Association of Immunosuppressive Maintenance Regimens With Posttransplant Lymphoproliferative Disorder in Kidney Transplant Recipients

Mendez National Institute of Transplantation, Los Angeles, CA, USA.
Transplantation (Impact Factor: 3.83). 11/2011; 93(1):73-81. DOI: 10.1097/TP.0b013e31823ae7db
Source: PubMed


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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    • "EBV seronegativity at transplantation is a very potent risk factor for the development of PTLD. Seronegative patients carry a 4-fold increased risk of PTLD [16–19]. The prognostic value of EBV monitoring after transplantation will be discussed separately. "
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    ABSTRACT: Patients after solid organ transplantation (SOT) carry a substantially increased risk to develop malignant lymphomas. This is in part due to the immunosuppression required to maintain the function of the organ graft. Depending on the transplanted organ, up to 15% of pediatric transplant recipients acquire posttransplant lymphoproliferative disease (PTLD), and eventually 20% of those succumb to the disease. Early diagnosis of PTLD is often hampered by the unspecific symptoms and the difficult differential diagnosis, which includes atypical infections as well as graft rejection. Treatment of PTLD is limited by the high vulnerability towards antineoplastic chemotherapy in transplanted children. However, new treatment strategies and especially the introduction of the monoclonal anti-CD20 antibody rituximab have dramatically improved outcomes of PTLD. This review discusses risk factors for the development of PTLD in children, summarizes current approaches to therapy, and gives an outlook on developing new treatment modalities like targeted therapy with virus-specific T cells. Finally, monitoring strategies are evaluated.
    Clinical and Developmental Immunology 09/2013; 2013(10):814973. DOI:10.1155/2013/814973 · 2.93 Impact Factor
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    • "These centers identified PTLD predominantly in older patients with an underlying diagnosis of COPD, as well as equally distributed between those with COPD, IPF, Eisenmengers, and alpha-1 antitrypsin deficiency [9] [11]. Immunosuppressant regimens may impact upon the development of PTLD, as recent reports from kidney transplantation cite an increased risk of PTLD in patients receiving mTOR inhibitors and tacrolimus compared to patients receiving cyclosporin and mycophenolate mofetil [27]. To date, few studies in the lung transplant literature have cited clear PTLD risk with distinct immunosuppressant regimens, other than overall immunosuppressant load and use of induction therapy. "
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    ABSTRACT: Posttransplant lymphoproliferative disease (PTLD) after lung transplantation occurs due to immunosuppressant therapy which limits antiviral host immunity and permits Epstein-Barr viral (EBV) replication and transformation of B cells. Mechanistically, EBV survives due to latency, escape from cytotoxic T cell responses, and downregulation of host immunity to EBV. Clinical presentation of EBV may occur within the lung allograft early posttransplantation or later onset which is more likely to be disseminated. Improvements in monitoring through EBV viral load have provided a means of earlier detection; yet, sensitivity and specificity of EBV load monitoring after lung transplantation may require further optimization. Once PTLD develops, staging and tissue diagnosis are essential to appropriate histopathological classification, prognosis, and guidance for therapy. The overall paradigm to treat PTLD has evolved over the past several years and depends upon assessment of risk such as EBV-naïve status, clinical presentation, and stage and sites of disease. In general, clinical practice involves reduction in immunosuppression, anti-CD20 biologic therapy, and/or use of plasma cell inhibition, followed by chemotherapy for refractory PTLD. This paper focuses upon the immunobiology of EBV and PTLD, as well as the clinical presentation, diagnosis, prognosis, and emerging treatments for PTLD after lung transplantation.
    Clinical and Developmental Immunology 03/2013; 2013(6):430209. DOI:10.1155/2013/430209 · 2.93 Impact Factor
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    ABSTRACT: INTRODUCTION: Kidney transplantation is the treatment of choice for patients with end-stage renal failure, and their survival after transplantation is gradually improving. Everolimus (EVL) is a mammalian target of rapamycin inhibitor, providing a safe and effective immunosuppressive regime after kidney transplantation. AREAS COVERED: The objective of this review is to summarize the clinical efficacy and safety of the EVL-based immunosuppressive regimen by analyzing peer-review reports and ongoing trials of its use after kidney transplantation in adult patients. EXPERT OPINION: Judging by the more recent trials, it seems that EVL, in association with calcineurin inhibitor (CNI) minimization, provides a well-tolerated regimen with a low risk of rejection and good graft function. Such regimens have been investigated intensively and should be preferable to complete elimination of CNI. In addition, future clinical studies should explore whether the pleiotropic effects of EVL are beneficial in the long term, leading to a reduction of cardiovascular diseases and de-novo malignancies.
    Expert Opinion on Pharmacotherapy 03/2012; 13(5):767-78. DOI:10.1517/14656566.2012.662955 · 3.53 Impact Factor
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