Epstein-Barr Virus (EBV) Associated Post-Transplantation Lymphoproliferative Disorder Confined to the Central Nervous System Despite Negative Serum EBV PCR Following Rituxmab Administration.

Abstract 4303

Post-Transplant Lymphoproliferative Disorders (PTLD) represents a wide spectrum of clinical disorders complicating immunosuppressive regimens in transplant recipients. The development of PTLD is linked to a deficient Epstein-Barr Virus (EBV) specific cellular immune response. In association with allogeneic stem-cell transplantation (SCT), PTLD has been considered a rare entity (incidence ≤ 1 percent). However risk factors such as HLA disparity, in vitro or in vivo T-cell depletion, and severe Graft Versus Host Disease (GVHD) confer an increased risk.

According to several observational historical studies on PTLD after SCT, CNS involvement in disseminated PTLD occurred in up to 28.6% of cases and was associated with poor prognosis. On the other hand, isolated EBV-related CNS PTLD, is exceedingly rare. In immunocompetent individuals, EBV immortalizes infected lymphocytes, but is kept in a quiescent state through the cytotoxic T-cell response. Without the benefit of a healthy immune system, EBV-infected lymphocytes may proliferate unchecked and lead to PTLD lesions. PCR technology has recently been used to monitor EBV load in high-risk patients following organ or marrow transplantation. Real-time PCR is a rapid and reproducible method for quantifying DNA that was first introduced for EBV in 1999.

Studies have demonstrated that EBV-driven PTLD is almost always accompanied by an increase in the level of circulating EBV DNA within the peripheral blood. These findings have led to the development of programs that monitor peripheral blood viral load in the post-transplant period by quantitative PCR. Such monitoring programs are noninvasive and have demonstrated success in detecting PTLD in its earliest stages. In many cases, early detection allows clinicians to treat by adjusting immunosuppressive regimens, rather than introducing cytotoxic chemotherapy in advanced lesions. More recently, clinicians have started relying on Rituximab to treat EBV reactivation.

The discovery of an EBV-driven CNS PTLD in our patient is unusual in that there was no evidence of EBV in the peripheral blood by PCR. Two similar cases have been reported in the literature. The nature of this phenomenon is uncertain. One plausible explanation is the effectiveness of Rituximab in clearing the virus from the peripheral blood but not from the CNS, given its poor blood-brain barrier penetration. If this was the case, one might fear an increase in the CNS localization of PTLD as clinicians increasingly rely on the use of Rituximab in face of rising EBV viral load in the peripheral blood.

In summation, we believe that clinicians should be aware of the potential possibility of CNS PTLD in the absence of PCR-evidence of EBV reactivation in the peripheral blood in patients treated with Rituximab. Efforts must continue to develop alternative approaches to preemptive treatments of EBV re-activation such as with adoptive immunotherapy.