Pediatric Posttransplant Lymphoproliferative Disease

Updated: Oct 02, 2015
  • Author: Vikas R Dharnidharka, MD, MPH; Chief Editor: Stuart M Greenstein, MD  more...
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Overview

Overview

Posttransplant lymphoproliferative disease (PTLD) is an unusual entity that has many features of an immune system malignancy. It is characterized by uncontrolled proliferation of lymphoid lineage cells (typically B cells, rarely non-B lineage) in a context of posttransplant immunosuppression. [1] In some situations, reducing the immunosuppression can reverse this proliferation, thus differentiating it somewhat from truly irreversible malignancies. Most but not all PTLD cases have a strong relationship with Epstein-Barr virus. This condition straddles the disciplines of transplantation, immunology, oncology, and virology.

PTLD has emerged as a significant complication of solid organ transplantation. This entity was rarely reported until the mid 1980s, when the incidence began suddenly rising. PTLD presents significant problems for the clinician because it is difficult to predict and has high morbidity and mortality rates secondary to the difficulty in prevention. In addition, it has the potential for graft loss due to disease itself or the need to reduce immunosuppression, which increases the risk of graft rejection.

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Incidence

Multiple reports from single-center studies, as well as registry reports, have illustrated that the incidence of posttransplant lymphoproliferative disease (PTLD) rose throughout most of the 1990s.

Alfrey et al reported an increase in the overall incidence of PTLD from 0.7% from 1965-1988 to 1.9% from 1988-1990. [2] Similarly, Ciancio et al reported only 2 cases of PTLD from 1977-1993, followed by 5 cases over the next 2 years (1993-1995). [3] Data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), which has been enrolling patients since 1987, showed a significant doubling of incidence density from 320 cases per 100,000 years of patient follow-up from 1987-1992 to 630 cases per 100,000 years of patient follow-up from 1992-1997. [4]

Some centers, particularly in the pediatric liver transplant population, have introduced prophylactic measures and have reported a reduction in the high prevalence of PTLD at their institutions. [5, 6] Current prevalence rates for posttransplant patients vary from 1-15%, depending on the organ transplanted and the immunosuppressive agents used. Adult kidney transplant recipients have a relatively lower cumulative incidence of 1% at 5 years and 2.1% at 10 years. [7]

Notably, the incidence of PTLD was higher than control groups in studies of recent biologic agents such a belatacept and tofacitinib. [8] An expert multidisciplinary panel felt that the incidence might rise also with higher-risk patients increasingly receiving transplants and needing intense immunosuppression, such as those with preformed high-level antibodies. [9]

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Risk Factors

The prevalence of posttransplant lymphoproliferative disease (PTLD) is different for each transplanted organ. The highest rates are reported for the intestine (as much as 20%), thoracic organs (heart 2-10%, lung 4-8%), and liver (2-8%). Prevalence in kidney transplants is usually lower (1%), but some centers have reported prevalence as high as 10%. Prevalence in bone marrow transplantation is low (1-2%), except in patients in whom T-cell–depleted marrow is used; in these patients, rates as high as 24% are reported. In an analysis of the very large national United Network for Organ Sharing (UNOS) in the United States, the prevalence of PTLD was highest in intestinal transplants (8%), then thoracic organs (3-5%), followed by liver and kidney transplants. [10] In addition, several different demographic, infectious, and immunosuppressive risk factors are associated with PTLD development.

Demographic risk factors

See the list below:

  • Age: The prevalence of PTLD is highest in the pediatric age group (age 0-18 y). According to analysis of UNOS data, the relative risk (RR) in this age group is 2.81 compared with adult recipients. [10] Some reports have suggested that prevalence is even higher in patients younger than 5 years. Age may not be an independent risk factor but may depend on the likelihood of the recipient being seronegative for Epstein-Barr virus (EBV) at the time of transplant. In general, among transplant recipients, the risk of lymphoma (a subgroup of PTLD) is highest in youngest patients, ranging from 23- to 37-fold in the ANZDATA registry and 200- to 1200-fold in the CTS registry. However, even adult recipients are at a higher risk than the general population (7- to 16-fold in both registries). [11, 12] . Adult transplant recipients older than 60 years or aged 47-60 years are at higher risk for PTLD than recipients aged 33-46 years. [7]
  • Race: Data from the NAPRTCS and UNOS registries have shown a markedly higher risk in white children; the RR for white transplant recipients is 2.22 compared with that in other races. [10]

Infectious risk factors

See the list below:

  • EBV serostatus: The single most important risk factor for PTLD is the lack of previous exposure to EBV in the transplant recipient. Across all recipient age groups and all organ types, recipient EBV seronegativity confers a 3- to 33-fold higher risk for PTLD. [13] This magnitude of elevation is by far higher than with any other factor. Walker et al determined from their data on 381 adult nonrenal transplant recipients, 14 of whom developed PTLD, that the prevalence rate for seronegative recipients was 24 times higher than that for seropositive recipients. [14]
  • Cytomegalovirus (CMV) infection: CMV has also been demonstrated to be associated with an increased risk of PTLD. Manez et al analyzed 40 adult liver transplant recipients, all of whom were seronegative for EBV. [15] Of these recipients, 33% developed PTLD, and a diagnosis of CMV disease posttransplant increased the relative risk to 7.3. Walker et al [14] studied the effect of primary CMV disease on PTLD by analyzing recipients who were seronegative for CMV and who received a CMV-positive allograft. In this group, the risk of PTLD was 4- to 6-fold higher.

Immunosuppression risk factors

See the list below:

  • PTLD was extremely rare when 2-drug immunosuppression regimens (steroids and azathioprine) were in standard use. Incidence of PTLD rose with the advent of more potent immunosuppression, beginning with cyclosporine (ie, cyclosporin A [CsA]). In addition, certain specific agents have been reported to increase the risk of PTLD.
  • Reports of PTLD were very rare prior to the introduction of cyclosporine. In one long-term study, the relative risk for PTLD with cyclosporine was significantly higher at 2.2. [16]
  • Swinnen et al first reported the increased prevalence of PTLD (more than 4-fold) in recipients of cardiac transplants who received more than a 10-mg cumulative dose of Muromonab-Cd3 (OKT3). [17] Walker et al reported that the use of OKT3 independently increased the risk of PTLD 5- to 6-fold in a multivariate analysis. [14] In combination with the risk factors of an EBV-seronegative recipient and CMV, the prevalence rate rose by a factor of 529.
  • Cox et al and Sokal et al reported that pediatric recipients of liver transplants who received FK506 had a higher prevalence of PTLD (13-20%) than those who received cyclosporine (2-3%). [18, 19] According to Newell et al, the combined use of OKT3 and FK506 appears to be synergistic, with the prevalence of PTLD increasing from 6% to 28%. [20] Initial data from NAPRTCS also suggested a marked increase in PTLD with FK506-based initial immunosuppression for renal transplantation. [4] However, more recent data suggest no increased risk. This may be related to lower levels of FK506 being deemed acceptable (8-12 ng/mL, compared with 12-15 ng/mL previously).
  • Penn has commented that each drug used is associated with a learning curve, during which time increased adverse effects may be observed. [21, 22] Whether rates of PTLD will decrease in liver transplantation with lower FK506 levels is unclear. The Cochrane Review Group compared cyclosporine with FK506 and found no significant differences in relative risk for PTLD in a meta-analysis of 30 different prospective trials. [23, 24]
  • Studies that have examined the risk for PTLD with mycophenolate mofetil have not shown any increase in relative risk; these studies included a UNOS data analysis, [25] , a case control study, [26] and a NAPRTCS registry data analysis. [27] However, other studies have documented an increased risk for BK virus nephropathy and CMV infection with mycophenolate use.
  • Sirolimus has unique properties, including retention of anti-EBV T-cell activity in vitro. A recent study by of UNOS data revealed a decreased relative risk for malignancy (a different outcome variable from PTLD) with sirolimus use. [25] However, more recent data from the same registry suggested a higher PTLD risk with early sirolimus use, so the issue may not be as clear-cut as thought. [28]
  • Data regarding PTLD risk with use of anti-interleukin (IL)-2R antibodies (basiliximab and daclizumab [no longer available in the U.S.) have shown conflicting results. Bustami et al analyzed data from the Scientific Registry of Transplant Recipients (SRTR) and documented significantly increased relative risk (1.83-1.92) for PTLD with these agents. [29] However, Cherikh et al, using similar source data from UNOS, suggested an insignificant 14% increase in relative risk. [25] Opelz and Henderson, who represented the Collaborative Transplant Study in Europe, found no increased risk for non-Hodgkin lymphoma within a 12-month follow up period after anti-IL-2R antibody use. [30] These differences may be related to different databases and different time periods of follow up.
  • To date, alemtuzumab has not been associated with a higher PTLD risk. [28] However, belatacept, a new co-stimulatory blockade agent, is associated with higher PTLD rates, especially in transplant recipients who were EBV seronegative at transplantation. [8]

Other

See the list below:

  • Some single-center studies have shown associations with individual HLA alleles, such as HLA-A2, -A3, -A8, or -A26. [31] But none of these allele associations has been reproduced by others yet.
  • While PTLDs are a heterogenous group, some separation may be possible between early- and late-onset PTLDs. Early-onset PTLDs tend to be EBV positive and, when extranodal, are more likely than late-onset PTLDs to be localized to the transplanted organ. Late-onset PTLD is less likely to be associated with EBV and, overall, is more likely than early-onset PTLD to be extranodal. [32]
  • In a French study, simultaneous kidney-pancreas transplantation and higher degree of HLA mismatch (5-6 versus 0-4) have been shown to impart higher risk. [7]
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Etiology and Pathogenesis

The pathogenesis of posttransplant lymphoproliferative disease (PTLD) is intimately linked to EBV. EBV is a lymphotrophic DNA gamma herpes virus that replicates in squamous epithelial cells of the oropharynx, uterine cervix, and male genital tract. The virus infects and immortalizes human or primate B lymphocytes that bear EBV membrane C3d receptors.

The free infectious virus can be recovered from saliva in essentially all healthy seropositive individuals. EBV is implicated in the pathogenesis of a spectrum of B-cell lymphoproliferative diseases in immunosuppressed organ transplant recipients, in immunodeficiency diseases (eg, common variable immunodeficiency, Wiskott-Aldrich syndrome, ataxia telangiectasia, severe combined immunodeficiency, acquired immunodeficiency syndrome), and in recipients of T-cell–depleted or mismatched bone marrow transplants.

EBV causes 2 types of cellular infections: (1) a productive replicative infection in which mature infectious virus particles are assembled and released, resulting in cell death (the lytic cycle), and (2) a nonproductive infection in which the virus is incorporated into and replicates with the host DNA but remains in the latent state in transformed B cells and no mature virus is produced.

Persistence of the EBV genome in the latent state in transformed B cells occurs following a primary EBV infection and results in a permanent carrier state, in which small numbers of latently infected B cells circulate in seropositive individuals. Elimination of these cells is carried out by human leukocyte antigen (HLA)-restricted, EBV-specific, cytotoxic T lymphocytes. Certain factors (eg, inhibition of anti-EBV T-cell immunity, such as that which occurs with posttransplant immunosuppression) allow latently infected cells to enter the lytic cycle. The suppression of EBV-specific CD8+ T cells also allows B-cell proliferation to go unchecked. In solid organ transplant recipients, the abnormal B cells are usually of recipient origin. In contrast, the abnormal B cells are usually of donor origin in recipients of bone marrow transplants.

According to the above paradigm, all PTLDs should represent B-cell proliferations secondary to EBV infection; however, T-cell and natural killer (NK)–cell PTLDs have also been reported. Penn estimated that 87% of all PTLDs were of B-cell origin, 13% were of T-cell origin, and 0.5% were of null cell origin. [22] PTLDs not associated with EBV have also been reported. A higher proportion of late-developing PTLDs (>2 y posttransplant) are more likely to be non–B-cell related or non-EBV related. Thus, gaps are still recognized in the understanding of the pathogenesis of PTLD.

Although the EB virus can express up to 100 genes, in the posttransplant situation only 9-10 genes are expressed. The EB genome adopts an episomal configuration and expresses proteins such as BCRF1 and BARF1 that help avoid immune detection. The latent membrane proteins LMP1 and LMP2 are believed to act as oncogenes, allowing B cells to escape cell death and proliferate in uncontrolled fashion. In one study, some PTLDs demonstrated mutations in bcl-6, an intracellular protein of the bcl group of proteins that are involved in passive cell death pathways. Polymorphisms in 2 key anti-inflammatory cytokines, IL-10 and tumor growth factor (TGF)-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD. [33] . Expression of latency III genes and XBP1 gene are associated with worse outcomes. [34]

Classification of posttransplant lymphoproliferative disease

Two major different classification schemes for PTLD were previously proposed to compare outcomes and determine prognosis: the World Health Organization (WHO) classification and the Harris classification. [35] Both of these schemes are based on the following characteristics: clinical, histologic, immunologic cell typing, cytogenetic, immunoglobulin gene-rearrangement, and virologic. The classification schemes have common features, including benign hyperplasia or mononucleosis as the mildest form, characterized by maintenance of the nodal architecture; malignant lymphoma, with all the features of malignancy, as the most severe form; and polymorphic or polyclonal proliferations (with nodal architecture destruction and local invasion) classified in the intermediate categories.

Neither system addressed the full range of clinical, virologic, immunologic, and disease markers, and they related poorly to disease prognosis and treatment. A third system, the Ann Arbor staging system, though applied to PTLD, was developed for Hodgkin lymphoma and has limitations in situations with localized intragraft disease, which actually has a good prognosis.

Therefore, more recently an expert multidisciplinary group, of which this author was a member, met in Seville and proposed a new classification. The group proposed to add important clinical and virologic features of PTLD to the 2008 WHO histologic classification system, making the schema more mechanistic and possibly more prognostic. [9]

Depending on the interplay of immunosuppressive effect and B-cell proliferation, patients may develop uncomplicated mononucleosis or polyclonal polymorphic B-cell hyperplasia, both of which depend on continued viral replication. These benign PTLDs can spontaneously resolve (if host immune response to the virus is adequate) and/or respond to antiviral therapy that interrupts the EBV replicative cycle. In some patients, these benign PTLDs may progress to an intermediate stage in which a small subpopulation of malignantly transformed cells is present in a predominantly polyclonal proliferation. This second step may involve a cytogenetic event or selection that confers malignant growth potential on an EBV-infected B cell, thus leading to the outgrowth of a malignant cell or single clone analogous to the pathogenesis of African Burkitt lymphoma.

In some patients, the malignant cell clone may become the dominant proliferating cell type, leading to frank lymphoma. Tsao et al have provided a recent review of the pathological classifications and evolutions. [36]

Much remains to be understood about the factors involved in determining the severity of PTLD in an individual patient.

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Clinical Features

Clinical features of posttransplant lymphoproliferative disease (PTLD) can be multiple, varied, and complex. In many patients, the early symptoms are nonspecific, including fever, malaise, and weight loss. Maintaining a high index of suspicion for PTLD in all transplant recipients is strongly recommended.

The most common presentation is of sudden-onset lymphoid mass swelling, either externally (eg, cervical lymph nodes) or internally (eg, abdominal or intracranial masses). Extranodal tumors are usually more common than nodal tumors. Occasionally, these masses may develop within the graft, such as the kidney or liver. The symptoms are then related to the secondary effects of the tumor, such as abdominal pain, respiratory difficulty, stridor, and seizures. CNS presentation is associated with a poorer prognosis. Extra-abdominal lymph node localization occurs in 10-33% and abdominal lymph node or GI tract localization in 10-29% of cases. [11, 13] CNS localization is rarer, seen in 9-13% of cases, except in the trials of belatacept, in which CNS localization was more frequent.

PTLD may present as a fever of unknown origin in the transplant recipient or may mimic graft rejection, particularly late rejection.

The time to PTLD diagnosis posttransplant can widely vary, ranging from a few months to several years. The mean time in most series is 20-35 months, but this is skewed by the long-range interval. The median times are much shorter, approximately 4-5 months. NAPRTCS data and a report by Alfrey et al show a reduction in median time to PTLD in recent years. [4, 2]

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Diagnosis

The diagnosis of PTLD may often be complicated. Initial studies are often focused on the manifesting symptoms, such as imaging localization of the mass and determination of its extent, invasiveness, and homogenicity. Ultrasonography, CT scanning, or MRI can be used, depending on the area of interest. Pickhardt et al have published an extensive series of reviews of imaging features of PTLD by body segment. [37, 38, 39, 40, 41] CT scanning is preferred for abdominal and chest imaging. Either CT scanning or MRI can be performed for neuroimaging. Bone marrow biopsies are necessary to help define marrow involvement, which may rarely be the only affected tissue. These imaging and biopsy tests may also be repeated after treatment to assess the response.

Concomitant serologic tests (ie, immunoglobulin [Ig] G and IgM) should be performed to determine recent EBV or CMV primary or secondary infection. The sera can also be analyzed for Epstein-Barr–viral capsid antigen (EB-VCA).

Histopathologic diagnosis of biopsy tissue remains the criterion standard for making the diagnosis of PTLD. Using light microscopy, infiltrates of polymorphous or monomorphous mononuclear cells (small lymphocytes and plasma cells) are observed that disrupt the architecture of the invaded tissue, such as the lymph node. Depending on the degree of proliferation and dedifferentiation, lesions may be characterized as hyperplastic, lymphomatous, or intermediate. Abnormal cells may be positive for the B-cell markers CD19, CD20, CD21, or CD22, although not in every patient. Lymphocyte CD20 expression is of value on determining therapy choices. Determination of cell surface heavy and light chain Ig expression allows for classification as polyclonal or monoclonal. Detailed cytogenetic studies may be needed in patients with nuclear changes suggestive of frank malignancy.

EBV can frequently be revealed within the abnormal cells using various methods. Epstein-Barr–encoded RNA can be detected by the Ebstein-Barr early region (EBER) immunostaining assay (see the image below). The EBV latent membrane protein (LMP) can also be identified through immunostaining. Some PTLDs demonstrate Reed-Sternberg–like cells that may cause confusion with Hodgkin disease; CD15 staining is typically positive in true Hodgkin disease and negative in the HD-like condition.

Epstein-Barr viral RNA can be detected by Epstein- Epstein-Barr viral RNA can be detected by Epstein-Barr early region (EBER) assay (dark-blue staining cells) in the abnormal B cells from tumor masses of posttransplant lymphoproliferative disease (PTLD).

PTLD may occur alongside acute rejection, and the diagnoses may be difficult to separate, especially with T-cell PTLD within the allograft. According to Nalesnik, the features that favor the diagnosis of PTLD in such cases include nodular infiltrates, serpiginous necrosis, plasmacytoid and immunoblastic cells, and absence of ancillary cells such as neutrophils. [42]

In an effort to improve the likelihood of successful therapeutic interventions, many investigators have studied methods that may result in early identification of disease in patients at high risk for this disorder. Monoclonal proteins, particularly IgM-related proteins, have been reported to appear with greater frequency in serum and urine of patients with PTLD (71%) than in patients without PTLD (27%). Darenkov et al reported that CD19+ B cells could be detected in the peripheral blood of patients with PTLD but not in those without PTLD, provided no antiviral prophylaxis was used. [43]

Of greater promise are the variations of quantitative or semiquantitative polymerase chain reaction (PCR) techniques to detect EBV viral DNA from the peripheral blood lymphocytes. These techniques measure DNA in blood that can be membrane bound or free. Multiple studies have demonstrated that increased EBV viral loads can be used to differentiate between latent infection and PTLD. Rooney et al showed that levels of EBV DNA between 20,000 and 200,000 copies per microgram of peripheral blood DNA were associated with subsequent PTLD (normal < 2000 copies per microgram). [44]

In a study by Rowe et al, an EBV genomic load greater than 500 copies per 100,000 lymphocytes was associated with PTLD development. [45] Wadowsky et al (2003) have reported that whole blood or peripheral blood mononuclear amplification by competitive reverse transcriptase–PCR gives comparable results but not amplification from plasma. However, different techniques in different labs and different cut-off values between labs prevent standardization of results between those labs.

In pediatric patients, viral load monitoring is associated with high sensitivity but poor specificity. Many pediatric patients exhibit higher viral loads than adults because of a primary EBV infection or a chronic high viral load state without ever developing PTLD. [46] In anecdotal cases, pediatric PTLD lesions that were EBER or LMP stain positive were not associated with a high viral load in peripheral blood. [47] In contrast, Tsai et al reported that in adult transplant recipients, EBV viral load monitoring was associated with a high specificity but low sensitivity, the opposite of what has been reported in children. [48] This may be related to a relatively higher prevalence of non-EBV, T-cell type or late-onset PTLD in adult patients.

Rooney et al reported that, in patients who had received bone marrow transplants, spontaneous outgrowth ex vivo of B cells transformed with EBV from the peripheral blood was associated with PTLD to a very high degree of sensitivity and specificity. [44]

DNA levels may also provide evidence of successful therapy. A drop in viral load after intervention suggests a good response. [49] However, this may not hold true after anti-CD20 antibody, where viral loads may remain high because of release of viral DNA from lysed B cells.

Differential diagnosis

A high index of suspicion for PTLD must be maintained in all transplant recipients. Dharnidharka et al reported several cases of catscratch disease that manifested with fever and lymphadenopathy and resembled PTLD. [27] The diagnosis was suspected after inquiry for cat exposures and was confirmed by (1) serological detection of IgM antibodies to Bartonella henselae and (2) detection of Bartonella species in the lesions by Steiner stain. This condition is often self-limiting in immunocompetent patients and amenable to antimicrobial therapy (sulfamethoxazole-trimethoprim, gentamicin) in immunosuppressed patients. In developing countries, tuberculosis is endemic and also manifests with fever and lymphadenopathy.

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Treatment and Prophylaxis

Treatment

No uniform consensus regarding optimal treatment options for posttransplant lymphoproliferative disease (PTLD) is available. This largely reflects the current multiple gaps in knowledge of this disorder. The American Society of Transplantation and American Society of Transplant Surgeons published an ad hoc joint committee consensus paper on management recommendations; however, they recognized that providing many evidence-based recommendations is impossible. [50] Thus, this paper reflects guidelines only and allows for considerable flexibility. Most centers recommend a staged treatment regimen based on the degree of clonality and aggressiveness. Treatment recommendations may rapidly change with newer understanding of the disease pathogenesis.

Reduction of immunosuppression is the first intervention recommended in most cases and was effective in an early PTLD series by Starzl et al (1984). [51] Most centers reduce the dose of calcineurin inhibitors, and many centers discontinue calcineurin inhibitors entirely if the disease is severe. Many centers also discontinue or reduce mycophenolate or azathioprine. Corticosteroids are usually continued without dosage modification. In mild cases, these steps may be the only interventions required. Graft rejection is an obvious risk but, surprisingly, is not observed in every patient. Immunomodulation by the underlying disease is speculated to prevent the normal alloimmune response in these patients. However, immunosuppression reduction alone seems less effective in all but the mildest PTLD grades in adults.

Anti-CD20 monoclonal antibody has recently been used, with promising results, to neutralize the CD20-expressing B cells. Several small uncontrolled series have documented good success rates (complete or partial remission) in the 60-70% range in polymorphic or polyclonal cases. In some situations, the PTLD lesions may not express CD20; thus, rituximab may not be useful in such cases. This agent has become the second-line therapy at many centers, overtaking the use of interferon-alfa. Some investigators have proposed its use as first-line therapy, but no data has compared rituximab to reduction of immunosuppression head on.

Interferon-alfa is also reported to be efficacious in treatment of PTLD that is unresponsive to immunosuppressive dose reduction alone. Some protocols combine this agent with intravenous IG (IVIG) or CMV-specific Ig. Because of a higher prevalence of acute rejection episodes after interferon use, this agent is less commonly used.

The role of antiviral drugs in treatment of PTLD is controversial. Acyclovir and ganciclovir are effective against replicating the virus but are reportedly not effective against latent EBV, which is the predominant form of EBV in PTLD. However, a few virions entering the lytic cycle are possible, and antiviral agents may eliminate these virions. Many centers thus add antiviral therapy to their regimens to eliminate any replicating virus that may be present. The expression of Z EBV replication activator (ZEBRA) in PTLD tumors suggests lytic cycle replication is ongoing. [52]

Standard cancer chemotherapy is reserved for patients with definitive features of malignancy. The usual regimen used has been the cyclophosphamide, doxorubicin (Adriamycin or doxorubicin hydrochloride), vincristine (Oncovin), and prednisone (CHOP) regimen used for non-Hodgkin lymphoma. Gross et al have used a modified CHOP protocol with lower doses of cyclophosphamide to prevent toxicity. [53] More recently, Trappe et al (2007) have shown that sequential use of chemotherapy when rituximab has failed (and vice versa) can be effective. [54, 55]

A sequential approach to immunosuppression reduction, followed by rituximab and CHOP chemotherapy, preserved the glomerular filtration rate (GFR) in kidney transplant recipients with PTLD. [56] This regimen has shown consistently good results in a larger recently published international trial. [57]

Another possible chemotherapy regimen that allowed for total discontinuation of immunosuppression in a small pediatric series incorporated fludarabine, cyclophosphamide, doxorubicin, and rituximab. [58]

Newer agents that have been tried in non-Hodgkin lymphoma but not tried yet in PTLD include radio-conjugated anti-CD20 antibodies such as tositumomab (anti-CD20 tagged to I131) and ibritumomab (anti-CD20 tagged to Y90). Resveratrol has shown some promise in in vitro models. [59]

Prognosis

The prognosis of PTLD widely varies. Most mild cases regress, but graft rejection may occur (reported rates vary widely from 10-60%). The outlook for more severe cases is less favorable, particularly in frank malignancies or CNS PTLD. Although individual centers with high PTLD rates report good patient and graft survival rates, multicentered registry data suggest somewhat poorer graft survival outcomes. Non-EBV positive or late onset cases have a poorer prognosis. Children generally have a better prognosis. More recent cases of PTLD have a better prognosis than those from older eras. [60] A prognostic score specific to PTLD has been developed in France. [61]

In cases in which graft loss occurs, retransplantation has been successfully performed. Johnson et al (2006) published a large national registry series of retransplants after PTLD. [62] PTLD recurrence in the repeat transplant has not been reported.

Prophylaxis

With the role of EBV and CMV infections in the development of PTLD now established, attention has recently turned toward prevention of these infections posttransplant in an effort to reduce prevalence of PTLD. Prevention can be primary or secondary.

Primary prevention includes the following: (1) antiviral vaccine, (2) immunization minimization to prevent infection, (3) immunoprophylaxis via intravenous immunoglobulin preparations, and (4) chemoprophylaxis via antiviral drugs.

Immunization

A gp350 glycoprotein–based EBV vaccine has been in trials. In healthy adults, the vaccine reduced symptomatic primary EBV infection but had little effect on EBV seroconversion rates. [63, 64] Results in patients awaiting organ transplant have not been reported.

Chemoprophylaxis and immunoprophylaxis

Ganciclovir and acyclovir are antiviral agents that have demonstrated efficacy against EBV and CMV. Davis et al reported in a retrospective analysis that the prevalence of PTLD appeared to be lower with the use of concomitant antiviral therapy (ie, initially IV ganciclovir, then oral acyclovir) in adult transplant recipients. [65]

Darenkov et al conducted a prospective trial of prophylactic antiviral agent use during antilymphocyte antibody administration to adult transplant patients. [43] Using acyclovir if both donor and recipient were CMV seronegative or ganciclovir if either were seropositive, prevalence of PTLD dropped to 0.5% in their study group, compared with 3.9% in historical controls. However, Green et al were unable to document any change in PTLD prevalence in a prospective trial utilizing acyclovir. [66] In their study, initial intravenous ganciclovir followed by prolonged oral acyclovir was associated with a trend towards increased PTLD and significantly higher CMV incidence. Similarly, CMV-Ig did not have any impact on EBV infection rate or PTLD rate. [67] In contrast, a large 2007 retrospective registry analysis by Opelz et al suggested a significant benefit to IVIG or CMV-specific Ig. [68]

Funch et al performed a large retrospective case-control analysis that showed that ganciclovir was associated with a significant reduction in the odds ratio for PTLD (0.62; 95% CI, 0.38-1.0). [69] Acyclovir was associated with a lower and nonsignificant reduction. The addition of IVIG to ganciclovir did not further reduce the PTLD rate. [70]

The newer oral agents, valacyclovir and valganciclovir, have greater bioavailability but have not been tested for PTLD prevalence reduction, although many centers now routinely use valganciclovir for prophylaxis. A recently published study demonstrated that oral valganciclovir is not inferior to intravenous ganciclovir for the treatment of CMV disease. [71]

Preemptive interventions

Using routine viral load monitoring and preemptive therapy, several studies have shown a reduction in PTLD prevalence based on historical controls, particularly in the pediatric liver transplant population. [5, 43, 65] These results have led many centers to perform routine viral load monitoring, particularly for preemptive interventions. These interventions have included reduction in immunosuppression or initiation of antiviral therapy when a significant rise in EB viral load occurs. To date, no prospective clinical trials have been performed to confirm these results, but these types of studies are difficult to perform. The hypothesis that early detection leads to improved outcome remains also remains to be confirmed. Wagner et al have suggested that prompt intervention rather than preemptive intervention may be a better strategy in combination with viral load monitoring. [72]

Viral load monitoring provides evidence of EBV-infected B-cell proliferation but does not provide information about the host T-cell response. Studies of EBV-specific T-cell counts or cytotoxic T-cell assays may add further information to EBV viral loads. [73] . The serum levels of the B-cell homing chemokine CXCL13 have been shown in a recent study to be elevated to greater degree in frank PTLD versus EBV reactivation. The serum CXCL13 levels also correlated with response to treatment and may thus serve as a useful surrogate marker if validated in further studies. [74]

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Summary and Future Directions

Posttransplant lymphoproliferative disease (PTLD) is a complex and puzzling entity that is now a significant complication of solid organ transplantation. Prevalence is still rising in many centers, and the outlook varies. Etiology is related to EBV infection of B cells, which cannot be controlled by cytotoxic T cells because of external immunosuppression that is required to prevent graft rejection. Clinical features can vary. Lymphoid masses are the most common manifesting features. Imaging and serologic tests provide supportive data, but histopathology is required for a definitive diagnosis. Treatment options include reduction of immunosuppression, anti-CD20 monoclonal antibody, alpha-interferon, and chemotherapy. Antiviral prophylaxis and early detection measures now are being used to prevent the disease and improve outcome.

The Seville multidisciplinary panel [9] made several recommendations for the future, as follows:

  • All transplantation trials should report if PTLD occurred or not and should report the incidence with a denominator of follow-up time that allows cross-study comparisons.
  • All prospective transplantation trials should collect and report the prophylactic or preemptive antiviral regimens planned and actually used in each subject.
  • Transplant registries should include a new data field indicating whether patients were enrolled in clinical trials. If yes, the clinical trial number and, if appropriate, the randomization arm, should be recorded. Such data then could be matched with a common clinical trials registration platform (eg, www.clinicaltrials.gov) to permit long term (5- to 10-y) safety assessments in transplantation patients, not just for PTLD but also for other morbidities.
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