Journal of Hepatology
Volume 44, Issue 1 , Pages 23-26, January 2006

What is the current treatment of PTLD after liver transplantation?

  • Jean-François Dufour

      Affiliations

    • Department of Clinical Pharmacology, University of Bern, Murtenstrasse 35, 3010 Bern, Switzerland
    • Corresponding Author InformationCorresponding author. Tel.: +41 31 632 3191; fax: +41 31 632 4997.
    • ,
  • Martin F. Fey

      Affiliations

    • Department of Medical Oncology, Inselspital, Bern, Switzerland

published online 08 November 2005.

Article Outline

Abbreviations: EBV, Epstein–Barr virus, OLT, orthotopic liver transplantation, PTLD, post-transplantation lymphoproliferative disorders

 

In the management of liver transplanted patients, post-transplantation lymphoproliferative disorders (PTLDs) represent a specific challenge. The factors associated with PTLDs, their clinical presentation and their diagnostic problems have recently been reviewed in the Journal [1]. Once PTLD has been diagnosed, the strategy consists of taking advantage of the special pathogenesis of lymphomas in immunocompromised hosts, and to choose the most effective and least toxic therapeutic option. The first aim should be to reduce immunosuppression to an absolute minimum. Despite the fact that PTLDs represent a wide spectrum of disorders ranging from natural killer cell lymphoma to localized plasmacytoma, the majority derive from B-cell lymphocytes and can potentially be targeted by monoclonal antibodies against specific antigens. Depending on the localisation and the aggressiveness of the tumour, conventional chemotherapy, surgery and radiotherapy may be of significant help. Strategies based on cytokines and immunotherapy have yet to prove their potential.

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1. Reduction of the immunosuppression 

The majority of PTLD, especially those occurring early after liver transplantation are of B-cell origin and Epstein–Barr virus (EBV)-associated. In immunosuppressed patients, EBV-infected B cells cannot be controlled by EBV-specific cytotoxic T cells. Restoring recipient immunity, despite the fact that it carries the risk of graft rejection, remains the most pathophysiologically sound option to take control of EBV-driven lymphoproliferation: it leads to tumour regression in up to 60% of the patients [2]. Depending on the severity of PTLD and the time elapsed since the transplantation, it may be justified to stop immunosuppression completely. In a retrospective analysis of 335 paediatric recipients of a liver transplant, Hurwitz et al. reported that immunosuppression could safely be withdrawn in all 19 cases of PTLD [3]. This was associated with an acceptable risk of manageable acute cellular rejection. There were no deaths caused by rejection and a significant fraction of patients could remain free of immunosuppression. They advocated to base the decision and the timing of immunosuppression restoration on a biopsy-proven graft rejection. In contrast, others witnessed acute graft rejection in 60–74% of the patients in the first 4 weeks following immunosuppression withdrawal with graft loss in 3–17% of the cases [4]. Serinet et al. reported the occurrence of fatal rejection in patient treated for PTLD [5]. In long-term survivors immunosuppressive agents were reintroduced without recurrence of the PTLD [6]. In such cases it might be advisable to select different immunosuppression regimes with better preservation of T-cells. Venzke restarted immunosuppression after treatment of PTLD with anti-CD20 antibodies with basiliximab monotherapy [7]. The role of new immunosuppressors such as mTOR inhibitors in this situation remains to be defined. On one hand, these drugs have anti-proliferative properties, but on the other hand they induce a potent immunosuppression favouring PTLDs [8].

Achieving the lowest immunosuppression possible can be a preemptive strategy. Data in the paediatric field of liver transplantation suggest that quantitative EBV PCR monitoring allows immunosuppression reduction before the diagnosis of PTLD [9]. In a series of nine patients, two children in whom it was not possible to decrease the immunosuppression developed low grade PTLD, whilst in seven children who could tolerate a reduction of immunosuppression no PTLD was noted [10].

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2. Surgery 

The role of surgery is chiefly restricted to obtaining diagnostic tissue, which should be supplied generously to the respective pathology laboratory. There may exist rare clinical situations where surgical interventions may contribute to therapy, for example, in cases where lymphoma causes bowel obstruction or biliary stricture [11], [12].

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3. Radiotherapy 

Radiotherapy may play a therapeutic option in patients with localised lymphoma, in analogy to its place in the treatment of immunocompetent patients with lymphomas. Typically, radiotherapy should be offered as a complement to systemic treatment. Frontline radiotherapy may be helpful for patients with large localised tumours and relative contraindication to immediate systemic treatment [13]. PTLD in the central nervous system should be treated with chemotherapy regimens suitable to overcome the blood–brain barrier, for example methotrexate or cytosine arabinoside in high doses, provided such treatment is feasible in a given patient. Radiotherapy may add to the therapeutic benefit of systemic treatment but its precise role (as in central nervous system (CNS) lymphoma in immunocompetent patients) remains to be defined [14].

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4. Antiviral therapy 

Despite the important role of EBV in the development of these disorders, antiviral drugs have a limited place in the treatment of PTLD. Acyclovir and ganciclovir are ineffective at preventing the persistence of the episomal form of EBV associated with latency. The lack of expression of the viral thymidine kinase due to viral latency jeopardizes the efficacy of acyclovir or ganciclovir since these nucleoside analogues cannot be converted in their monophosphate form. Administration of arginine butyrate induces the expression of the viral thymidine kinase restoring sensitivity toward ganciclovir. This strategy resulted in complete clinical remission in four out six patients treated [15]. Treatment with foscarnet, a direct inhibitor of the viral-DNA polymerase, resulted in complete remission in three patients, none of them recipient of a liver graft [16]. In EBV-negative children recipients of EBV-positive grafts and therefore at high risk to develop PTLD the pre-emptive use of intravenous ganciclovir has been reported [17]. The literature supplies very limited information on anti-viral treatments in patients with PTLD, and none of these strategies have so far produced results convincing enough to prepare the ground for their widespread use.

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5. Interferon-alpha 

Interferon-α not only interferes with viral replication, but it also stimulates the immune response enhancing cytotoxic T-cell activity against tumoral lymphocytes. Complete remissions with this approach have been reported [18]. Inherent to the interferon therapy is the risk of graft rejection, which occurred in one out of eight liver transplanted patients [18]. In therapeutic doses, interferons can be fairly toxic, with fever and other unpleasant side effects which further limit their long-term use in transplant patients.

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6. Conventional chemotherapy 

The same regimens which are used for lymphoproliferative disorders in immunocompetent hosts such as CHOP and its variants can be applied in aggressive PTLD not responding to a period of 2–3 weeks of radical withdrawal of the immunosuppression [19]. This is particularly the case for EBV-negative monoclonal lymphomas occurring years after OLT, which can worsen despite withdrawal of immunosuppression, but respond to chemotherapy [20]. Drug interactions between the chemotherapy and the immunosuppression are rarely an issue since the treatment of PTLD implies the reduction of the immunosuppressive drugs and when possible their withdrawal. It is important to measure precisely the renal function which may have been affected by months of immunosuppression with calcineurin-inhibitors. The liver function provided by the graft should not be a limiting factor as long as the PTLD does not directly involve the parenchyma or the extrahepatic biliary tree (Table 1).

Table 1. Stepwise treatment approach
1.Immunosuppression reduction
2.No improvement after 2–3 weeks: conventional chemotherapy
3.CD20-positive lymphoma: Rituximab
4.EBV-positive: ev. Foscarnet
5.Localized problematic: surgery, radiotherapy

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7. Monoclonal antibodies 

Humanized monoclonal anti-B cell antibodies targeting the CD20 surface antigen, which is found only on B-lymphocytes, offer an effective adjunction to treat PTLD [21]. Rituximab is a chimaeric antibody with constant human gamma-1 and kappa-regions and variable murine region [22]. Its binding to B-lymphocytes leads to complement-mediated cell death [23]. Rituximab can be used to treat CD20-positive aggressive diffuse large cell non-Hodgkin's lymphoma, which occur late after liver transplantation and fail to respond to discontinuation of immunosuppression [24]. For optimal results, treatment with monoclonal antibodies should be used in combination with conventional chemotherapy (see above). One report mentions successful treatment of PTLD with prolonged rituximab treatment without chemotherapy in recipients of intestinal graft [25]. Treatment with monoclonal antibodies is no option for patients with PTLD localized to the CNS since the antibodies do not easily pass the blood–brain barrier, and recurrence of PTLD in the CNS after treatment with anti-CD20 antibodies has been described [5]. Fatal transplant rejection in paediatric cases treated with rituximab for PTLD have been reported [5], suggesting that restarting immunosuppression early should be considered.

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8. Adoptive immunotherapy with virus-specific T cells 

In immunosuppressed patients, the expansion of EBV-infected B-cells is not any more controlled by cytotoxic T cells. In adoptive transfer, anti-EBV cytotoxic T-cells are expanded in vitro and infused to the patient reconstituting the EBV-specific cellular immune response [26]. Transfer of autologous EBV-specific cytotoxic T-cells can lead to regression of post-liver transplantation EBV-driven lymphoproliferative disorders [27]. A complete regression has also been described with the use of partially matched cytotoxic T-cells [28]. Comoli et al. reported that adoptive transfer can prevent the development of PTLD in EBV-replicative recipients of a solid organ graft [29]. This approach is restricted to clinical trials and therefore not recommended for treatment on a routine basis. Intravenous administration of immunoglobulin, which has been considered as a prophylactic measure to prevent the development of EBV-related PTLD has no place in the treatment of PTLD [30].

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9. Interleukin-6 

Based on the fact that IL-6 promotes the growth of EBV-infected B cells and that patients with PTLD have high levels of IL-6, Haddad et al. tested a monoclonal anti-IL-6 antibody in a multicenter clinical trial. Anti-IL-6 treatments were well-tolerated and lead to complete remission in 45% and to partial remission in 25% of the 12 enrolled patients. In this series three patients were recipient of a liver transplantation: one died, two responded to the treatment [31]. Therapy with IL-6 must still be regarded as experimental, and no prospective large trials in PTLD patients treated with anti-IL-6 antibodies have been reported in the literature.

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10. Liver re-transplantation 

In exceptional cases of PTLD not responding to medical treatment and localized to the liver, liver re-transplantation can be undertaken [31], [32].

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11. Follow up 

Once complete remission has been achieved these patients require follow-up to detect early relapse. It has been shown that in lymphoma early diagnosis of asymptomatic relapse, with the implication of early salvage treatment may improve the prognosis. According to guidelines on the follow-up of immunocompetent lymphoma patients, in patients treated for PTLD serial clinical examinations, full blood cell counts, assessment of LDH, and CT scans may be recommended. Positron emission tomography, which can be useful in the staging of PTLD [33], might be helpful but its relevance remains to be established. The optimal intervals are usually confined to 3–6month visits after the end of treatment.

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References 

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PII: S0168-8278(05)00675-6

doi:10.1016/j.jhep.2005.10.009

Journal of Hepatology
Volume 44, Issue 1 , Pages 23-26, January 2006

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