Association of Immunosuppressive Maintenance Regimens With Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients
ABSTRACT The association of immunosuppressive regimens (ISRs) with posttransplant lymphoproliferative disorder (PTLD) may be related with the Epstein-Barr virus (EBV) recipient serostatus.
We selected primary kidney transplant recipients from Organ Procurement Transplant Network/United Network for Organ Sharing database (2000-2009) who were discharged with a functioning graft and were receiving an ISR including an antiproliferative drug and a calcineurin inhibitor as follows: mycophenolate mofetil (MMF)/mycophenolate sodium+tacrolimus (TAC), MMF+cyclosporine A (CsA); mammalian target of rapamycin inhibitor (mTORi)+TAC; and mTORi+CsA. Adjusted risks of PTLD, rejection, death, and graft failure were examined in all recipients and compared between EBV+ and EBV- recipients.
Of 114,025 recipients, 754 developed PTLD (5-year incidence of 0.84%). Adjusted hazard ratio for PTLD was 4.39 (95% CI: 3.60-5.37) for EBV- versus EBV+ recipients; and 1.40 (95% CI: 1.03-1.90) for mTORi+TAC, 0.80 (95% CI: 0.65-0.99) for MMF+CsA, and 0.90 (95% CI: 0.57-1.42) for mTORi+CsA, versus MMF+TAC users. In EBV- recipients, hazard ratio for PTLD was 1.98 (95% CI: 1.28-3.07) for mTORi+TAC, 0.45 (95% CI: 0.28-0.72) for MMF+CsA, and 0.84 (95% CI: 0.39-1.80) for mTORi+CsA users versus MMF+TAC. No difference was seen in EBV+ recipient groups. Rejection rates were higher among MMF+CsA recipients in both EBV groups. Death and graft failure risk were increased in all EBV+ISR groups, while in EBV- these risks were only increased in mTORi+TAC group versus MMF+TAC.
In EBV- recipients, immunosuppression with mTORi+TAC was associated with increased risk of PTLD, death, and graft failure, while MMF+CsA use was associated with a trend to increased risk of rejection, lower PTLD risk, and similar risk for graft failure when compared with MMF+TAC.
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ABSTRACT: The most modifiable risk factor for post-transplant lymphoproliferative disease (PTLD) is the type and dose of induction and maintenance immunosuppressive therapy. It is challenging to identify the contribution of a single agent such as rabbit antithymocyte globulin (rATG) in the setting of multidrug therapy. Registry analyses can be helpful but are limited by methodological restrictions and inclusion of historical patient cohorts. These are typically from eras when rATG dosing was markedly higher than currently (e.g. total dose 14 mg/kg versus 6 mg/kg now), accompanied by higher exposure to maintenance therapies, and often an absence of antiviral prophylaxis. The largest registry analysis to assess rATG specifically found no risk of PTLD after kidney transplantation, but conflicting results have been reported, highlighting the difficulty of interpreting this type of analysis. The relative rarity of PTLD means that individual controlled trials are underpowered to assess its occurrence, but the available data do not suggest an effect of rATG. A pooled analysis of data from studies of rATG induction in kidney and heart transplantation found the incidence of PTLD to be comparable to published reports in the overall transplant population. Data on the effect of rATG dose are inconclusive, but in patients receiving antiviral prophylaxis it does not appear to be influential. Nevertheless, it would seem reasonable to employ the lowest dose of rATG compatible with effective induction, particularly in EBV-seronegative recipients and other high-risk groups such as heart-lung transplant recipients. Overall, the risk of PTLD following rATG induction therapy with modern dosing regimens and under current management conditions appears unlikely to make an important contribution to the risk: benefit balance. Copyright © 2015. Published by Elsevier B.V.Transplant Immunology 04/2015; 28. DOI:10.1016/j.trim.2015.04.003 · 1.83 Impact Factor
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ABSTRACT: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disease usually diagnosed in childhood. Subependymal giant cell astrocytomas (SEGA) are benign brain lesions occurring in up to 20% of patients with TSC. Treatment with mTOR inhibitors has been proven effective in inducing SEGA shrinkage, but discontinuation results in re-growth. Evidence suggests that mTOR inhibition seems a disease-modifying treatment for TSC beyond inducing SEGA shrinkage; however concerns remain regarding negative long-term effects. Through this retrospective case series, an attempt was made to determine the minimal mTOR inhibitor dose needed to maintain radiological response of SEGA in six pediatric patients treated at The Hospital for Sick Children since 2007. This study reviews medication doses and blood levels as related to SEGA size on MRIs at 3-month intervals. Blood levels were monitored every 3 months and 2 weeks after dose adjustment. Total dose reduction by 25% was considered after SEGA shrinkage was maintained on two consecutive MRIs. All patients demonstrated SEGA shrinkage greater than 50% when treated with mTOR inhibition at therapeutic doses (4-5 mg/m(2) ). When sirolimus doses were weaned in two patients by 50%, SEGAs regrew by 84% and 32%. In two patients, responses have been maintained with 30% decrease in sirolimus dose. One patient underwent SEGA resection and one remains on therapeutic dose. Therapeutic dose of mTOR inhibitor is effective in shrinking TSC-related SEGAs. Doses less than 2.5 mg/m(2) were insufficient to maintain response in this limited series. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.Pediatric Blood & Cancer 04/2015; DOI:10.1002/pbc.25573 · 2.56 Impact Factor
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ABSTRACT: There is limited clinical evidence on the utility of the monitoring of Epstein Barr virus (EBV) DNAemia in the preemptive management of post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients. We investigated current preventive measures against EBV-related PTLD through a web-based questionnaire sent to 669 SOT programs in 35 European countries. This study was performed on behalf of the ESGICH study group from the European Society of Clinical Microbiology and Infectious Diseases. A total of 71 SOT programs from 15 European countries participated in the study. EBV serostatus of the recipient is routinely obtained in 69/71 centers (97%) and 64 (90%) have access to EBV DNAemia assays. EBV monitoring is routinely used in 85.9% of the programs, and 77.4% reported performing preemptive treatment for patients with significant EBV DNAemia levels. Preemptive treatment for EBV DNAemia included reduction of immunosuppression in 50.9%, switch to m-TOR inhibitors in 30.9%, and use of rituximab in 14.5% of programs. Imaging by PDG-PET total body is used in 60.9% of centers in order to rule out PTLD and complemented computer tomography in 50%. In 10.9% of centers, PDG-PET is included in the first-line diagnostic work-up in patients with high risk EBV DNAemia. Despite the lack of definitive evidence, EBV load measurements are frequently used in Europe to guide diagnostic work-up and preemptive reduction of immunosuppression. We need prospective and controlled studies to define the impact of EBV monitoring in reducing the risk of PTLD in SOT recipients. Copyright © 2015. Published by Elsevier Ltd.