Prognosis of Patients with Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder (PTLD-CNS) Treated with Immunossupression Reduction, Intrathecal Chemotherapy and Whole-Brain Radiotherapy: An Analysis of 23 Patients in a Brazilian Cohort

Introduction: Post-transplant lymphoproliferative disorders are a rare heterogenous group of diseases occurring in the setting of post-transplant immunossupression (IS). Clinically, extranodal involvement is common, and it occurs in the central nervous system (CNS) in approximately 7-15% of cases. Most data on PTLD-CNS are based on case series/reports and due to paucity of data no treatment algorithms have been established. In our series, we retrospectively analyzed 23 consecutively cases of PTLD-CNS in Hospital do Rim, Sao Paulo, Brazil.

Methods: We retrospectively reviewed all cases of PTLD-CNS diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of 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.

Results: From 2001 to 2014, from a total of 98 PTLD patients, 23 patients (23%) were diagnosed with PTLD-CNS. Median age at time of diagnosis was 36, with a male:female ratio of 0.9:1. Fifteen (65%) patients received anti-thymocyte globulin (ATG) at the time of transplant and 17 (74%) had at least one episode of acute rejection. The most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (15, 65%). Median time from transplant to PTLD diagnosis was 31 months (ranging from 8.4 to 153). EBV was positive in tumor lymphocytes by in situ hybridization in 21 cases (91%). Monomorphic cases were diagnosed in 21 (91%) patients. All patients had their IR reduced, usually with suspension of azathioprine and calcineurin inhibitors and change from prednisone to dexamethasone, 19 (82%) patients underwent WBRt (from 25 to 40 Gy) together with intra-thecal (IT) chemotherapy with methotrexate (MTX) 12mg and dexamethasone 2mg. Only 1 patient received high dose MTX and died due to treatment-related toxicities 1 month after diagnosis and 2 patients died before starting WBRt due to disease progression and poor performance status (PS). For those patients who received WBRt together with IT chemotherapy, fourteen patients (74%) had CR, 2 patients (10%) had refractory disease and 3 patients (16%) had relapsed disease within 2 years. Overall Survival (OS) for the group treated with WBRt and IT chemotherapy was 62% in 5 years (CI95% 69-82%). In our series, induction therapy with ATG and acute rejection were associated with increased risk of PTLD-CNS. Age and PS at diagnosis were the only 2 factors predictive of survival. No serious cognitive impairment was identified among the survivors.

Conclusions: The current study demonstrated that PTLD-CNS is a serious late EBV-induced B-cell lymphoma, mostly monomorphic with an incidence of 23%, higher than previously described in the post renal transplant setting. Treatment with immunossupression reduction, intrathecal chemotherapy and whole-brain radiotherapy showed a high CR rate with favorable survival in many cases.