Clinical Outcome of 96 Post-Transplant Lymphoproliferative Disease Patients in a Renal Transplant Cohort

Introduction: Post-Transplant Lymphoproliferative Disease (PTLD) is a rarewell-recognized group of lymphoid and or plasmacytic proliferations that occur following both solid organ (SOT) and allogenic hematopoietic stem cell transplantation (HSCT) as a result of immunossupression. A continuum of disease has been described, including early lesions, polymorphic PTLD and monomorphic PTLD. Epstein-bar virus (EBV) is considered the most important causative factor, with EBV positivity observed within up 90% of tumor lymphocytes. Optimal risk stratifications specific to kidney transplantation are still lacking.

Patient and Methods: In our series, we retrospectively analyzed 98 consecutively cases of PTLD diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of São Paulo, São Paulo, Brazil. HRim is considered the leading renal transplant hospital in the world for the past 15 years. For this study, only PTLD patients with tumors whose histology could be confirmed by hemopathologist review, EBV-association established and whose clinical, epidemiological and laboratorial parameters could be retrieved were included in this study. Response was defined as complete (CR) or less than CR (partial response or refractory disease). Event was defined as treatment related mortality, progression (defined as time for initiation of second-line therapy) or relapse. Patients with conflicted data or loss of follow up were excluded.

Results: A total of 98 patients were diagnosed with PTLD from 7665 renal transplants performed in this period, with a incidence of 1,3%. Two patients were excluded from the analysis due to conflicting clinical data. Median age at diagnosis was 41.4 years (range from 4-74), with a 0,6:1 Female:Male ratio. Median time of transplant to PTLD diagnosis was 56 months (range 1-967). Thirty-six patients (37.5%) received anti-thymocyte globulin (ATG), and the most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (66, 69%). Monomorphic PTLD was observed in 75 (78%) patients, and two patients presented with HL. EBV positivity was seen in 67 patients (70.5%), being more frequent within PTLD cases diagnosed during the first 3 years of transplantation (90%). All patients had their IR reduced after PTLD diagnosis. The incidence of loss of engraftment following IR reduction was 19% (20 patients). Overall responses were: CR in 67% (n=64) and Partial response/Refractory disease in 33% (n=32); 30 patients died due to treatment-related toxicity and/or disease progression. Overall Survival (OS) for the entire group was 63% in 5 years (CI95% 73-83%), with a progression free survival (PFS) of 58% (CI95% 91-97%). EBV positivity was seen in 67 patients (70.5%). Median number of extra nodal sites involved was 1,2. The median overall survival time was 97 months. Patient survival following diagnosis was 77% at 1 year, 63% at 5 years and 38% at 10 years. The most common extra-nodal sites involved were: Gastro-intestinal Tract (43, 45%) followed by Central Nervous System (23, 24%). Extra nodal involvement was correlated with poorer outcome (p 0.014) as was the loss of engraftment (p<0.0001).

Conclusions: PTLD is a rare complication of immunossupression, usually related to EBV, specially for PTLD diagnosed within the first 3 years of transplantation. Basically, the initial treatment consists of reduction or withdrawal of the immunossupressive regimen followed by specific imuno-chemotherapy as needed. In our cohort, the incidence of loss of engraftment was low, although it was correlated with inferior outcome, together with extranodal involvement. To date this is the largest cohort of post-renal transplant lymphoproliferative disease ever reported.