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CARDIAC TRANSPLANTATION: Edited by James K. Kirklin

Post-transplant lymphoproliferative disease and other malignancies after pediatric cardiac transplantation

an evolving landscape

Haynes, Susan E.a; Saini, Sherminib; Schowengerdt, Kenneth O.a

Author Information
Current Opinion in Organ Transplantation: October 2015 - Volume 20 - Issue 5 - p 562-569
doi: 10.1097/MOT.0000000000000227
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Abstract

INTRODUCTION

Survival after pediatric heart transplantation has improved steadily since its inception, primarily due to the development of more specific and effective immunosuppressant medications to prevent and treat acute cellular rejection. Nonetheless, long-term survival may be limited by the development of other associated conditions, including post-transplant lymphoproliferative disease (PTLD). Although the outcomes have improved, PTLD continues to contribute significantly to morbidity and mortality after solid organ transplantation (SOT). Refined treatment regimens continue to be sought with the goal of achieving effective cure of PTLD while preserving allograft function.

Box 1
Box 1:
no caption available

DEFINITION

Post-transplant lymphoproliferative disease encompasses a broad spectrum of lymphoid disorders, and is most commonly related to proliferation of B cells in the setting of reduced T-cell activity induced by the immunosuppression required after transplantation. Nearly all PTLDs are associated with Epstein–Barr virus (EBV) infection, which is typically latent in the setting of normal T-cell function. The spectrum of PTLD encompasses indolent polyclonal proliferations to aggressive lymphomas [1]. Given the broad range of presentations of PTLDs, the WHO has developed a classification system with four categories: early lesions, polymorphic PTLD, monomorphic PTLD, and classical Hodgkin's lymphoma [2].

INCIDENCE AND RISK FACTORS

Cases consistent with PTLDs were first described in 1968, in which herpes virus infections were found to be associated with malignancy in renal transplant patients [3]. Since that time, EBV has been demonstrated to be the most important risk factor, given its ability to transform and ‘immortalize’ B cells [4]. Most young children are EBV-negative and acquire EBV during childhood or adolescence. EBV-seronegative status at the time of transplant corresponds with a higher prevalence of PTLDs (17–33%) [4]. This early peak typically occurs in the first few months after transplant and often coincides with primary EBV infection. Chinnock et al.[5] recently reviewed data obtained over a 16-year span from the multicenter Pediatric Heart Transplant Study and found that freedom from PTLD was 98.5% at 1 year, 94% at 5 years, and 90% at 10 years. They observed that positive donor EBV status was a ‘strong risk factor in the seronegative recipient’, but the risk was dependent on the age of the recipient at the time of transplant (Fig. 1). Among the seronegative recipients between 4 and 7 years of age transplanted with an EBV+ donor, 25% developed PTLD, which was significantly higher than in infants and adolescents. Speculatively, maternal protection in infancy and more robust immune systems in adolescence may be protective in these age groups [5].

FIGURE 1
FIGURE 1:
Hazard for PTLD as a function of age at time of transplant. PTLD, post-transplant lymphoproliferative disorder.

Although EBV remains the most important risk factor for PTLD, various immunosuppressive regimens have been examined for their role in contributing to PTLD in renal and hepatic transplants. A general agreement is that the overall burden of immunosuppression in pediatric heart transplantation is an important contributor, and the increased incidence of PTLD in those with frequent episodes of rejection supports this theory. Over the history of pediatric heart transplantation, three recognized eras of immunosuppression regimens and experience have been studied [6] and each subsequent era has demonstrated an improved percentage freedom from PTLD [5] (Fig. 2). Evaluation of the role of lympholytic induction therapy in the subsequent development of PTLD demonstrated that more routine use of induction therapy was not correlated with an increase in PTLD [7].

FIGURE 2
FIGURE 2:
Incidence of PTLD during different eras in pediatric heart transplantation. PTLD, post-transplant lymphoproliferative disorder.

CLINICAL PRESENTATION

Since 60–86% of the presentations of early PTLDs have an otolaryngologic presentation, a high level of suspicion should be maintained for the pediatric cardiac transplant recipient who presents with upper respiratory infection symptoms, noisy breathing, or changes in the quality of the voice [4]. Although airway obstruction can result from rapid growth of tumor mass, most early forms of PTLD have a more benign course than polymorphic or monomorphic disease. When these nondestructive early lesions are excluded, the overall incidence of PTLD falls to around 5% [8]. In the remaining polymorphic or monomorphic PTLD, the most common sites of presentation are is the gastrointestinal tract (39%) and lungs or airways (25%). The initial presentation of gastrointestinal involvement can be perforation [4]. Rarely the patient may present with shock and multisystem organ failure.

DIAGNOSIS

Post-transplant lymphoproliferative disease should always be suspected in the setting of prolonged constitutional symptoms, particularly in high-risk patients (EBV-negative at time of transplant). These may include persistent fever, diaphoresis, and/or weight loss. Localized symptoms and physical findings may point toward the primary area of involvement, most commonly upper airway, lower respiratory, or gastrointestinal in nature. Localized or generalized adenopathy may be present.

Excisional biopsy of suspected PTLD based on clinical and imaging findings (superficial lymph nodes, tonsillar tissue, peripheral pulmonary lesions, gastrointestinal masses, etc.) is useful in confirming the diagnosis and establishing PTLD type [2]. Pathologic evaluation typically includes clonality assessment by PCR [9] and determination of immunophenotype by flow cytometry. In addition, EBV determination may be carried out by in-situ hybridization EBV-encoded RNA and immunohistochemical staining.

TREATMENT

The goal of treatment of PTLD is to eliminate the abnormal lymphoproliferative process while preserving allograft function. Due to the histologic heterogeneity of the disease and variability in disease severity and clinical presentations, there is, to date, no consensus on a standardized approach to treatment. Reduction of immunosuppression has historically been the mainstay of the therapy. The intent of reduction of immunosuppression is to help restore cytotoxic T-cell function to curb B-cell proliferation, which is especially important in EBV-positive PTLD [10]. Only about half of the patients respond to this approach, however, and of those who do, durable remissions are rare. The majority of patients requires additional therapy, including rituximab, alone or in combination with chemotherapy. Surgery or radiation for local control may be required in select cases.

Reduction of immunosuppression

Although reduction of immunosuppression has been utilized for decades as part of the initial management of PTLD, objective tumor responses are highly variable with this approach, and durable responses are seen in a minority of cases. Additional concerns regarding this strategy include the considerable length of time before initial responses are observed (median 3–5 weeks) and the associated risk of allograft rejection that can occur following reduction of immunosuppression. Although it remains to be determined which patients would benefit from reduction of immunosuppression alone, the evidence supports implementing reduction of immunosuppression (typically a 50–75% dose reduction [1]) as part of the initial therapy for most cases of PTLD. Reduction of immunosuppression is most likely to benefit patients with early lesions and polymorphic PTLD [10]. However, in patients with multiorgan involvement, significant disease burden, aggressive histology, or progression in need of rapid interventions, reduction of immunosuppression alone is generally considered insufficient.

Rituximab

Rituximab is a humanized chimeric monoclonal antibody against the cell surface protein CD20, which is primarily expressed on the surface of B cells. By inducing apoptosis of B cells, rituximab is used to treat diseases and disorders in which B cells are excessive in number, overactive, or dysfunctional. Prior to the widespread use of rituximab, 3-year overall survival (OS) rates in most PTLD series ranged from 30 to 50% [1]. Around 2005, data emerged showing rituximab's efficacy in reduction of immunosuppression-refractory PTLD. In the postrituximab era, the overall response rates (ORRs) and median OS for PTLD have improved considerably. Approximately 70% progression-free survival (PFS) of 3 years and 73% OS have been reported among adult patients who receive front-line rituximab-based therapy, versus 21% PFS of 3 years and 33% OS without rituximab [11]. Published series of pediatric patients with PTLD refractory to reduction of immunosuppression have shown similar outcomes following rituximab therapy [10]. The standard dose schedule is typically four weekly infusions of 375 mg/m2[12]. The total number of doses may vary, particularly if used in combination with chemotherapy.

Chemotherapy

Cytotoxic chemotherapy is directed towards curbing the aberrant lymphoproliferation of PTLD. By suppressing T-cell function, chemotherapy can offer the added benefit of helping to prevent rejection. Despite the potential risks of chemotherapy in SOT recipients, including the risks of life-threatening infections, allograft rejection, and even treatment-related mortality (TRM), combination chemotherapy remains an important component of effective PTLD treatment [1]. Treatment-related morbidity can be minimized through the aggressive use of supportive care strategies, including growth factors and prophylactic anti-infectives. The most commonly used chemotherapeutic regimen for PTLD in adults has been cyclophosphamide, doxorubicin, oncovin, and prednisone (CHOP), preferably in a risk-stratified approach that reduces or intensifies treatment based on tumor response. There are, however, some concerns over this chemotherapeutic regimen in pediatrics. Although the anthracyclines (e.g. doxorubicin) are effective against lymphoma, their associated risk of cardiotoxicity can be clinically significant, especially in heart-transplant recipients. There is also a theoretical risk of conventional chemotherapy suppressing anti-EBV cytotoxic T lymphocytes (CTLs) and patients subsequently being unable to develop normal T-cell-mediated immunity against EBV. In response to these concerns, low-dose chemotherapy has been explored as an alternative to standard conventional-dose chemotherapy. In 2005, the results of the first large prospective pediatric trial were published. Thirty-six children with EBV-positive PTLD following SOT, who had failed first-line therapy, were treated with a combination of cyclophosphamide [600 mg/m2 intravenous (i.v.) for 1 day] and prednisone (2 mg/kg orally for 5 days) every 3 weeks for six cycles. Of the 36 patients, 75% achieved a complete response (CR) [13]. This was the largest published series of patients with PTLD treated with a uniform regimen of low-dose chemotherapy, and clearly demonstrated the efficacy of an anthracycline-free regimen in children with EBV-positive PTLD. Despite the promising results, 22% of children relapsed, a higher percentage than is typically observed with standard non-Hodgkin's lymphoma (NHL) chemotherapy. Additionally, patients with fulminant PTLD (disseminated, rapidly progressive disease with multiorgan failure) did not show significant disease response, and all succumbed to disease progression.

Despite concerns over excessive toxicity with standard NHL treatment, there are clearly some PTLD patients for whom more intensified therapy is necessary. In 2007, the Children's Oncology Group (COG) completed enrollment of a phase II study combining the previously reported low-dose cyclophosphamide and prednisone regimen with rituximab in children with EBV-positive CD20-positive PTLD. There were 11 heart-transplant recipients among the total of 55 patients enrolled. Early results showed a 2-year event-free survival of 71% and a 2-year OS of 83% [10]. The results of this trial demonstrated that the addition of rituximab to the cyclophosphamide–prednisone backbone is feasible, tolerable, and promising in terms of long-term outcomes. Although adding rituximab to the CHOP regimen is now a common practice for adults with PTLD, the intensive anthracycline-containing regimen is not considered front-line therapy in most pediatric PTLDs. More intensified therapy is reserved for patients with refractory or recurrent disease, Hodgkin's-like or central nervous system (CNS) PTLD [14].

Figure 3 outlines a suggested approach to current PTLD treatment options.

FIGURE 3
FIGURE 3:
Suggested treatment algorithm.

Local therapy

Select cases of localized PTLDs may benefit from surgery and/or radiation, usually in combination with reduction of immunosuppression [1]. Radiation probably plays the most significant role in CNS PTLD – a form of PTLD with a particularly poor prognosis. Several strategies are frequently employed in the treatment of CNS PTLD, including high-dose chemotherapy, intrathecal rituximab, and radiation.

Cytotoxic T-cell therapy

An important contributor to the development of PTLD is chronic immunosuppression, and the consequently impaired cytotoxic T-cell response to EBV and other virally driven lymphoproliferation. As applications for cellular immunotherapy emerge and show promise in the treatment of both infections and malignancy, there is a growing interest in developing CTLs for PTLD treatment. Numerous studies have demonstrated the efficacy of CTLs, especially in EBV-positive lymphoproliferative disorders, following both SOT and hematopoietic stem cell transplant (HSCT) [15–22]. The development and application of EBV CTLs has been most robust in HSCT patients, in whom use of donor-derived EBV-specific CTLs as monotherapy has shown very encouraging complete remission rates [21,23]. The engineering of EBV-specific CTLs for SOT recipients with PTLD is more challenging for a number of reasons, one of which is the lack of availability of a T-cell donor. To work around this issue, various centers are exploring the use of patient-derived (autologous) EBV CTLs and third-party EBV CTLs [10].

The use of infection-specific CTLs for a virally driven malignancy is logical. Harnessing the immune system's inherent ability to fight infections and abnormal cell proliferation is a far more attractive prospect than subjecting patients to the toxicity of chemotherapy. Although it is unlikely that chemotherapy will be avoidable entirely, especially for patients with higher-risk subtypes of PTLD (fulminant, recurrent/refractory disease, or CNS PTLD), it might be possible to spare patients from conventional dose or intensified chemotherapy if CTLs can be utilized in combination, along with rituximab.

ADJUNCTIVE THERAPIES

Adjunctive therapies offer the opportunity for enhanced prophylaxis and more effective treatment of EBV-driven PTLD.

Mammalian target of rapamycin inhibitors in prevention and treatment of post-transplant lymphoproliferative disorder

The mammalian target of rapamycin (mTOR) inhibitors sirolimus (rapamycin) and everolimus have proven efficacy and are widely used in the prevention of allograft rejection. Use of these agents allows a concomitant reduction in the dosage of calcineurin inhibitors (CNIs) (cyclosporine or tacrolimus) without increasing rejection risk, thus potentially minimizing the occurrence of post-transplant malignancies associated with CNI [24–27]. In addition, mTOR inhibitors exhibit both antiproliferative and antineoplastic activity via downstream interruption of the phosphatidylinositol-3-kinase (PI3K) signaling pathway [28,29], making them potential candidates for the prevention and treatment of PTLD. mTOR inhibitors also have antiangiogenic properties that may inhibit tumor growth [30]. El-Salem et al.[31] showed activation of multiple components of the mTOR signaling pathway in tissue samples from patients with PTLD. Notably, activation of this pathway occurred in all PTLD subtypes (both B and T cell), irrespective of the EBV status [31]. Previous studies by Majewski et al. described the effects of the immunosuppressive macrolide RAD (derived from rapamycin) on the growth of human EBV-transformed cells, noting significant inhibition of EBV-positive lymphoblastic B-cell lines both in vitro and in vivo[32].

Study findings supporting a treatment approach inclusive of mTOR inhibitors include a large multicenter analysis of post-transplant malignancies in renal-transplant recipients who demonstrated a significantly decreased risk of developing any post-transplant malignancy when maintenance immunosuppression included a TOR inhibitor [33]. Although no similar studies have been reported specifically for pediatric heart-transplant patients, mTOR inhibitors have been used in this patient population for indications that include minimization of long-term renal toxicity related to CNI, reduction of CNI dosage to reduce PTLD risk, and potential direct mTOR inhibitor effects on the prevention and/or treatment of PTLD.

Antiviral therapy and post-transplant lymphoproliferative disorder risk

Epstein–Barr virus infection after SOT may lead to clinical manifestations ranging in progression and severity from asymptomatic viremia to infectious mononucleosis through PTLD or lymphoma. EBV infection may be either primary in origin, or secondary due to reactivation of latent EBV in response to immunosuppression. Patients who are seronegative at the time of transplant are at increased risk of developing PTLD [34]. Treatment regimens that include antiviral agents have therefore been studied as a means of prevention and treatment of PTLD after SOT. Both acyclovir and ganciclovir have been studied for this purpose, as they are known to inhibit EBV DNA replication during the viral lytic phase. Ganciclovir and valganciclovir are more widely used in the clinical setting as they are more potent and are also effective for the prophylaxis and treatment of cytomegalovirus (CMV) infection that may be seen after transplantation.

Höcker et al.[35] previously prospectively studied the association between treatment with ganciclovir or valganciclovir and the occurrence of EBV viremia in EBV-negative pediatric renal-transplant recipients who had received an organ from an EBV-positive donor. Over the course of a 1-year study period, 45% of patients receiving antiviral prophylaxis with either ganciclovir and/or valganciclovir developed primary EBV infection compared to 100% of patients in the nontreated group [35]. Given the association of EBV seroconversion and the increased risk of developing PTLD, other studies have focused on the effect of antiviral prophylaxis in reducing the incidence of lymphoproliferative disorders after SOT. Previous studies have demonstrated a significant reduction in the risk of PTLD in both lung and renal-transplant recipients who received chemoprophylaxis with acyclovir, ganciclovir, or valganciclovir [36,37].

Antiviral therapy in the treatment of post-transplant lymphoproliferative disorder

As acyclovir and ganciclovir inhibit EBV DNA replication during the lytic phase, the ability of EBV to undergo latency presents a challenge to the effective treatment of infected tumor cells. With this in mind, various ‘lytic inducers’ have been studied to evaluate their utility in rendering these cells susceptible to ganciclovir therapy. Treatment of latent EBV-related malignancies with the combination of arginine butyrate and ganciclovir has been shown to produce a significant antitumor response [38]. Similarly, several other histone deacetylase inhibitors have been shown to induce gene expression in latent EBV and sensitize lymphoma cells to ganciclovir in vitro[39]. Bortezomib, a proteasome inhibitor, has also been shown to activate lytic gene expression of EBV in Burkitt lymphoma [40].

OTHER POST-TRANSPLANT MALIGNANCIES

Since the late 1990s, as the risk of acute rejection has decreased and long-term survivorship from SOT has improved, the risk of malignancy following SOT has become a growing concern. Historically, post-transplant patients have had a known risk of developing lymphoma/lymphoproliferative disorders and skin cancers. Recent large series, however, have demonstrated that transplant recipients have a significantly higher risk of developing atypical solid tumors as well, at least a four-fold higher risk than the general population. In contrast, the risk of malignancies seen more commonly in the general population, such as breast and colon carcinoma, although increased in SOT patients, are less dramatically increased compared to more atypical, frequently more aggressive malignancies [41,42▪▪]. However, regardless of tumor type (whether typical or atypical), SOT recipients afflicted by cancer typically have greater TRM and lower long-term survival than their nontransplant counterparts with similar malignancies.

Skin cancers are among the most common malignancies seen in SOT recipients, and include squamous cell carcinoma, basal cell carcinoma, Kaposi sarcoma, malignant melanoma, and Merkel cell tumors. Although in pediatric SOT recipients, PTLD is the most common malignancy, accounting for approximately 50% of all tumors, skin cancers occur in 20% of patients, with melanoma and cancers of the lip seen more commonly than in adults. The underlying pathogenesis for post-transplant malignancy stems from a number of risk factors, most notably the need for chronic immunosuppression. The cumulative exposure to immunosuppressive agents appears to correlate strongly with overall cancer risk, presumably by interfering with antitumor immune surveillance and antiviral infection-fighting capability. In addition, some immunosuppressive agents have been found to actually promote malignant transformation as an undesirable side effect (e.g. cyclosporine and azathioprine), whereas others have been shown to have anticancer properties (e.g. mycophenolate mofetil and sirolimus). In developing strategies to minimize cancer risk, one important consideration is to minimize the intensity and cumulative exposure to immunosuppression – a strategy that obviously needs to be balanced carefully against the risk of rejection. One recent large series of heart-transplant recipients reported that although the distribution of tumor types is unique in this population, the overall risk of malignancy in recent years appears to be declining, approaching that of the US general population. The most likely explanation for this favorable trend is the significant change in immunosuppressive protocols during the 15-year study period, trending towards lower doses of immunosuppression and less toxic maintenance and rescue agents used for treatment of rejection [42▪▪]. Despite this improvement in cancer incidence, however, the outcomes from cancer treatment remain poor.

CONCLUSION

Post-transplant lymphoproliferative disorder remains a significant potential complication after SOT, particularly in pediatric patients who are more likely to be EBV-negative at the time of transplant and subsequently undergo EBV seroconversion. Risk for PTLD may be reduced by employing strategies such as EBV prophylaxis in seronegative patients along with close monitoring of EBV viral load, minimizing overall intensity of immunosuppression, and utilizing newer agents that have both immunosuppressive and antiproliferative properties, such as mTOR inhibitors.

Post-transplant lymphoproliferative disorder treatment frequently requires a multifaceted approach, including reduction of immunosuppression, rituximab, and frequently chemotherapy as well. With this strategy, long-term survivorship from PTLD has improved considerably in the past 10 years. As the technology for developing CTLs is applied more broadly, future treatment protocols for PTLD will likely incorporate this strategy as well.

As a result of improved long-term graft and patient survival following SOT, mortality from malignancy in general is becoming a growing concern. Minimizing cumulative immunosuppressive intensity is a critical component to mitigating this risk; however, more work is needed to improve cancer outcomes in this population.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

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Keywords:

cytotoxic T-cell therapy; Epstein–Barr virus; immunosuppression; post-transplant lymphoproliferative disease; rituximab; target-of-rapamycin inhibitors

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