Bortezomib and Rituximab in the Treatment of Post-Transplant Lymphoproliferative Disorders

Post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation is an aggressive disease that is difficult to treat, and has a high mortality rate and poor overall survival. While rituximab has become an important part of the treatment for this disorder, additional therapies are needed.

Adults > 18 years with a diagnosis of CD 20-positive PTLD following solid organ transplantation were invited to participate in a clinical trial between 2009–2011 if they had adequate kidney and liver function. No patient had central nervous system disease or bone marrow involvement. Patients received four weekly doses of rituximab 375 mg/m² and bortezomib 1.4 mg/m² days 1, 8, 15, 22. One month following the completion of this induction therapy, patients who achieved a partial remission (PR) or stable disease (SD) (as assessed by positron emission tomography [PET]) received additional bortezomib 1.4 mg/m² on days 1, 4, 8, 11, repeated every 3 weeks for 4 additional cycles. Patients who had achieved a complete remission (CR) were given maintenance rituximab and bortezomib (four weekly doses 375 mg/m² and 1.4 mg/m², respectively) on an every-six-month basis for a total of two years. If at any time a patient had progressive disease, they were removed from the clinical trial. Immunosuppression was decreased at the time of diagnosis and treatment at the discretion of the primary treating transplant physician.

Three patients (ages 29, 48 and 72 y) developed PTLD following kidney (n=2) or bilateral lung/kidney transplantation (n=1), and were enrolled at the University of Minnesota. All three patients' tumors were histologically diffuse large-cell lymphomas of B-cell lineage. 2/3 were positive for Epstein-Barr virus by EBER. Time from transplantation to the development of PTLD was 5, 15, and 17 years. One patient achieved a PR after the initial induction chemotherapy and went on to achieve a CR after additional bortezomib administration. The patient remains in CR after 18 months. One patient had progressive disease within the first month of treatment and was removed from the clinical trial. This patient had a previous diagnosis of PTLD six years earlier and had received prior rituximab; she remains alive more than six months after diagnosis and the administration of systemic chemotherapy with an anthracycline based regimen. The final patient achieved a CR after induction with bortezomib and rituximab alone and remains disease free at more than 7 months after diagnosis. 1/3 patients developed grade 3 neuropathy. No other significant toxicities were seen that were attributable to the drug administration.

PTLD is a difficult disease to treat. While the data from this study reflect only three patients, two of the three patients treated achieved CR after receiving rituximab plus bortezomib. The addition of a proteosome inhibitor such as bortezomib to rituximab may lead to increased durable remission rates and improved overall survival. Additional studies are warranted.

No relevant conflicts of interest to declare.