Post-Transplantation Lymphoproliferative Disorders (PTLD) Management in Solid Organ Transplantation (SOT) Recipients

PTLD are lymphoid proliferations that develop as a consequence of immunosuppression in 1% of SOT recipients. The majority of PTLD are associated with Epstein-Barr virus (EBV) infection, as therapeutic immunosuppression causes decreased T-cell surveillance, increasing the proliferative potential of EBV in latently infected B-cells. PTLD may manifest as early lesions including polyclonal plasmacytic hyperplasia and infectious mononucleosis-like PTLD as well as monoclonal polymorphic PTLD. Patients who develop polymorphic PTLD, universally associated with EBV and occurring early after transplant, usually have good prognosis and respond well to reduction of immunosuppression and antiviral therapy. Monomorphic PTLD is indistinguishable from a subset of B-cell and much less frequently T-cell lymphomas that occur in immunocompetent individuals. Monomorphic PTLD in SOT patients frequently involve extranodal sites as well as the allograft and causes significant morbidity and mortality in this group of patients. There is no universally accepted treatment strategy for monomorphic PTLD as randomized trials are lacking with most of the data coming from prospective and retrospective cohort trials evaluating heterogeneous populations of patients. Standard therapy consists of a stepwise treatment approach, aimed at partially restoring cellular immunity by reduction of immunosuppression (RI) sometimes in combination with or followed by rituximab. If there is no response chemotherapy is initiated. However, this strategy is vague as there are no clear rules for how much and for how long immunosuppression is reduced and may be associated with both graft loss and disease progression. We believe that aggressive monomorphic PTLD patients can be successfully treated by employing aggressive chemo-immunotherapy and withdrawal of standard immunosuppressive agents. We prefer to use “dose dense” administration schedule to 1) provide intensive therapy and 2) provide strong enough immunosuppression to prevent rejection. This retrospective study was designed to assess the outcome of such a strategy in monomorphic PTLD patients treated at the Yale Cancer Center (YCC) over a 15 year period.

We identified patients with the PTLD after SOT by searching Yale Tumor Registry. Patients were eligible for selection if they were diagnosed with PTLD after SOT between January 1^st of 1995 and December 31^st of 2009 provided they were 18 years of age or older at the time of diagnosis (diagnosis criteria). We planned to analyze the outcomes among patients treated with combined approach (treatment criteria). Sixteen patients met inclusion criteria.

Out of 16 identified patients 11 received kidney, 1 kidney and pancreas, 3 heart and 1 liver transplants. Thirteen patients (81%) were diagnosed with diffuse large B cell lymphoma (DLBCL), 3 with Burkitt or Burkitt-like lymphoma (19%). All patients were treated with a combined approach with most of the patients (n=11, 69%) receiving CHOP-R every 2 weeks (“dose dense”). 10 out of the 16 patients had EBV positive lymphoma (62%). Only one patient had early PTLD (< 1 year after SOT) which was EBV positive. 6 out of 15 patients with late PTLD had EBV negative tumors. 9 (56%) patients had an advanced stage disease and 13 (81%) had extranodal involvement. One patient who developed PTLD after kidney transplantation had graft involvement with PTLD. Complete response (CR) was seen in all but one patient (94%). Median overall survival and median progression free survival were 5.39 years. Only 3 patients died due to PTLD and median cause specific survival time has not been reached. Out of the 16 patients, 4 had graft rejection and graft loss due to PTLD. Both the PTLD related-graft-rejection rate and graft loss rate were 25% with 95% CI (0.07-0.52).

Combined therapy approach utilized at the YCC yields excellent results for patients with monomorphic PTLD after SOT. High CR rate, low number of PTLD-related deaths and low graft rejection /graft loss rate make this strategy an appealing option in the treatment armamentarium for this disease.

No relevant conflicts of interest to declare.