Response-Adapted Sequential Immuno-Chemotherapy of Post-Transplant Lymphoproliferative Disorders in Pediatric Solid Organ Transplant Recipients: Results from the Prospective Ped-PTLD 2005 Trial
Authors: Maecker-Kolhoff Britta , Beier Rita , Zimmermann Martin , Schlegelberger Brigitte , Baumann Ulrich , Mueller Carsten , Pape Lars , Reiter Alfred , Rossig Claudia , Schubert Stephan , Toenshoff Burkhard , Wingen Anne-Margret , Meissner Barbara , Kebelmann-Betzing Christian , Henze Guenter , Kreipe Hans H. , Klein Christoph 
Published: October 2019

Abstract
Post-transplant lymphoproliferative diseases (PTLD) are severe complications of immunosuppressive treatment after solid organ transplantation (SOT). Most pediatric cases are associated with Epstein-Barr virus (EBV). Despite morphologic features similar to de novo lymphomas PTLDs are sensitive to immune interventions alone. We conducted a non-randomized prospective multicenter study to test a response-adapted sequential treatment with rituximab +/- chemotherapy in pediatric patients with CD20+ PTLD (Ped-PTLD Pilot 2005).
Pediatric patients (<18 years) with biopsy proven CD20+ PTLD without CND involvement were treated with 3 weekly infusions of rituximab 375 mg/m2. If at least a partial response was obtained in week 3 patients received 3 further rituximab administrations every 3 weeks. In case of stable disease or progression patients were stratified to receive a moderate chemotherapy regimen (mCOMP: day 1 vincristine, prednisone, cyclophosphamide, and day 15 methotrexate; repeat every 4 weeks for 6 cycles). Overall (OS) and event-free (EFS) survival at 2 years were the primary endpoints of the trial. Epstein-Barr virus (EBV) in tumor tissue was evaluated by EBER in situ hybridization, immunohistochemistry for LMP-1 or EBNA-2, and/or EBV-PCR.
49 patients (mean age 9.8 [0.8-17.4] years) were included, among them 18 renal, 11 liver graft recipients, and 20 patients after heart or lung transplantation. Median time from SOT to PTLD was 4.7 [0.15 – 15] years (17 early, 32 late PTLDs). Tumor cells contained EBV products in 44 of 49 cases. Histology was polymorphic in 12 patients, diffuse large B cell lymphoma (DLBCL) in 24, Burkitt lymphoma in 7, and other high grade B cell lymphomas in 6 patients upon central review. Median follow-up is 4.5 years. 32 patients (64%) received rituximab only, of which 26 (81% of responders, 53% of total study population) remain alive and in continuous complete remission with a median follow up of 4.9 years. The remaining 6 rituximab responders experienced relapse (n=4), secondary malignancy (n=1), or death unrelated to PTLD (n=1). 15 patients had stable or progressive disease after initial rituximab treatment and proceeded to chemotherapy. Of these, 10 patients (66%) converted to complete remission while 4 patients (27%) progressed and went off study to receive intensive chemotherapy. 1 patient died during mCOMP treatment, which could not be distinguished between tumor progression and infection. 2/49 patients died of PTLD before rituximab response could be evaluated. 2-year OS was 86% +/- 5% with 67% +/- 7% surviving event-free. Estimated 5-year OS and EFS were 83% +/-5% and 67% +/-7%, respectively. 6/7 patients with Burkitt histology required mCOMP chemotherapy. Patients after thoracic organ transplantation had a significantly inferior outcome compared to liver or renal graft recipients (5-years EFS 79%+/-8% vs 44% +/-11%, p=0.01). There was no significant impact of tumor EBV-status, histology, stage or early/late PTLD development. Treatment-related mortality was attributed to bowel perforation (n=1) and infection (n=2). No episode of graft rejection occurred during treatment for PTLD.
In conclusion, response-adapted immuno-chemotherapy is an effective and well tolerated treatment regimen for CD20-positive PTLD after SOT in children. Chemotherapy could be spared in half of the PTLD patients, but was necessary in almost all Burkitt PTLD patients. Prognosis was significantly worse in patients after heart or lung transplantation compared to renal or liver allograft recipients. Future studies are envisioned to evaluate whether the inclusion of cellular immunotherapy may contribute to avoid chemotherapy in the majority of patients.

Disclosures
No relevant conflicts of interest to declare.