WORKUP	Section 5 of 11
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Lab Studies:

• Rooney et al (1995) investigated methods that could be used for early identification of PTLD and, therefore, earlier and more successful treatment in patients receiving bone marrow transplant. They postulated that spontaneous outgrowth of EBV-positive peripheral blood mononuclear cells in culture would be associated reliably with the development of disseminated lymphoproliferative disease. Additionally, they looked at the relationship between EBV DNA levels in peripheral blood lymphocytes and disease onset.

• They were able to demonstrate that the ability of EBV-infected peripheral blood lymphocytes to grow out rapidly in culture showed a 100% correlation with the emergence of lymphoproliferative disease. Outgrowth was detectable several weeks before the disease was apparent clinically.

• They concluded that large numbers of EBV-transformed B cells are likely to circulate in the blood prior to disease onset. They also deemed that measurement of EBV DNA levels in the peripheral blood appeared to be a useful marker for those patients at high risk of development of PTLD.

• These factors alone, or in combination, potentially are potent predictors of patients at high risk for the development of PTLD. Positive results would prompt early therapeutic intervention. The authors sampled peripheral blood every 1-2 months after bone marrow transplantation but suggested that more frequent sampling would be more informative.

• The EBV status of the recipient usually is established pretransplantation. Donor EBV status is not always sought routinely because the incidence of infection with EBV in the general population is so high.

• In primary EBV infection, EBV viral capsid antigen (VCA) immunoglobulin M (IgM) titers are elevated. Reactivation of EBV infection is characterized by more than a 4-fold rise in EBV VCA immunoglobulin G (IgG) titers, compared with previously recorded EBV VCA IgG titers. No change in titer suggests past infection.

• These tests can be performed as part of a PTLD workup. Elevated titers of antibodies to VCA have been identified in recipients of solid organ grafts who developed PTLD. Note that absence of change in EBV antibody titers does not exclude a diagnosis of PTLD. However, increases in EBV viral load in the peripheral blood have been detected in patients prior to the onset of lymphoproliferative disease, and a decrease in these levels has occurred following effective treatment of PTLD. EBV viral load can be monitored by means of polymerase chain reaction (PCR).

• Evaluation of tumor for the presence of EBV is very important. Nondetection of EBV is associated with tumors that present late, usually are monoclonal, and are more resistant to treatment. They are more likely to be disseminated and are less likely to achieve complete remission. T-cell PTLD usually is not associated with EBV infection and does not respond to immunosuppression dose reduction. It carries an unfavorable prognosis. Polyclonal lesions, however, have a more favorable prognosis. They, unlike monoclonal lesions, tend to occur early and are responsive to reduction of immunosuppression. Primary CNS involvement is associated with significantly higher mortality rates, 88% at 6 months in one study. CNS disease requires intrathecal therapy or localized radiation therapy because intravenous chemotherapy and monoclonal antibodies do not cross the blood-brain barrier adequately.

• Lactate dehydrogenase (LDH) measurements in LeBlond's (2001) series did not correlate with survival data. High levels of LDH simply may represent cell turnover, as opposed to being a marker of tumor load. However, if elevated, LDH levels may be useful in following disease progression or regression.

Imaging Studies:

• Radiological evaluation includes computerized tomography scan of chest, abdomen, pelvis, and head, looking for evidence of hepatosplenomegaly, lymphadenopathy, or abnormal mass.

Other Tests:

• In addition to a high degree of vigilance in the appropriate clinical setting, histological confirmation of lymphoproliferation is mandatory. It also requires demonstration of the presence of EBV DNA, RNA, or protein in the biopsied tissue. Histopathologically, the lesion may demonstrate plasmacytic hyperplasia, B-cell hyperplasia, B-cell lymphoma, or immunoblastic lymphoma. Immunohistologic staining can be used to confirm the presence of EBV. In situ hybridization with the EBV-encoded RNA (Epstein-Barr early region [EBER]-1) probe (labels EBV-encoded RNA in infected cells) is a reliable means of detecting EBV in tissue. EBV viral load in the peripheral blood can be determined using PCR. High viral loads have been found in a high proportion of patients with PTLD, but a high EBV viral titre is not diagnostic. This test is not standardized, and not all patients with PTLD have a high viral load.

Procedures:

• Obtaining bone marrow aspirate and biopsy is appropriate to determine if marrow is involved in the disease process. If a suspicion of CNS or neurological involvement exists, lumbar puncture should be performed for cerebrospinal fluid evaluation. In addition to the standard tests, the fluid should be analyzed using PCR for EBV DNA.

• Establishing the clonality of the lesion is important. Tumors can be monoclonal, oligoclonal, polyclonal, or mixed. Some lymphomas may appear polyclonal by surface immunoglobulin staining but are monoclonal by immunoglobulin rearrangement. Reports of patients with multiple disease sites, one lesion of which was monoclonal while a distant lesion was polyclonal, have occurred. Monoclonal PTLD has a worse prognosis, so multiple biopsy sites may be useful in defining prognosis in an individual with more than one lesion. Do not assume that if one site is polyclonal, all disease sites are polyclonal. PTLD does not demonstrate the 8;14 or 8;22 translocations associated with Burkitt lymphoma. PTLD cannot be differentiated into benign or malignant tumors. The mortality rate is high, independent of histology. With regard to T-cell lymphoproliferative disorders, these lesions predominantly are monoclonal.

Histologic Findings: Knowles et al (1995) have classified PTLD into the following 3 distinct categories: (1) plasmacytic hyperplasia, which arises most commonly in the oropharynx or lymph nodes and nearly always is polyclonal, with a lack of oncogene or tumor suppressor gene alteration; (2) polymorphic B-cell hyperplasia and polymorphic B-cell lymphoma, which can be nodal or extranodal, nearly always are monoclonal, usually contain a single form of EBV, and lack oncogene or tumor suppressor gene alteration; and (3) immunoblastic lymphoma with widely disseminated disease, which is monoclonal, contains a single form of EBV, and contains alterations of 1 or more the oncogene or tumor suppressor genes.

	TREATMENT	Section 6 of 11
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Medical Care: Starzl et al (1984) were the first to suggest reduction, or withdrawal, of immunosuppression as a treatment option for PTLD. This serves to allow the patient's natural immunity to recover and gain control over proliferating EBV-infected cells. Most patients with more benign PTLD respond well to this management approach. People with more malignant disease often respond inadequately to these measures, and more aggressive treatment is necessary.

Reduction or withdrawal of immunosuppression is the cornerstone for the treatment of EBV-driven B-cell PTLD, independent of histology, but the role and timing of other therapeutic modalities is less clear. Comparative data to evaluate these treatment options are deficient, and many reports are anecdotal. In patients who underwent solid organ transplant, a balance must be sought between reduction of immunosuppression and the risk of allograft rejection. In allogeneic bone marrow transplantation, graft versus host disease is a critical concern. This approach has resulted in complete and lasting resolution of the tumor in some cases. Additional measures that have been used include surgical excision of the lesion (which can be curative in cases of localized disease), antiviral therapy, radiation therapy and chemotherapy, alfa interferon, intravenous gamma globulin, cytotoxic T lymphocytes, and monoclonal antibodies, each with varying degrees of success.

In Cohen's (1991) review, two thirds of transplant recipients with PTLD whose cases were managed with reduction of immunosuppression survived, compared with an overall survival rate of 31%. Benkerrou et al (1998) reported complete regression in 40% of patients after reduction or discontinuation of immunosuppressive therapy. Polyclonal lesions have a favorable prognosis. They, unlike monoclonal lesions, tend to occur early and are responsive to reduction of immunosuppression. A reduction in immunosuppressive therapy is not effective for CNS PTLD. Primary CNS involvement is associated with significantly higher mortality rates, 88% at 6 months in one study. CNS disease requires intrathecal therapy because intravenous chemotherapy and monoclonal antibodies do not cross the blood-brain barrier adequately. T-cell PTLD usually is not associated with EBV infection and does not respond to immunosuppression dose reduction.

The use of acyclovir for treatment of PTLD generally has been reported as not being of significant value. Acyclovir and ganciclovir both inhibit lytic EBV DNA replication in vitro. Ganciclovir is approximately 10 times more potent than acyclovir. However, the majority of EBV-infected cells in lymphoproliferative lesions are transformed B cells. Acyclovir inhibits the replication of linear EBV DNA and is ineffective against episomal EBV DNA, which is the conformation of the EBV genome in latent B lymphocytes, and so does not prevent their proliferation.

Srivastava et al (1999) report treatment of PTLD in a group of 84 pediatric renal transplant recipients. These patients all received intense immunosuppression with antilymphocyte globulin/antilymphocyte globulin, methylprednisolone, cyclosporine, and mycophenolate mofetil or azathioprine, thus rendering them at high risk for development of PTLD. All additionally had received prophylactic acyclovir. Treatment involved reduced immunosuppression and ganciclovir/acyclovir. Chemotherapy was used in 1 patient and hyperimmune globulin in 2 patients resistant to first-line treatment. The PTLD resolved in all patients, and allograft function was universally preserved. Authors concluded that reduction of immunosuppression plus antiviral therapy is adequate treatment for PTLD in the majority of patients.

One group demonstrated acyclovir, in addition to reduction of immunosuppression, to be effective in the treatment of a polyclonal B-cell lymphoma, with dramatic regression of both patient symptoms and objective disease. The reduction in immunosuppression was suggested to assist in maintenance of the remission. However, one patient experienced an episode of allograft rejection 2 months later, which required treatment with steroids. Within 1 month, the PTLD had recurred. On this occasion, no regression of the tumor occurred in response to acyclovir.

Interferon alfa has been effective in the treatment of B-cell PTLD in some patients. 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 are anecdotal.

Faro et al (1996) report the case of an 11-year-old boy who is EBV seronegative with emphysema of unknown etiology and who underwent double lung transplantation from a donor who is EBV seropositive. He developed PTLD following treatment of an episode of severe rejection. Initial management was unsuccessful with reduction of immunosuppression and acyclovir therapy. Subsequent treatment with interferon alfa for a period of 9 months led to dramatic clinical and histologic improvement, with no evidence of recurrence of PTLD at 18 months.

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. Faro also reported in the same study that interferon alfa therapy significantly decreased the levels of IL-4 and IL-10 messenger RNA (mRNA), which had been noted prior to interferon therapy to be markedly elevated in bronchoalveolar lavage cells. The reduction in these cytokines correlated with the patient's improvement.

Shapiro et al (1988) describe 5 patients with monoclonal and polyclonal PTLD who were treated with interferon alfa and intravenous gamma globulin with good response. O'Brien and colleagues (1997) report a case of monoclonal nodal PTLD in a renal transplant recipient who did not respond to reduction in immunosuppression, acyclovir therapy, or intravenous immunoglobulin. The patient then was treated for a period of 3 months with subcutaneous injections of interferon alfa 3 times a week with good response and remained in remission 12 months after treatment.

Intravenous immunoglobulin has been used as adjunctive therapy in the management of PTLD. Deficiency or absence of antibody against one of the EBNAs in patients posttransplantation 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 EBNAs. These 2 factors provide the rationale for the use of intravenous immunoglobulin in the management of PTLD. It has been used mainly in combination with interferon alfa.

A high mortality rate has been associated with the use of chemotherapy in the management of transplant-associated lymphoproliferative disease. In Cohen's (1991) review of the value of chemotherapy and radiotherapy for the treatment of PTLD in transplant recipients, neither chemotherapy nor radiotherapy demonstrated any survival advantage compared with overall survival rates of 31%. In fact, survival rates were worse, at 23% and 20%, respectively.

Swinnen et al (1995), however, report a retrospective study of 19 cardiac transplant recipients with PTLD who initially were treated with reduced immunosuppression and acyclovir. The patients had all received OKT3 (ie, monoclonal anti–T-cell antibody) as part of their immunosuppressive regimen. A statistically significant reciprocal relationship exists between the dose of OKT3 used and time interval between transplantation and the onset of PTLD.

Six of the patients had polyclonal disease, and 13 had monoclonal. A large proportion of these patients presented early posttransplantation with diffuse and aggressive disease. Those who survived and did not respond to initial management were treated with the combination chemotherapeutic regimen ProMACE-CytaBOM (prednisone, Adriamycin, Cytoxan, etoposide, arabinoside cytosine, bleomycin, Oncovin, and methotrexate). Of the 8 patients who received chemotherapy, all had monoclonal disease. This regimen was felt to be adequately immunosuppressive to obviate the need to continue with other immunosuppressive agents during chemotherapy, and no episodes of graft rejection occurred. Seventy five percent of patients achieved a complete remission, and no cases of relapse occurred at 38 months.

The CHOP combination (cyclophosphamide, Adriamycin, Oncovin, and prednisone) has been used with high remission rates in cardiac transplant patients. However, the dose of doxorubicin in ProMACE-CytaBOM is half that used in CHOP, making ProMACE-CytaBOM less cardiotoxic and a more attractive therapeutic regimen. Although not used frequently now, ProMACE-CytaBOM also was effective for the treatment for non-Hodgkin lymphoma.

Anti-CD21 and anti-CD24 monoclonal antibodies have been used to treat PTLD following bone marrow and solid organ transplantation. Leblond et al (1995), in a single center study, used anti–B-cell monoclonal antibodies, in addition to reduction of immunosuppression, in a series of 12 patients with PTLD. Four of 7 patients with monoclonal lesions and 4 of 5 patients with polyclonal PTLD achieved a complete remission.

Anti–B-cell antibodies were used by Fischer (1991) in 26 patients following bone marrow and solid organ transplantation. They received anti-CD21 and anti-CD24 monoclonal antibodies for a period of 10 consecutive days. Treatment was well tolerated, aside from transient neutropenia (granulocytes express CD24 molecules). Complete remission was achieved in patients who had oligoclonal lesions not involving the CNS. Patients with monoclonal lesions or CNS lesions either did not respond in the case of the former or relapsed in the case of the latter. The authors concluded that anti–B-cell antibodies could be effective treatment for severe, diffuse oligoclonal lesions confined outside the CNS.

Benkerrou et al (1998) reported the long-term outcome of severe, aggressive PTLD following bone marrow and solid organ transplantation treated with the same B-cell antibodies as Fischer (1991). Eligibility criteria included lymphoproliferations not responsive to reduction in immunosuppression or rapidly progressive disease. Complete remission was achieved in 61% of patients, with a relapse rate of 8%. The overall long-term survival rate was of the order of 46% at 61 months, although survival rates were lower among bone marrow transplant recipients (35%) compared with solid organ transplant patients (55%). They also identified as poor prognostic markers multivisceral disease, CNS involvement, and late-onset PTLD, which are findings that are consistent with results published by other authors.

Rituximab is a new anti-CD20 monoclonal antibody, which has been used to treat non-Hodgkin lymphoma. Milpied et al (2000) in France reported promising results, with response rates of 65%, in patients with PTLD treated with rituximab following solid organ transplantation.

PTLD associated with EBV infection in bone marrow transplant recipients usually presents as B-cell lymphoma of donor origin, which often is aggressive, progressive, and fatal. Chemotherapy and radiation therapy are not effective. Papadopoulous et al (1994) postulated that the use of donor-leukocyte infusions might treat PTLD effectively in the allograft recipient. They based this hypothesis on the premise that the donor has cytotoxic T lymphocytes, which are presensitized to the EBV responsible for the lymphoproliferation in the recipient—the EBV being donor in origin. They studied 5 patients who developed malignant B-cell lymphoma after receiving T-cell depleted allogeneic bone marrow transplantation. EBV DNA was detected in each tissue sample. All patients achieved complete clinical and pathological remission in response to unirradiated infusions of donor leukocytes.

The EBV-specific cytotoxic T lymphocytes from the donor, in the case of bone marrow transplantation, have the capability of recognizing and destroying EBV-infected B cells in the recipient. Solid organ transplant patients, however, develop PTLD that can be recipient or donor in origin, which in each case would have to be determined before initiation of treatment. In the case of PTLD that is recipient in origin, to obtain cytotoxic T lymphocytes the recipient's T cells would need to be stimulated against EBV ex vivo—technology that is not yet available.

Strategies to prevent EBV infection posttransplantation also may be considered. Prophylactic measures may include screening of donors and recipients for baseline EBV data, risk stratification, and using grafts from donors who are EBV seronegative where possible for seronegative recipients. EBV may be transmitted in blood transfusions, so the use of leukocyte filters may reduce the risk of EBV transmission from blood products. The use of routine acyclovir as prophylaxis is felt to be largely ineffective, as reported by Trigg et al (1985) and others.

Darenkov et al (1997) reported a dramatic reduction in the incidence of PTLD in high-risk patients treated with antilymphocyte globulin when prophylactic therapy was administered in the form of ganciclovir (if donor/recipient were cytomegalovirus [CMV] positive) or acyclovir (if CMV negative) during anti–lymphocyte antibody therapy. Davis et al (1995) looked at the benefit of antiviral prophylaxis (intravenous ganciclovir followed by high-dose oral acyclovir) in kidney-pancreas and liver allograft recipients, again in the context of the use of antilymphocyte globulin. They found that the incidence of PTLD was lower with prophylactic antiviral treatment.

Birkeland et al (1999) reported that primary or reactivated EBV infection correlated with acute graft rejection and the incidence of PTLD. They additionally found that the use of acyclovir (3200 mg/d for 3 mo posttransplantation) was protective against primary or reactivated EBV infection and that the addition of mycophenolate mofetil resulted in further reduction of infection or reactivation. These patients also had been treated with antilymphocyte globulin. Serial monitoring of EBV viral load may be beneficial in the recognition of early PTLD and could be used to prevent progression with the introduction of preemptive therapy.

Surgical Care: In addition to boosting the immune system by reducing immunosuppression, surgical resection or the use of localized radiation therapy has been of value in some patients with PTLD. For a lesion that is focal, this approach may be curative. Surgical management or focal radiation therapy is useful, especially for the treatment of localized complications of the disease. In Cohen's (1991) review, survival rates of the order of 74% were noted for patients treated by surgical excision of the lesion, compared with an overall survival rate of 31%. Field radiation therapy now is felt to be the most effective treatment for PTLD involving the CNS.

	MEDICATION	Section 7 of 11
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Numerous treatment options for PTLD exist. The general consensus is that immunosuppression should be reduced, or withdrawn, in the first instance; however, no strict guidelines exist for this process. The issue of which drug to withdraw or which drug to dose reduce is still an individual decision for the clinician. The aim is to achieve balance—to improve immune function to gain remission from lymphoproliferation while at the same time preserving the allograft. Many immunosuppressive drug combinations and permutations are used in practice, adding to the complexity. Reducing immunosuppression depends to a large degree on the allograft in question. In the case of renal transplantation, an option to cut the immunosuppression significantly or withdraw it altogether is available. If allograft rejection or failure ensues, an adequate form of replacement therapy is available. In the case of heart transplantation, serious allograft rejection and/or failure likely heralds patient demise.

Other treatment options already have been discussed (see Treatment). The second line of treatment varies, and the dose/duration of treatment depends on patient weight, response, complications, tolerance of treatment, and so forth. Bearing in mind that PTLD is an umbrella term that encompasses a wide spectrum of lymphoproliferative diseases, management of PTLD has to be tailored to the needs of the individual patient. Details provided regarding the medications below are to be regarded as general information. Doses or treatment durations provided here are not necessarily those utilized in the management of PTLD. Much of the information provided pertains to treatment of disease entities remote from PTLD. Many of these drugs have been used experimentally for the purpose of treating lymphoproliferative disease, and reports of their efficacy largely are anecdotal.

Drug Category: Immunosuppressive agents -- Inhibit key factors that mediate immune reactions, which in turn decrease inflammatory responses.

Drug Name	Cyclosporine (Sandimmune, Neoral) -- Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs. For children and adults, base dosing on ideal body weight.
Adult Dose	Initial PO dose: 14-18 mg/kg/d 4-12 h before organ transplantation Maintenance PO dose: 5-15 mg/kg/d qd or divided bid Initial IV dose: 5-6 mg/kg qd 4-12 h prior to organ transplantation Maintenance IV dose: 2-10 mg/kg/d divided q8-12h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because it may increase risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Drug Name	Tacrolimus (Prograf) -- Suppresses humoral immunity (T-lymphocyte) activity.
Adult Dose	0.15-0.3 mg/kg/d PO divided bid 0.05 mg/kg/d IV
Pediatric Dose	0.3 mg/kg/d PO 0.1 mg/kg/d IV
Contraindications	Documented hypersensitivity
Interactions	Tacrolimus levels may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, and clarithromycin; tacrolimus levels may reduce with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not administer simultaneously with cyclosporine; tonic clonic seizures may occur

Drug Name	Mycophenolate (CellCept) -- Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.
Adult Dose	1 g PO bid
Pediatric Dose	Not established; 15-23 mg/kg PO bid suggested
Contraindications	Documented hypersensitivity
Interactions	May elevate levels of acyclovir and ganciclovir; antacids and cholestyramine decrease absorption (do not coadminister); probenecid may increase levels of mycophenolate; salicylates may increase toxicity of mycophenolate
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk for infection; increases toxicity in patients with renal impairment; caution in active peptic ulcer disease

Drug Name	Prednisone (Deltasone, Orasone, Meticorten, Sterapred) -- Used as an immunosuppressive, anti-inflammatory agent and also as a component of both CHOP and ProMACE-CytaBOM chemotherapeutic regimens, which have been used to treat PTLD. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.
Adult Dose	5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI tract disease
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with use

Drug Category: Antiviral agents -- Nucleoside analogs initially are phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate. These molecules inhibit herpes simplex virus (HSV) polymerase with 30-50 times the potency of human alpha-DNA polymerase.

Drug Name	Acyclovir (Zovirax) -- Inhibits activity of both HSV-1 and HSV-2. Has affinity for viral thymidine kinase and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase. Routinely used to treat infections with HSV, mainly HSV-1 and HSV-2. EBV also is a herpes virus, but its use as prophylaxis against and treatment for EBV-related illness posttransplantation is controversial. If used for these purposes, doses and duration of treatment are variable and are determined by the clinician.
Adult Dose	5 mg/kg/dose IV q8h or 750 mg/m2/d divided q8h for HSV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Concomitant use of probenecid or zidovudine prolongs half-life and increases CNS toxicity of acyclovir
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure or when using nephrotoxic drugs

Drug Name	Ganciclovir (Cytovene) -- Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo. Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly due to preferential phosphorylation of ganciclovir in virus-infected cells. For patients who experience progression of CMV retinitis while receiving a maintenance treatment with either dosage form of ganciclovir, the re-induction regimen should be administered.
Adult Dose	1 g PO tid with food for prevention of CMV disease in patients with advanced HIV infection and normal renal function
Pediatric Dose	<3 months: Not established >3 months: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Concomitant administration with cytotoxic drugs (eg, dapsone, vinblastine, doxorubicin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim and sulfamethoxazole combinations) or other nucleoside analogs may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); coadministration with imipenem and cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine may increase following concurrent use of ganciclovir with either cyclosporine or amphotericin B; in the presence of probenecid, ganciclovir renal clearance is reduced; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously with ganciclovir; bioavailability of ganciclovir may decrease in the presence of zidovudine, while bioavailability of zidovudine is increased in the presence of ganciclovir
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Clinical toxicity of ganciclovir includes granulocytopenia, anemia, and thrombocytopenia; because PO ganciclovir is associated with a higher rate of CMV retinitis progression compared to IV formulation, use only when benefits outweigh risks (advanced HIV disease); half-life and plasma/serum concentrations of ganciclovir may be increased as a result of reduced renal clearance; doses >6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at site of IV infusion despite further dilution in IV fluids; adequate hydration should accompany administration of ganciclovir; photosensitization (photoallergy or phototoxicity) may occur

Drug Category: Immunomodulator agents -- Rituximab (anti-CD20 monoclonal antibody) has been used primarily in the treatment of lymphoma; however, it has been reported to have successfully treated PTLD in some patients. Other monoclonal antibodies, such as anti-CD21, CD24, and anti-CD3 (OKT3), also have been used successfully for treatment of PTLD. Interferon alfa also has been used in the treatment of PTLD.

Drug Name	Rituximab (Rituxan) -- Antibody genetically engineered. Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of normal and malignant B-lymphocytes. Antibody is an IgG1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.
Adult Dose	375 mg/m2/wk IV for 4 doses (on days 1, 8, 15, and 22)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hypotension, bronchospasm, and angioedema may occur; discontinue treatment if life-threatening cardiac arrhythmias occur

Drug Name	Immune globulin intravenous (Gamimune, Gammagard S/D, Sandoglobulin) -- Neutralizes circulating myelin antibodies through anti-idiotypic antibodies. Down-regulates proinflammatory cytokines, including INF-gamma. Blocks Fc receptors on macrophages. Suppresses inducer T and B cells and augments suppressor T cells. Blocks complement cascade. Promotes remyelination. May increase CSF IgG (10%).
Adult Dose	2 g/kg IV over 2-5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; IgA deficiency; anti-IgE/IgG antibodies
Interactions	Increases toxicity of live virus vaccine (MMR); do not administer within 3 mo of vaccine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Check serum IgA before IVIG (use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; infusions may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; laboratory result changes associated with infusions include elevated antiviral or antibacterial antibody titers for 1 mo, 6-fold increase in ESR for 2-3 wk, and apparent hyponatremia

Drug Name	Interferon alfa-2b (Intron A) -- Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity is not understood clearly; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. Doses and duration of treatment are as determined by the involved clinicians.
Adult Dose	5 million U/d IM/SC or 10 million U IM/SC 3 times per wk for 16 wk; reduce dose by 50% if severe reactions occur or temporarily discontinue therapy until symptoms from adverse reactions improve
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; patients who have anaphylactic sensitivity to mouse immunoglobulin (IgG), egg protein, or neomycin; autoimmune hepatitis
Interactions	Potential risk of renal failure when administered concurrently with IL-2; theophylline may increase interferon alfa toxicity by reducing clearance; cimetidine may increase antitumor effects of interferon alfa; zidovudine and vinblastine may increase toxicity of interferon alfa
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage is reported in association with alfa interferon therapy; prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if patient does not respond within 6 mo, discontinue treatment; if response occurs, continue treatment until no further improvement is observed; whether continued treatment after that time is beneficial is unknown

Drug Category: Antineoplastic agents -- Disrupt DNA replication or cell division, thereby inhibiting cell growth and proliferation.

Drug Name	Cyclophosphamide (Cytoxan, Neosar) -- Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Component of CHOP and ProMACE-CytaBOM chemotherapeutic regimens.
Adult Dose	50-100 mg/m2/d PO or 400-1000 mg/m2 PO in divided doses over 4-5 d 400-1800 mg/m2 (30-40 mg/kg) IV in divided doses over 2-5 d; may repeat at 2- to 4-wk intervals; alternatively, administer 10-15 mg/kg IV q7-10d or 3-5 mg/kg bid
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Name	Doxorubicin (Adriamycin, Rubex) -- Inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can, in turn, inhibit the growth of neoplastic cells. Component of CHOP and ProMACE-CytaBOM chemotherapeutic regimens.
Adult Dose	60-75 mg/m2 IV as a single dose; repeat q21d; alternatively, 20-30 g/m2/d for 2-3 d; repeat in 4 wk
Pediatric Dose	35-75 mg/m2 IV as a single dose; repeat q21d; alternatively, 20-30 mg/m2/wk
Contraindications	Documented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; preexisting myelosuppression
Interactions	May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels of doxorubicin; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity of doxorubicin; cyclophosphamide increases cardiac toxicity of doxorubicin
Pregnancy	D - Unsafe in pregnancy
Precautions	Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in patients with impaired hepatic function

Drug Name	Vincristine (Oncovin, Vincasar PFS) -- Mechanism of action is uncertain. May involve a decrease in reticuloendothelial cell function or an increase in platelet production. However, neither of these mechanisms would fully explain the effect in TTP and HUS. Component of CHOP and ProMACE-CytaBOM chemotherapeutic regimens.
Adult Dose	2 mg IV push
Pediatric Dose	1.4 mg/m2 IV push; not to exceed 2 mg
Contraindications	Documented hypersensitivity; IT administration (may be fatal)
Interactions	Acute pulmonary reaction may occur when taken concurrently with mitomycin-C; asparaginase, CYP450 3A4 inhibitors (eg, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir), GM-CSF (eg, sargramostim, filgrastim), or nifedipine increase toxicity; CYP450 3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in severe cardiopulmonary disease, hepatic impairment (adjust dose), or preexisting neuromuscular dysfunction

Drug Name	Etoposide (Toposar, VePesid) -- Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of the cell cycle. Component of ProMACE-CytaBOM regimen.
Adult Dose	100 mg/m2 IV on days 1-5
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IT administration (may cause death)
Interactions	May prolong the effects of warfarin and increase the clearance of methotrexate; cyclosporine and etoposide have additive effects in cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Bleeding and severe myelosuppression may occur

Drug Name	Bleomycin (Blenoxane) -- Glycopeptide antibiotic that inhibits DNA synthesis. For palliative measure in the management of several neoplasms. Component of ProMACE-CytaBOM regimen.
Adult Dose	0.25-0.5 U/kg (10-20 U/m2) IV/IM/SC 1-2 times per wk; reconstitute the 15-U vial with 1-5 mL of sterile water or NS for injection
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; significant renal function impairment; compromised pulmonary function
Interactions	May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity of bleomycin when administered systemically
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; vasoocclusive phenomenon with distal necrosis of digit; permanent damage to nail matrix may occur

Drug Name	Methotrexate (Folex PFS, Rheumatrex) -- Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction in malignant cells. Satisfactory response observed 3-6 wk following administration. Adjust dose gradually to attain satisfactory response. Component of ProMACE-CytaBOM regimen.
Adult Dose	30-40 mg/m2/wk PO/IV/IM up to 100-7500 mg/m2 with leucovorin rescue
Pediatric Dose	7.5-30 mg/m2/wk PO/IM 10-12,000 mg/m2 IV bolus or continuous infusion over 6-42 h q2wk
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
Interactions	Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; probenecid, NSAIDs, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, can increase MTX plasma levels; may decrease phenytoin plasma levels; may increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor CBCs monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occur; fatal reactions reported when administered concurrently with NSAIDs

	FOLLOW-UP	Section 8 of 11
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Further Outpatient Care:

• Follow-up of EBV viral load may provide useful information regarding disease status and the patient's response to treatment. Green (2001) at the University of Pittsburgh recommends weekly monitoring of EBV viral titers in the peripheral blood of patients with PTLD. A declining viral load is suggestive of response to treatment. Persistently high or rising viral load suggests the presence of disease progression and the need for therapeutic modification. This especially is true if clinical, radiological, or other markers also support progression or lack of response to treatment. Serial physical examinations, radiological evaluation, and assessment for any evidence of allograft rejection are essential. Note that rebounds in viral load can occur with reintroduction of immunosuppression; these are less likely to represent a recurrence of disease in the absence of other findings. In any case, once cured, PTLD has a relapse rate of approximately 10%.

• Management of PTLD is somewhat of 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, and immunosuppression reduction/withdrawal has to be tailored accordingly, 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 the backbone of management.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Transplantation and the accompanying immunosuppression put patients at risk for potentially fatal infection and malignancy. Transplant candidates must be fully informed of these risks as part of the consent process pretransplantation.

• PTLD can assume an astonishing number of guises. It can mimic relatively benign conditions in its presentation, so a high degree of clinical vigilance and an awareness of its highly variable presentation are required if the diagnosis is not to be missed.

• Treatment of PTLD risks allograft dysfunction. Patients need to be made aware that PTLD is a serious consequence of transplantation and immunosuppression, and it requires treatment; however, this treatment may result in the loss of the allograft.

• Failure to inform the patient of relevant risks and possible outcomes at every stage puts the physician at risk for medical litigation.

• Additionally, care must be taken on the part of the treating physician to consider a diagnosis of PTLD in patients who are immunosuppressed, even when clinical symptoms or signs are atypical, and to perform the appropriate diagnostic tests to exclude the diagnosis of PTLD.

	PICTURES	Section 10 of 11
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Caption: Picture 1. 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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Caption: Picture 2. 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).
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	BIBLIOGRAPHY	Section 11 of 11
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• Armitage JM, Kormos RL, Stuart RS, et al: Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression. J Heart Lung Transplant 1991 Nov-Dec; 10(6): 877-86; discussion 886-7[Medline].
• Benkerrou M, Durandy A, Fischer A: Therapy for transplant-related lymphoproliferative diseases. Hematol Oncol Clin North Am 1993 Apr; 7(2): 467-75[Medline].
• Benkerrou M, Jais JP, Leblond V, et al: Anti-B-cell monoclonal antibody treatment of severe posttransplant B