Hematology/Oncology

The patient is a 32-year-old man with cystic fibrosis, who is Epstein-Barr virus naive and underwent a bilateral lung transplant in January 2006. He was readmitted to the hospital one and a half months after his lung transplant for intussusception. He required surgical intervention, with the pathologic specimen revealing hyperplasia of Peyer’s patches.

The patient recovered but had persistent abdominal discomfort and nutritional issues. Approximately seven months after his transplant, he was admitted to the hospital with the onset of new gastrointestinal symptoms and escalating abdominal pain. He underwent a laparoscopically-assisted small bowel resection for intussusception. The ileal specimen contained a 2 cm ulcer that showed a posttransplant lymphoproliferative disorder (large B-cell lymphoma) that was EBV positive. A small lymphocytic infiltrate was identified at the surgical margins.

At the time of evaluation after recovery from surgery, the patient had no known fevers or infections. He reported true night sweats that have been present for years. He had occasional nausea and vomiting, precipitated primarily by coughing spells. His bowels had been somewhat loose.

• Past medical history: Cystic fibrosis with accompanying pancreatic insufficiency and diabetes, hypertension, nephrolithiasis.
• Medications: Reglan (metoclopramide hydrochloride), CellCept (mycophenolate mofetil), dapsone, enalapril, eszopiclone (Lunesta, Sepracor), metoprolol, prednisone, tacrolimus (Prograf, Astellas), pantoprazole sodium (Protonix, Wyeth), voriconazole (Vfend, Pfizer), sertraline hydrochloride (Zoloft, Pfizer), multivitamins.
• Social history: Married without children. No tobacco, rare alcohol.

A physical examination demonstrated normal vital signs with oxygen saturations of 100% on room air. He had no scleral icterus and no lymphadenopathy. His heartbeat was regular and his lungs clear. The abdomen was scaphoid with a liver span of 9 cm. An abdominal incision was healing. There was evidence of clubbing.

A MUGA demonstrated normal cardiac function. Bone marrow biopsy was negative. PET/CT scan revealed a new finding of an ileal intussusception with a focal area of hypermetabolic activity that was not obstructive. EBV studies show an IgG antibody of 1.04 (equivocal) and an IgM of 0.5 (not detectable). EBNA is 0.62 (not detectable), and there were fewer than 1,000 copies of EBV in the blood. Hepatitis B serologies were negative.

How would you approach treating this patient?

A. Repeat surgical resection of the ileum.
B. Single agent rituximab (Rituxan, Genentech) therapy.
C. CHOP chemotherapy.
D. Reduction in immunosuppression and treatment with acyclovir.

DISCUSSION

Posttransplant lymphoproliferative disorders (PTLD) are a rare but serious complication following solid organ and bone marrow transplant. Initially described in 1969, it has been observed that the risk of malignancies in recipients of solid organ transplants is up to 100 times that of the general population when matched by age. The most common malignancies are skin or lip carcinomas followed by lymphoproliferative disorders. Lymphoproliferative disorders have been found to have a different histology, to be more clinically aggressive and, in general, to result in poorer outcomes than “de novo” non-Hodgkin’s lymphomas.

The development of PTLD is felt to be bimodal. There are a group of cases that are typically EBV-related that develop within the first year after transplant (ranging from three to five months after solid organ transplant). There are a group of cases, typically EBV-negative, that develop late after transplant (range 50 to 77 months). The outcome is felt to be similar in both groups.

It has been thought for many years that EBV plays a key role in the pathogenesis and the development of PTLD. The role of EBV was initially suspected when transplant recipients were found to have increased oropharyngeal shedding of the virus and had symptoms of primary and secondary EBV infection. Since that time, the association of EBV has been demonstrated by immunohistochemistry and EBV-DNA hybridization studies in patients with PTLD.

It is felt that EBV is a polyclonal stimulator of B-cell proliferation. In a normal host, B cells are defected by the TH1 immune response. Additionally, infected cells display latency and are lysed by EBV-specific cytotoxic T lymphocytes (CTLs), resulting in memory cells. In solid organ transplant recipients, six months after transplant, there is a complete loss of EBV-specific CTLs. Although it is unknown why this occurs, EBV-specific CTL activity will increase to pretransplant levels beginning six months after transplant. However, during the time period where EBV-specific CTLs are lacking, CD4+ cells predominate and no CD56+ natural killer cells are detected. As a result, the B-cells proliferate. Additionally, many of the immunosuppressants that transplant recipients are taking to prevent organ rejection, such as tacrolimus, cyclosporine and azathioprine, either interfere with T-cell activation or block the T-cell response. This also allows the B cells to proliferate.

EBV infection clearly has a role in the pathogenesis of EBV-positive PTLD. However, this type of PTLD only develops in some patients; not all patients develop PTLD. It suggests that a few EBV-infected cells have the capacity to proliferate. Some investigators have suggested cofactors in the development of PTLD such as chronic antigenic stimulation by the allograft, IL-4, IL-10 and IL-6 that may promote B-cell growth. It has also been hypothesized that late-onset PTLD may have a different pathogenic mechanism involving secondary oncogenic events such as BCL-2 rearrangements, C-MYC mutations, N-RAS and p53 mutations and LMP1 deletions that are responsible for de novo lymphoma.

With the pathologic heterogeneity, the clinical presentation of PTLD can vary significantly. Early lesions are typically found incidentally and asymptomatically. In one series, lung transplant recipients with PTLD were most commonly picked up asymptomatically on chest X-ray. In contrast, in late disease, patients typically present with bulky, extranodal lymphadenopathy. Fifty-six percent presented with involvement of the gastrointestinal tract (nonhealing ulcers, bowel perforation). Involvement of the central nervous system and the bone marrow at the time of presentation is rare in solid organ transplant recipients.

A reduction in immunosuppression has been shown to be helpful in selected patients with variable response rates of 31% to 75%. However, it is usually only successful in patients with early lesions. Surgical resection and radiotherapy have been implemented and shown to be effective, primarily in patients with limited-stage disease. In the 1980s, antiviral therapies with acyclovir were evaluated and shown to have some benefit in individuals with EBV infection. However, a large review demonstrated that the survival rate for transplant recipients treated with acyclovir was similar to the overall survival rate in similar patients not treated with acyclovir. In addition, acyclovir inhibits viral replication, not EBV-induced B-cell transformation. Therefore, acyclovir and other antivirals would not be expected to be effective in EBV-PTLD when the vast majority of cells are latently infected with EBV.

Combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without rituximab can provide effective results; however, the toxicities of these therapies in patients that are already immunosuppressed is too great, particularly in those who develop late PTLD. Dotti et al evaluated 30 patients with PTLD that developed more than one year from transplant, of whom 55% had stage III or IV disease. Of those patients, 33% that were treated with chemotherapy had a response. However, 50% died of toxicities to the chemotherapy, either infectious complications or multisystem organ failure.

More recently, immunotherapy with monoclonal antibodies such as rituximab (anti-CD20) has demonstrated some efficacy, offering a potentially safe and effective treatment. Overall response rates with single agent rituximab vary from 37% to 69% with median survivals of 14 months. In general, it has been felt that single agent rituximab is better tolerated than systemic chemotherapy. It also appears that patients who have failed treatment with single agent rituximab can still respond well to systemic chemotherapy.

Our patient was treated with single agent rituximab 375 mg/m² weekly for four weeks, given on an every six month basis. He is now two years out from diagnosis with no evidence of recurrent PTLD.

Anne H. Blaes, MD, is a Fellow at the University of Minnesota and a member of the HemOnc Today Editorial Board.

For more information:

• Blaes AH. Cancer. 2005;104:1661-1667.
• Dotti G. Transplantation. 2002;74:1095-1102.
• Hanto DW. NEJM. 1982;306:913-918.
• Ho M. J infect Dis. 1985;152:876.
• Jain AB. Transplantation. 2005;80:1692-1698.