Post-Transplant Lymphoproliferative Disorder: Evaluation of Effectiveness of Reduction of Immunosuppression or Systemic Chemotherapy

BACKGROUND: Post transplant lymphoproliferative disorder (PTLD) is the commonest malignancy associated with pharmacologic immunosuppression after organ transplantation. Reduction in immunosuppression (RI) is a common initial strategy, but many pts require systemic therapy (ST) because of rapid disease progression. We evaluated the treatment and outcome of PTLD at a large multi-organ transplant programme to examine prognostic factors and predictors of outcome with RI and ST. METHODS: Patients (pts) were identified from the UHN Multi Organ Transplant Database and the Cancer Registry at Princess Margaret Hospital. Pts were included if they had a pathologic diagnosis of PTLD and adequate information to assess response to treatment. Variables evaluated for their influence on response to treatment and survival included age, organ transplanted, pathology, CD20+, time to PTLD from transplant, organ dysfunction, EBV+ lymphoma, stage, extranodal disease, B symptoms, CMV infection prior to PTLD, and LDH. RI was defined as a trial of „□10 days of reduction or discontinuation of calcineurin inhibitor (CNI), reduction or discontuation of mycophenolate mofitel or azathioprine and maintenance prednisone, with or without surgical resection of all known disease with repeat imaging to assess response. (Paya, Transplantation68(10):1517, 1999). Chemotherapy consisted of CHOP or equivalent regimens. Rituximab was given as a single agent 375 mg/m2 weekly ×4 doses. RESULTS: 80 pts were identified; 3 pts were excluded from the current analysis for a diagnosis of marginal zone lymphoma (2) or primary body cavity lymphoma (1). Of the 77 pts included 53 (69%) were males. 66% (51) of pts had monomorphic PTLD (44 diffuse large B cell lymphoma, DLBCL), 31% (24) had polymorphic PTLD, 3 (2%) pts had Hodgkin lymphoma-like PTLD; 79% were EBV positive by in-situ hybridization. Organ transplanted: liver 34 (44%), kidney 22 (29%), lung 16 (21%), heart 5 (7%). Fifty percent of pts presented with stage III/IV disease, 81% with extranodal disease, 52% with B symptoms and 69% with an elevated LDH. Initial therapy: RI 43 pts, chemotherapy 31 pts, RI + rituximab 1 pt, surgical resection and re-transplantation 1 pt. For those treated with RI, extent of reduction of CNI did not influence response rate, overall survival (OS) or rate of organ rejection. Overall response rate to RI was 74%; only CD20 expression on the lymphoma was associated with a higher rate of response (p=0.026). Inclusion of antiviral therapy (generally gancyclovir) reduced the risk of relapse in those responding to RI (p=0.026). Response to RI did not vary by time to PTLD diagnosis from transplantation (p=.355), however, the rate of relapse following RI was significantly higher in pts developing PTLD >1 year from transplantation (p=.017). OS in pts undergoing RI as initial treatment was 73% at 3 yrs and 66% at 5 yrs. Nine pts received single agent rituximab, either with RI or because of progression after RI; 4 of the 9 pts responded, and 3 are progression-free. Of the 31 pts treated with primary chemotherapy, 24 had a CR or PR (78%); 4 pts died of toxicity (13%). OS of pts undergoing chemotherapy as initial treatment was 62% at 3 yrs and 58% at 5 yrs. Pts who received RI +/− rituximab followed by chemotherapy for lack of response or relapse had no significant difference in OS compared to those who received frontline chemotherapy (p=0.36). Evidence of graft rejection during treatment was seen in 13 pts (30%) treated with first line RI, compared to 6 (19%) in pts treated initially with chemotherapy. The rate of graft loss was low in both groups at 7% (3) in the RI group and 3% (1) in the chemotherapy group. Median follow up of survivors is 92 months. Overall survival (OS) for the entire cohort was 110 months (95% CI: 67.6, 152.7). Investigation of independent variables affecting OS revealed that organ dysfunction at diagnosis was significantly associated with shorter survival (p=.028). CONCLUSIONs: The outcome of pts with PTLD managed with initial RI is similar to those receiving ST; however the latter is toxic and there are no reproducible variables predicting response to RI as primary treatment. OS is similar in pts receiving RI followed by ST, versus those that received first line chemotherapy, suggesting that a delay in ST for a trial of RI may be justified. Prospective controlled trials of antiviral therapy and the timing and addition of rituximab and chemotherapy are still needed to improve patient outcome and guide future therapy.