The Management of EBV-Associated Post-Transplant Lymphoproliferative Disorder with Central Nervous System Involvement After Allogeneic Hematopoietic Stem Cell Transplantation

Epstein-Barr virus (EBV) -associated post-transplant lymphoproliferative disorder (PTLD) with central nervous system (CNS) involvement is a rare, but life-threatening complication in the recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The management of systemic PTLD, including EBV molecular monitoring, preemptive therapy, and treatment with reduction of immunosuppression, chemotherapy, rituximab and cellular therapy is reported, but there is no uniform approach to the management of PTLD with CNS involvement. To date, limited data exist for treatment in patients with CNS-PTLD.

Eight CNS-PTLD patients from 198 patients undergoing allo-HSCT between April 2009 and March 2012 in our single institution were enrolled in this prospective study. Diagnosis of CNS-PTLD was based on clinical manifestations, EBV-DNA in blood and cerebrospinal fluid (CSF), immunophenotypic analysis of CSF cells and neuroimaging. The treatment of patient with CNS-PTLD included reduction of immunosuppression, antiviral agents, intravenous rituximab-based treatment, cellular therapy as well as intrathecal rituximab.

The median time of diseases onset was 63 (range 49 to 186) days post-transplants. Six patients had systemic PTLD with CNS involvement, while two patients revealed isolated CNS-PTLD. All patients were EBV-DNA positive of blood and CSF, except one patient was EBV-DNA positive of CSF but negative of blood. EBV-DNA-emia appeared 7 (range 2–13) days before clinical manifestations. The EBV-DNA levels of CSF were significantly higher than that of blood (201321 ± 202053 copies/ml vs. 28083 ± 35706 copies/ml, P=0.032). The immunophenotypic analysis of CSF cells revealed that 7 cases had CD19⁺CD20⁺ B cell monoclonality and 1 case had CD3⁺ T cells, CD19⁺ B cells and CD14⁺ monocytes polyclonality. Magnetic resonance imaging (MRI) of CNS on the early stage of diseases onset showed normal (n=1), inflammatory changes (n=2) and space-occupying lesions (n=5).With the development of diseases, 2 cases who initially presented as normal and encephalitis MRI, had space-occupying lesions on CNS imaging. Immunosuppressive agents were withdrawn in all patients (ie, total dose reduced by 20%/week). Two patients were only treated with antiviral agents, 5 received rituximab-based treatments and 1 abandoned. The two patients underwent antiviral agents were unresponsive and died of PTLD. Of the 5 patients underwent intravenous rituximab-based treatments, 2 cases obtained complete remission (CR) and 3 did not. Three patients who had failed to respond to intravenous rituximab-based treatments all obtained CR after the administration of intrathecal rituximab in dose 10–30 mg. Five patients who were CR all received donor lymphocyte infusion after CR. With a median follow up of 183 (range 7 to 918) days, four cases were alive and 4 died. The causes of death included progression of CNS-PTLD (n=3) and cytomegalovirus pneumonia (n=1).

EBV-DNA detection of CSF is an important indicator for early diagnosis and therapeutic evaluation of CNS-PTLD. The immunophenotypic analysis of CSF cells is helpful in diagnosis of EBV-associated CNS-PTLD. The administration of intrathecal rituximab is an effective method for patients who had failed to respond to intravenous rituximab-based treatments. Cellular therapy may be beneficial for long term survival.

No relevant conflicts of interest to declare.