactivation.

Patients and Methods:
Sixty-nine pts received Rituximab for EBV reactivation at Saint-Louis Hospital (Paris, France) between January 2005 and January 2010, 44 males and 25 females, mean age 33 years (range, 10–68). Primary diseases were malignant hematopoietic disorders (70%) and aplastic anemia (30%). Fifty-two per cent received peripheral blood stem cells, 39% bone marrow and 9% cord blood. Myeloablative conditioning regimen was given in 71% of pts and reduced-intensity in 29%. Antithymocyte globulin (ATG) was given in 70% of pts before Rituximab therapy. EBV-quantitative polymerase chain reaction (PCR) was performed weekly during the first 3 months post-HSCT and then monthly until 1 year post-HSCT. Rituximab was administered weekly at the dose of 375mg/m2 after a positive PCR result (>10.000copies/ml) and discontinued as soon as a negative PCR result was available. Median time from transplant to Rituximab treatment was 43 days. Patients were followed-up until death or relapse. Median follow-up from the date of first Rituximab infusion was 27 months (range 4 to 61).

Results:
All treated pts cleared their EBV viremia after Rituximab. However, one patient developed PTLD despite Rituximab. Incidence of relapse was 5.9% (95%CI: 1.9–13.4) and non-relapse mortality was 41% (95%CI: 29–53) at 36 months. During follow-up, 43 pts developed a bacterial infection, 44 a viral infection and 16 a fungal infection. Infections occurred mainly during the first 12 months after Rituximab. The cumulative incidence of infection at 36 months was 64% (95%CI 50.7 to 74.6) for bacterial, 62.5% (95%CI 49.7 to 72.9) for viral and 24.6% (95%CI 14.7 to 35.8) for fungal infections. Reconstitution of lymphocytes, neutrophils and gammaglobulins after Rituximab therapy was assessed in the 36pts alive and relapse-free at 12 months. Starting from one month after initiation of Rituximab, lymphocyte counts gradually increased, by an average of 11.3% per month (95%CI 10.8 to 11.5; P<0.0001). Gammaglobulins significantly decreased during the first month after Rituximab, on average by 1.54g/L (95%CI 2.34 to 0.75; P=0.0002). After 3 months, a significant mean increase of 0.13 per month was observed (95%CI 0.01 to 0.26; P=0.037). CD19+ B and CD3+ T-lymphocytes reached normal values only at 1.5 years post-HSCT (median=172/μ L and 1339/μ L respectively at 1.5 years). Age, gender, stem cell source, type of donor, conditioning regimen, use of ATG and acute graft-versus-host disease (aGVHD) were assessed as possible risk factors for the development of infection. Acute GVHD grade≥3 or steroid-resistant aGVHD were statistically significant risk factors for bacterial (HR: 2.84, 95%CI: 1.12–7.23, P=0.028) or viral infection (HR: 4.03, 95%CI: 1.58–10.2, P=0.003). Cord blood transplantation and HLA-mismatch were significant risk factors for viral infection (HR: 2.62, 95%CI: 0.96–7.18, P=0.018 and HR: 3.47, 95%CI: 1.24–9.72, P=0.033 respectively). No significant risk factor was found for fungal infections.

Conclusions:
Rituximab pre emptive treatment has decreased PTLD incidence but is associated with high infection rate and prolonged immune defect. The question of over-treatment can be raised and further studies are needed to select candidates for pre-emptive treatment in order to avoid systematic anti-CD20 treatment and its later potential complications.

Disclosures:
No relevant conflicts of interest to declare.