Department of Internal Medicine Wake Forest University School of Medicine Winston-Salem North Carolina USA
Sir,
Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. The incidence of PTLD varies with the organ transplanted. Following allogeneic bone marrow transplantation the incidence is 0.6%1.2% [1]. Following liver and lung transplantation, the incidence has been reported at 2.4% [2] and 7.9% [3] respectively. According to the Collaborative Transplant Study a cumulative incidence of 5% was reported for heart recipients and 1% for kidney recipients [4].
Case.
We report a case of a 41-year-old male who was diagnosed with systemic lupus erythematous 16 years ago. Two years after diagnosis he developed renal failure, despite therapy with cyclophosphamide and prednisone. Ten years ago he received a cadaveric renal allograft which was complicated by rejection. He underwent a second cadaveric transplant 6 years ago. Immunosuppression was achieved with cyclosporine and azathioprine after the second transplantation. His renal function has remained stable with a baseline creatinine approximately 2 mg/ml and his lupus erythematosous has been in remission. Recently, the patient developed lymphadenopathy in the left posterior cervical chain with additional lymph nodes involved in the left submandibular, jugulo-digastric, spinal accessory and supraclavicular areas, with the largest measuring 4.8x2x4.0 cm. No other evidence of disease was found on bilateral bone marrow examination and on CT scan of the chest, abdomen and pelvis. There was no fever and no night sweats. Excisional biopsy of one of the involved cervical lymph nodes showed diffuse large B-cell lymphoma, CD20 positive by immunohistochemistry. Epstein-Barr viral DNA was not detected from serum by PCR using primers specific for simple repeat sequences (IR3) of EBV and EBV-specific probes, recombinant plasmid pBR322 containing the BamHI K fragment. IgG against viral capsid antigen of EBV and IgG against Epstein-Barr nuclear antigen were present. There was no detectable IgM against viral capsid antigen. Other laboratory findings included: white cell count 4700/µl, haemoglobin 15.2 g/dl, platelet count 125 000/µl, LDH 288 U/l (normal 90250 U/l), AST 17 (normal 535), ALT 27 (normal 036), ANA negative, HIV-1 and 2 antibodies were negative, serum BUN 49 mg/dl, creatinine 3 mg/dl.
After the diagnosis was established, azathioprine was stopped, cyclosporin was continued at the same dose and he was treated with four weekly doses of intravenous rituximab 375 mg/m2. The patient tolerated the infusion without any side-effects. This was immediately followed by 41 Gy involved field radiation to the Waldeyer's ring and 10 Gy to the left posterior neck area. The patient had a complete response with no worsening of renal function. He remained without evidence of disease until 7 months later, when retroperitoneal and mediastinal lymphadenopathy was detected on routine follow-up CT examination. The patient was treated with combination chemotherapy containing cyclophosphamide, adriamycin, vincristine and prednisone.
Comment.
Post-transplant lymphoproliferative disorders are mostly of B-cell origin and are often associated with EBV detected either serologically, in the peripheral lymphocytes, or in the tumour tissue [5]. Among those with a late occurrence after transplant (>l year), there is an increased incidence of EBV negative disease which is associated with worse overall survival suggesting the possibility of a distinct clinical entity [6].
The best approach to the treatment of post-transplant lymphoproliferative disease is not fully defined. Successful therapeutic approaches include surgical resection of solitary disease site and radiation therapy to localized disease. The reduction of immunosuppression is generally utilized if clinically feasible, however, it is rarely sufficient alone. Antiviral agents have been frequently used but only with occasional responses [7,8]. Daily use of 3 000 000 units/m2 subcutaneous alpha interferon therapy has resulted in response rate of 50% after at least 3 months of treatment. Systemic side-effects include fever, myalgias, anorexia, depression, marrow suppression and allograft rejection [9]. Infusion of IL-2 activated autologous lymphocyte activated killer cells has been reported as an effective therapy for several Epstein-Barr virus positive PTLD [10,11]. Recently a humanized anti-CD20 mouse antibody, rituximab (IDEC Pharmaceuticals Corp, San Diego, CA and Genentech, San Francisco, CA) was approved for use in recurrent non-Hodgkin lymphoma. Rituximab, an anti-CD20 chimeric monoclonal antibody, has been demonstrated to be effective in recurrent non-Hodgkin's lymphoma and it is commercially available. Rituximab is directed against the B-cell specific CD20 antigen expressed on normal pre-B and B-cells and on neoplastic B-cells. It is a chimeric antibody consisting of a human IgG-1 constant region and a murine variable region. The mechanism of action is thought to be mediated via complement-dependent and antibody-dependent cellular toxicity. In a retrospective analysis including solid organ (n=26) and bone marrow (n=6) transplant patients, a 69% response rate was observed with minimal toxicity [12]. The use of cytotoxic chemotherapy known to be active for B-cell lymphoma is usually successful but generally poorly tolerated by this patient population. Our case shows the potential role of rituximab in the treatment of post-transplant lymphoproliferative disorder.
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