Posttransplant Lymphoproliferative Disease Treatment & Management

Updated: Apr 19, 2017
  • Author: Phillip M Garfin, MD, PhD; Chief Editor: Ron Shapiro, MD  more...
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Treatment

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 remains the cornerstone for treatment of 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. [42] 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. [43] Patients with less-aggressive or polyclonal PTLD tend to respond more favorably to this management approach, as compared to patients with clinically aggressive PTLD.

Additional therapeutic measures that have been used, each with varying degrees of success, include the following [44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56] :

  • Surgical excision of the lesion (may be curative in cases of localized disease)
  • Antiviral therapy
  • Intravenous gamma globulin (IVIG)
  • Alfa interferon
  • Radiation therapy and chemotherapy
  • Monoclonal antibodies
  • Cytotoxic T lymphocytes

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.

Antiviral therapy—acyclovir, ganciclovir, or 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 are often used together with reduction of immunosuppression as a first step in management. [57]

B lymphocytes that are latently infected with EBV are generally not susceptible to nucleoside-type antiviral agents, because the viral enzyme target of antiviral drugs, thymidine kinase (TK), is not expressed. However, administration of arginine butyrate has been shown to increase expression of some lytic phase genes, including EBV-TK, in latently infected B cells. In a novel approach to therapy, administration of arginine butyrate together with ganciclovir has been shown to render latently infected and previously antiviral-resistant EBV-lymphoma cells, sensitive to ganciclovir. This strategy remains an investigational but promising new therapy for EBV-PTLD. [58]

Interferon alfa has historically been considered a potential therapeutic option in the treatment of B-cell PTLD. [31, 46, 47] 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.

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. [59] 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.

The use of anti–B-cell antibodies as a treatment strategy for a series of patients with PTLD was reported in 1991 by Fischer et al. In that study, 26 patients with B-cell lymphoproliferative syndromes following HSCT and SOT were treated with murine anti-CD21 and anti-CD24 monoclonal antibodies. The authors concluded that anti–B-cell antibodies could be effective treatment for diffuse oligoclonal lymphoproliferative disease, but that monoclonal PTLD or disease involving the CNS did not respond to this therapy. [48]

Benkerrou et al subsequently reported the long-term outcome of 58 patients with PTLD after SOT or bone marrow transplantation who were treated with the same regimen of anti-CD21 and anti-CD24 antibodies. Complete remission was achieved in 61% of patients, with a relapse rate of 8%. The overall long-term survival rate was 46% at 61 months, with survival rates lower among HSCT patients (35%) compared with SOT patients (55%). They also identified multivisceral disease, CNS involvement, and late-onset PTLD as poor prognostic features, consistent with results published by other authors. [44]

More recently, rituximab, a humanized anti-CD20 monoclonal antibody, has been used to treat CD20-expressing non-Hodgkin lymphomas and PTLDs. In 2000, Milpied et al published their retrospective experience of 32 patients with PTLD after SOT or HSCT treated with rituximab and reported an overall response rate of 69%. [49] Subsequently, several reports have also demonstrated the safety and efficacy of single-agent rituximab in the treatment of CD20-expressing PTLD, generally with a response rate of approximately 50%. [60, 61, 62]

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.

An international multicenter, prospective, phase II trial found rituximab followed by CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine [Oncovin], and prednisone) chemotherapy to be a safe and effective treatment for adult SOT patients with PTLD who had previously failed upfront reduction in immunosuppression. [63] Patients received 4 weekly courses of rituximab followed by CHOP. In this study, 60% of the patients had a complete or partial response to rituximab alone, and this overall response rate improved to 90% following CHOP therapy. There was, however, an 11% CHOP-associated mortality rate and a 9% rate of toxicity significant enough to halt CHOP treatment.

The authors conclude that sequential first-line therapy with rituximab followed by CHOP chemotherapy is efficacious in the management of PTLD and may be superior to rituximab monotherapy followed by chemotherapy at the time of disease progression or relapse. In this series, patients who were rituximab nonresponders were at greatest risk for treatment-relatedmorbidity and mortality. [63]

Historically, a high mortality rate has been associated with the use of chemotherapy in the management of transplant-associated lymphoproliferative disease. [64] The CHOP combination, which is a standard chemotherapy regimen for non-Hodgkin lymphoma, has been used in patients with PTLD, often achieving high remission rates. [64] A modified CHOP regimen was used in a small series of 6 pediatric patients, with a 67% overall survival rate. [65] However, the toxicities of this regimen were significant, including prolonged myelosuppression and one death from sepsis. In recipients of SOT other than cardiac transplantation, various anthracycline-based regimens have been used with some success. [66]

However, 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 HSCT are often notable 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. [67] 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. [68] 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.

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. [69, 70, 54] 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 intrathecal rituximab administered to treat isolated CNS PTLD. One study reported a series of 8 children with isolated CNS PTLD. [71] Seven of the patients responded after a median of 2 courses of rituximab, and the therapy was generally well tolerated. Radiotherapy also remains an effective modality for the treatment of CNS PTLD. [72]

With the understanding that EBV PTLD arises in SOT or HSCT patients in whom the normal balance is disrupted between latently infected B cells and the anti–EBV-specific T-cell response, the idea of using adoptive T-cell immunotherapy presented a logical idea for proof of principle. In 1994, Papadopoulous et al reported on the administration of donor-leukocyte infusions 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 cytotoxic T cells 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 novel therapy for PTLD.

The expanding field of T-cell–based therapy for the treatment of PTLD was reviewed by Heslop in 2012. Donor EBV-specific cytotoxic T lymphocytes administered to HSCT recipients with PTLD have recently been reported to achieve an overall response rate of 68% and without inducing graft versus host disease. [56] The use of donor cytotoxic T lymphocytes is more problematic for SOT patients, and so the development of “third party” EBV cytotoxic T lymphocytes - that could potentially be available from a bank of HLA-typed EBV-specific T-cell lines is being actively investigated. [73, 74] Currently, this approach is available only at a few centers in the United States and has not been adapted for larger-scale production.

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. [3] 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. 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. 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.

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Surgical Care

Surgical management alone is rarely the sole mode of therapy for posttransplant lymphoproliferative disease (PTLD). Diagnostic tissue must be obtained for histologic examination 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.

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