) Treatment of EBV associated post-transplant lymphoproliferative disease (PTLD) following solid organ transplantation (SOT) is a therapeutic challenge because maintenance of the allograft must be balanced with the increased toxicity from chemotherapy and increased susceptibility to life-threatening infections. Immune enhancement, antiviral and monoclonal antibody therapy, as well as multi-drug chemotherapy regimens have been attempted, but one year overall survival remains less than 50 percent. Since AIDS patients with non-Hodgkin's lymphoma (NHL) have a better survival with less aggressive chemotherapy, we conducted a pilot study treating 8 patients with disseminated PTLD using a """"""""low-dose"""""""" chemotherapy regimen consisting of six cycles of only cyclophospha-mide and precinisone (CY/Pred) given every three weeks. All patients achieved complete remissions, but one patient relapsed at 15 months. No treatment-related mortality was observed. Four patients experienced rejection, all patients are alive (median follow-up 12 months) with functioning allografts, but two await second transplants. Though encouraging, a larger study is required to determine if the long-term outcome using this regimen is superior to other therapeutic approaches. Viral load is a useful biomarker for monitoring therapeutic response for several viral associated diseases. A quantitative ELISA-based polymerase chain reaction (QE-PCR) assay has been developed, characterized, validated and utilized in the clinical pilot study. Levels of EBV DNA correlated well with response to therapy, and increased EBV DNA levels preceded relapse. Therefore, in this study we propose to: (1) conduct a phase II multi-institutional clinical trial to evaluate the CY/Pred regimen in the treatment of EBV associated PTLD following SOT. The primary endpoint is one year overall survival, and secondary endpoints are response rate and death while on chemotherapy; and (2) determine the value of peripheral blood EBV DNA viral load as a biomarker for monitoring therapeutic response and relapse. To complete this phase II trial, 40-50 fully evaluable patients will be required; therefore, other institutions have been asked and have agreed to participate in this study. This study will be the largest experience of uniformly diagnosed and treated patients with PTLD following SOT to date. Though this study has limited endpoints, it will establish a baseline for future trials. The collaborations established will allow us to not only complete this trial in a timely fashion but facilitate the conducting of more ambitious therapeutic trials in the future, i.e., prophylactic or pre-emptive therapy, novel agents and/or randomized trials.
|Gross, Thomas G; Bucuvalas, John C; Park, Julie R et al. (2005) Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23:6481-8|
|Okano, M; Gross, T G (2000) A review of Epstein-Barr virus infection in patients with immunodeficiency disorders. Am J Med Sci 319:392-6|
|Greiner, T C; Abou-Elella, A A; Smir, B N et al. (2000) Molecular epidemiology of EBNA-1 substrains of Epstein-Barr virus in posttransplant lymphoproliferative disorders which have infrequent p53 mutations. Leuk Lymphoma 38:563-76|