Medical Care
The management of posttransplant lymphoproliferative disease (PTLD) remains a challenge and generally without a standardized therapeutic approach that can be applied to all patients. Despite this diversity, reduction of immunosuppression (RIS) remains the cornerstone for treatment of Epstein-Barr virus (EBV)–driven B-cell PTLD, independent of histology.
Starzl et al were the first to suggest reduction, or withdrawal, of immunosuppression as a treatment option for PTLD. [46] This strategy allows the patient's natural immunity to recover and gain control over proliferating EBV-infected cells. Benkerrou et al reported complete regression in about 40% of patients after reduction or discontinuation of immunosuppressive therapy. [47] Patients with less-aggressive or polyclonal PTLD tend to respond more favorably to this management approach, as compared with patients with clinically aggressive PTLD.
In patients who have an inadequate response to reduction of immunosuppression, the humanized anti-CD20 monoclonal antibody rituximab has become a standard of care. Rituximab can be given as monotherapy or in combination with chemotherapy, concurrently or sequentially. [48] Reports have demonstrated the safety and efficacy of single-agent rituximab in the treatment of CD20-expressing PTLD, generally with a response rate of approximately 50%. [49, 50, 51]
However, relapse of PTLD is not uncommon after rituximab monotherapy. In addition, the kinetics of disease response to rituximab may be slower than what is observed with chemotherapy, making it a less effective therapeutic option for patients with clinically aggressive or fulminant PTLD. These observations have led investigators to combine rituximab with chemotherapy.
The PTLD-1 trial, a prospective, international, multicenter, phase II study, found rituximab followed by CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) chemotherapy to be a safe and effective treatment for adult solid organ transplant (SOT) patients with PTLD that fails to respond to reduction in immunosuppression. Patients received 4 weekly courses of rituximab followed by CHOP. However, the efficacy of chemotherapy was offset by its toxicity, with an 11% CHOP-associated mortality rate and a 9% rate of adverse events significant enough to halt CHOP treatment. [52]
Further analysis of PTLD-1, along with the subsequent PTLD-2 trial, suggested a protocol for the use of rituximab and chemotherapy in CD20-positive B-cell PTLD in adults that balances risks and benefits. The studies established that patients who enter complete remission with rituximab induction therapy, or who have less than three international prognostic index (IPI) risk factors at diagnosis and enter partial remission, are at low risk and can continue with rituximab monotherapy. [53]
In contrast, other patients are at high risk and can benefit from the addition of CHOP. This includes patients who have three or more IPI risk factors and attain partial remission, those with stable disease, and those with progressive disease who are non-thoracic SOT recipients. Thoracic SOT (ie, lung, heart) recipients with progressive PTLD are at very high risk, and even with intensive chemoimmunotherapy their prognosis remains poor. [14]
National Comprehensive Cancer Network (NCCN) guidelines recommend CHOP, given sequentially or concurrently with rituximab, as chemoimmunotherapy for monomorphic PTLD (B-cell type) and polymorphic PTLD. For frail patients who cannot tolerate anthracycline, no specific regimen has been identified but options may include CEOP ( cyclophosphamide, etoposide, vincristine, prednisone) or CVP (cyclophosphamide, vincristine, prednisone). For T cell–type monomorphic PTLD, the NCCN recommends brentuximab vedotin plus CHP (cyclophosphamide, doxorubicin, prednisone) for CD30+ cases, CHOP, or CHOP plus etoposide (CHEOP). [54]
SOT patients are often not able to tolerate full-dose chemotherapy owing to end-organ toxicity or risk of allograft dysfunction. For cardiac transplant patients, the dose of doxorubicin is often reduced over concerns of myocardial toxicity. Patients who develop PTLD after hematopoietic stem cell transplant (HSCT) are often not able to tolerate chemotherapy owing to myelotoxicity.
Despite these challenges, with diligent supportive care and careful monitoring for toxicity, chemotherapy can be safely administered to most SOT patients. Given the risk of treatment-related morbidity and mortality, this strategy is often reserved for patients in whom front-line therapy with reduction of immunosuppression and/or rituximab failed, for patients with CD20-negative PTLD, or for patients with clinically fulminant PTLD, including those with CNS involvement.
In an effort to decrease the chemotherapy-related toxicity observed in SOT recipients, a low-dose chemotherapy regimen consisting of cyclophosphamide and prednisone was piloted in 36 children with PTLD in whom initial reduction of immunosuppression failed. [55] The overall response rate was 83%, and 2 patients died of treatment-related toxicity. The PTLD relapse rate was 19%.
To further assess the efficacy of this regimen, a Children’s Oncology Group phase II trial of low-dose cyclophosphamide and prednisone together with rituximab was conducted. [56] Fifty-four pediatric patients with PTLD were enrolled in the study, and the majority had monomorphic disease. The complete response rate in this study was 69%, and the 2-year event-free survival rate was 71%; there was one death due to infection during therapy.
The choice of therapy ideally attempts to balance the risk of life-threatening PTLD with the risk of allograft failure and treatment-related morbidity. In patients who have undergone solid organ transplantation (SOT), reduction of immunosuppression may risk allograft rejection. In addition, SOT recipients are often at greater risk for organ toxicity and opportunistic infections that may complicate chemotherapy administration. In hematopoietic stem cell transplantation (HSCT) patients with PTLD, reduction of immunosuppression may increase the risk of graft versus host disease.
Additional therapeutic measures that have been used, each with varying degrees of success, include the following [57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69] :
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Surgical excision of the lesion (may be curative in cases of localized disease)
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Radiation therapy
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Cytotoxic T lymphocytes
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Antiviral therapy
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Intravenous gamma globulin (IVIG)
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Interferon alfa
Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) is based on the understanding that EBV PTLD arises in SOT or HSCT patients from disruption of the normal balance between latently infected B cells and the anti–EBV-specific T-cell response. In 1994, Papadopoulous et al reported on the infusion of donor leukocytes to treat PTLD that had developed in 5 patients following T-cell–depleted allogeneic HSCT. Infusions of unirradiated leukocytes from EBV-seropositive donors resulted in complete clinical responses of PTLD in all patients. However, the infusion of CTLs was complicated in some patients by the development of graft versus host disease.
Since these early experiments, adoptive immunotherapy techniques have been refined and continue to show promise as a therapy for PTLD. Donor EBV-specific CTLs administered to HSCT recipients with PTLD have been reported to achieve an overall response rate of 68% and without inducing graft versus host disease. [69] A prospective study of rituximab treatment followed by donor or autologous EBV-CTL infusion reported 5-year overall survival of 70.7% and progression-free survival of 68.9%. [70]
The use of donor CTLs is more problematic for SOT patients. This prompted the development of “third party” EBV cytotoxic T lymphocytes, which could potentially be available from a bank of HLA-typed EBV-specific T-cell lines. [71, 72] Tabelecleucel (Ebvallo) an allogeneic EBV-specific T-cell immunotherapy, has been approved by the European Medicines Agency. [73]
Antiviral therapy (eg, acyclovir, ganciclovir, foscarnet) in the absence of reduction of immunosuppression is not considered effective treatment for PTLD. While these drugs have not shown efficacy as single-agent therapy for PTLD, they have been used together with reduction of immunosuppression as a first step in management. [74] However, current European guidelines recommend against the use of antiviral drugs for treatment of PTLD. [75]
IVIG has been used as adjunctive therapy in the management of PTLD. Deficiency or absence of antibody against one of the EBNAs in patients post transplantation has been associated with the subsequent development of PTLD. Decreasing EBV viral load has been reported to be associated with increased levels of antibody against Epstein-Barr nuclear antigens (EBNAs). These 2 factors provide the rationale for the use of IVIG in the management of PTLD.
IVIG or anti-cytomegalovirus (CMV) immunoglobulin (CytoGam), which contains anti-EBV antibodies, is most commonly used in conjunction with antiviral therapy as prophylaxis against CMV in SOT or HSCT patients. This anti-CMV prophylactic regimen may also provide some protection against developing EBV-PTLD. [76] In clinical practice, this strategy is frequently initiated in SOT patients with rising EBV viral loads who are considered to be at risk for developing PTLD.
Interfen alfa has historically been considered a potential therapeutic option in the treatment of B-cell PTLD. [34, 59, 60] Interferon alfa is recognized to inhibit the outgrowth of EBV-transformed B cells, and it decreases the oropharyngeal shedding of EBV. It also is known to inhibit T helper cells, which release cytokines (ie, interleukin [IL]–4, IL-6, IL-10) that promote B-cell proliferation. Interferon functions as both a proinflammatory and antiviral agent. Because no prospective clinical trials have been conducted to date, many of the reports of its success in the management of PTLD are anecdotal.
Clinical trials are underway to evaluate the efficacy of EBV-specific inhibitors, including inhibitors of EBNA1 and EBNA2 as well as heat-shock protein 90 (HSP90) inhibitors, but none have been approved for clinical use. [77]
For patients with CNS involvement of PTLD, the prognosis remains poor even with aggressive therapy. High-dose methotrexate has been reported to be a tolerable and effective therapy for CNS PTLD. [78, 79, 67] Intrathecal therapy is also considered advisable because many systemic chemotherapy agents and monoclonal antibodies do not cross the blood-brain barrier adequately. Small series have described treatment of isolated CNS PTLD with intrathecal rituximab. [80] In one study, 7 of 8 children with isolated CNS PTLD responded after a median of 2 courses of rituximab, and the therapy was generally well tolerated. [81] Radiotherapy also remains an effective modality for the treatment of CNS PTLD. [82]
Prophylaxis
In 2012, an international multidisciplinary panel of experts published a consensus statement on the classification and risk factors for PTLD and outlined approaches to minimize the risk of developing PTLD. [2] The first of these recommendations from the Seville Workshop group is that EBV status of both the donor and the recipient should be ascertained prior to donor selection, and whenever possible, EBV-negative recipients should receive grafts from EBV-negative donors.
The next suggestion is to minimize upfront immunosuppression as much as possible and potentially to use reactivation of other viruses, such as CMV or BK virus, as cues to reduce immunosuppression. Although antiviral therapy has not proven to be an effective treatment for PTLD, in selected high-risk patients prophylactic or preemptive antiviral therapy may be considered. However, current European guidelines recommend against the use of antiviral drugs for preemptive therapy. [75]
An alternative approach to antiviral prophylaxis is to administer IVIG or CytoGam to maintain high titers of anti-EBV antibodies that may help prevent the development of EBV PTLD.
The last recommendation from the Seville Workshop is to consider preemptive treatment for those patients who appear to be developing PTLD. A rising EBV viral load in a high-risk patient may warrant preemptive reduction in immunosuppression, while continuing to monitor closely for allograft dysfunction.
In patients with significant EBV DNA blood levels but without clinical symptoms of EBV disease, European guidelines recommend preemptive treatment with rituximab, combined with reduction in immunosuppression if possible. Consideration of EBV-CTL therapy, if available, is recommended. [75] A retrospective study by Stocker et al in 219 high-risk recipients undergoing allogeneic HSCT concluded that preemptive rituximab is associated with a low incidence of EBV-PTLD and may be considered worthwhile, despite inducing a delayed B-cell reconstitution and a high risk of neutropenia. [83]
Surgical Care
Surgical management alone is rarely the sole mode of therapy for posttransplant lymphoproliferative disease (PTLD). Obtaining tissue for histologic examination is necessary for diagnosis in patients with clinical concern for PTLD. Occasionally, when PTLD is localized to a single nodal or extranodal site (eg, in localized small bowel lesions that present as intussusception), the diagnostic surgical procedure may remove the only site of disease. In such a situation, the decision as to whether the patient will benefit from adjuvant therapy (reduction of immunosuppression, rituximab, or chemotherapy) depends on the pathologic diagnosis and the patient’s individual risk factors.
Long-Term Monitoring
Following the Epstein-Barr virus (EBV) viral load provides useful information regarding disease status and response to treatment. Green at the University of Pittsburgh recommends weekly monitoring of EBV viral titers in the peripheral blood of patients with posttransplant lymphoproliferative disease (PTLD), [84] although for lower-risk patients the interval of monitoring may appropriately be monthly to every 3 months.
Declining viral load may suggest a response to treatment. Persistently high or rising viral load may suggest development of PTLD or disease progression. However, serial physical examinations, radiological evaluation, and assessment for any evidence of allograft rejection are essential in conjunction with EBV viral load monitoring, as some patients have wide fluctuations in blood EBV levels that do not clinically correlate with PTLD.
Management of PTLD remains a balancing act between eradication and cure of the disease and preservation of graft function. The degree of graft loss that can be tolerated depends on the graft in question. Reduction or withdrawal of immunosuppression has to be tailored accordingly, after multidisciplinary discussion, and with due consideration of other treatment options. At this time, treatment has not been standardized beyond the generally accepted belief that reduction or withdrawal of immunosuppression is initial step in PTLD management, following which the treatment is usually tailored to the specific needs of the patient.
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Biopsy of gingival tissue (400 X) with hematoxylin and eosin stain demonstrates polymorphous infiltrate of atypical lymphoid cells, which is consistent with posttransplant lymphoproliferative disease (PTLD).
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Biopsy of gingival tissue (400 X). Epstein-Barr virus encoded RNA (EBER) study shows numerous positive cells, which is consistent with posttransplant lymphoproliferative disease (PTLD).
