Reduction of Immunosuppression and Subsequent Rituximab Monotherapy or CHOP-Based Chemotherapy +/− Rituximab as a Treatment for PTLD Does No Impair the Renal Graft Function: A Matched Pair Control Analysis in 55 Renal Transplant Recipients with PTLD and 1075 Renal Transplant Controls
Authors: Appel Ulrike , Hinrichs Carl , Reinke Petra , Babel Nina , Neumayer Hans H , Budde Klemens , Dreyling Martin , Dührsen Ulrich , Kliem Volker , Schüttrumpf Silke , Hauser Ingeborg A , Mergenthaler Hans G , Dörken Bernd , Anagnostopoulos Ioannis , Riess Hanno , Trappe Ralf ,   On behalf of the German Study Group on PTLD
Published: April 2020

Abstract
Purpose: Post transplant lymphoproliferative disorder (PTLD) is a serious and often devastating complication after solid organ transplantation. The initial therapeutic action is reduction of immunosuppression (IR). Patients not responding to IR usually are treated with rituximab monotherapy and/or CHOP-based chemotherapy. The impact of treatment on the renal graft function is to be analyzed.
Methods: A retrospective data analysis was performed on adult renal transplant recipients with PTLD requiring further therapy after failing to respond to IR. All patients gave their informed consent to this study and all had been treated within one of the prospective German PTLD Study Group protocols: PT-LPD-1 (rituximab monotherapy), PTLD-1 (sequential treatment with rituximab and CHOP chemotherapy) or PTLD D2006–2012 (different treatment protocols). Renal graft function was analyzed 6 months (6m) before, during and up to 2 years after treatment of PTLD. From our renal transplant database altogether 1075 transplant recipients that had transplantation between January 1998 and June 2008 served as a control. Controls were matched for sex, patient age, transplant age and transplant function at time of diagnosis of PTLD.
Results: Median age at diagnosis of PTLD was 49 years. 38/55 pts. were male, 43/55 had late onset PTLD. 53/55 had B-cell PTLD: 2 polymorphic, 37 aggressive B-cell, 3 Hodgkin or Hodgkin-like PTLD and 11 others. 2/55 had T-cell PTLD. 34/55 had an advanced stage of disease and 26/51 had elevated LDH levels. 1 patient had renal graft involvement. Renal transplantation for endstage renal disease was either due to autoimmune disorders (26/55), to diabetes (4/55), to cystic renal degeneration (5/55) or to metabolic dysfunction (1/55, 19 others). At diagnosis of PTLD 10 patients were on calcineurin-inhibitor (CNI) therapy only, 16 were on CNI plus mycophenolate mofetil (MMF), 13 were on CNI plus azathioprin (AZA), 4 were on CNI plus mTor-inhibitor, 4 were on mTor-inhibitor plus MMF or AZA and 7 were on single agent immunosuppression with MMF, AZA or prednisone. Immunosuppression was reduced in all patients immediately after diagnosis of PTLD. 15/55 patients received further therapy with single agent rituximab, 40/55 patients received CHOP or CHOP-like chemotherapy +/− rituximab. 36/53 (68%) patients reached a complete remission (CR). At a median follow up of &gt;2 years 4 patients relapsed and 17 died: 5 from PTLD, 7 from infections, 1 from myocardial infarction and 3 of unknown reason. Matching criteria were equally distributed in the patient and control group. After successful treatment of PTLD 4 of 38 PTLD survivors (10%) had failed renal allografts and recommenced hemodialysis: 1 due to a haemolytic uremic syndrom, 1 due to acute renal failure after a septic complication, 2 due to chronic transplant dysfunction. With a mean transplant age of 6.2 years transplant survival at 1 year after diagnosis of PTLD is 92% in the stable CR group. In a longitudinal analysis in 27 and 44 patient pairs evaluable not requiring hemodialysis we found a drop in eGFR values from 50.9 ml/min 6m before diagnosis of PTLD to 46.8 ml/min at time of diagnosis of PTLD that was statistically significant (p=0.04) suggesting a negative impact of the lymphoma (and/or of IR) to the graft function. With treatment of PTLD the graft function improved up to a mean eGFR of 56.3 ml/min 4 weeks after completing therapy (p=0.014). In subsequent subgroup analyses we found this effect to be restricted to and more durable in patients that had been treated with chemotherapy resulting in an eGFR of 57.6 ml/min, 55.7 ml/min and 58.6 ml/min 4 weeks, 6 months and 12 months after therapy, respectively. The graft function in this subgroup of patients was even superior to controls (p=0.012 at 6m, p=0.004 at 12m), which may result from the immunosuppressive effect of chemotherapy.
Conclusion: PTLD may be associated with a worsening of graft function in renal transplant recipients but the graft often ameliorates during therapy. Beside rare acute complications like acute renal failure during septic complications there is no evident negative impact of therapy on renal graft function with rituximab and chemotherapy based 1st-line protocols in PTLD. Transplant survival in the disease free survival group is excellent.