The Chemotherapy Conundrum: Central Nervous System Post-Kidney Transplant Lymphoproliferative Disorder Successfully Treated with Chemotherapy Escalation and Autologous Stem-Cell Transplantation

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after kidney transplantation. Central nervous system (CNS) involvement is associated with poor outcomes. Epstein-Barr virus (EBV) infection and cumulative immunosuppression are major risk factors. First-line treatment involves reducing immunosuppression, which increases the risk of allograft rejection or even failure, which limits future chemotherapeutic options. We present a case of EBV-positive CNS PTLD successfully treated with high dose chemotherapy and rescue autologous stem cell transplantation. Case Description: A 22-year-old woman with a history of kidney transplant due to lupus nephritis and high-risk EBV serostatus (donor positive/recipient negative) presented 14 months post-transplant with neurological symptoms (headache, diplopia, dysarthria). Imaging revealed a brain mass, and biopsy confirmed EBV-positive diffuse large B-cell lymphoma (DLBCL) with no extracranial disease. EBV viral load was 4,660 copies/mL. Her immunosuppressive regimen (tacrolimus, mycophenolate mofetil, prednisone) was stopped, and she began rituximab therapy, but showed poor response and persistent EBV viremia. Donor-derived cell-free DNA (dd-cfDNA) monitoring revealed a spike to 4.1%, indicating acute cellular rejection (Banff 2a). She was treated aggressively with steroids, thymoglobulin, and resumption of maintenance immunosuppression to preserve graft function, which was essential for further chemotherapy. Subsequent treatment with methotrexate, cytarabine, and rituximab (Ferrari protocol) led to disease progression. The regimen was escalated to the MATRix protocol (including thiotepal), resulting in tumor reduction and clearance of EBV. She later underwent autologous stem cell transplantation, achieved successful engraftment, and remains in remission on low-dose sirolimus and prednisone, with stable dd-cfDNA and graft function. Discussion: This case underscores the complexity of managing CNS PTLD in transplant recipients, the utility of dd-cfDNA for rejection surveillance, the importance of maintaining allograft function to enable aggressive chemotherapy and the value of a multidisciplinary approach in achieving successful outcomes.