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Treatment of refractory acute rejection in a lung transplant recipient with campath 1H.

2002; Wolters Kluwer; Volume: 74; Issue: 6 Linguagem: Inglês

10.1097/00007890-200209270-00034

1534-6080

B. Diane Reams, R. Duane Davis, Julia Curl, Scott M. Palmer,

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Lung transplant recipients are at high risk for acute rejection, especially in the first 6 months after transplantation. During this time, biopsy-proven acute rejection is reported to occur in 60% to 100% of patients (1). The initial treatment for acute rejection at our center is to administer methylprednisolone, 500 mg intravenously (IV) each day for 3 days, then the prednisone is tapered. Despite symptomatic improvement, surveillance biopsies may demonstrate persistent rejection in one third of patients who initially respond to a steroid pulse (2). Persistent or high-grade acute rejection has emerged as the most significant risk factor for the development of bronchiolitis obliterans syndrome (BOS). Options for refractory acute rejection in solid-organ transplant recipients include tacrolimus rescue therapy, monoclonal or polyclonal antilymphocyte preparations, extracorporeal photopheresis, and intravenous immunoglobulin. This report describes the use of the anti-CD 52 antibody alemtuzumab (Campath, Ilex, San Antonio, TX) in its humanized form for the treatment of persistent acute rejection in a lung transplant recipient. R.T. is a 41-year-old male patient who underwent bilateral lung transplantation for sarcoidosis. He did well after the surgery and was discharged on postoperative day 13. Immunosuppressive medications at discharge included cyclosporine, prednisone, and mycophenolate. The patient developed persistent neutropenia, and mycophenolate was discontinued 1 month after transplantation and replaced with sirolimus. Sirolimus was discontinued after a 3-week course secondary to thrombocytopenia. Immunosuppression was then maintained with cyclosporine and prednisone alone. Initial posttransplant surveillance biopsies were initiated according to institutional protocol (i.e., biopsies every 3 months for the first year and when clinically indicated). Biopsies on months 1 and 4 were negative for rejection (International Society for Heart and Lung Transplantation [ISHLT] grade 0). A 7-month posttransplant surveillance transbronchial biopsy, however, revealed mild-acute cellular allograft rejection (ISHLT grade 2). The patient did not exhibit any signs or symptoms of rejection at that time, and forced expiratory volume (FEV1) remained at baseline (2.64L, 64% predicted). The patient was treated with IV methylprednisolone, 500 mg every 24 hr for 3 days, then underwent a prednisone taper. At that time, he was also started on tacrolimus, and cyclosporine was discontinued. Two months after the previous rejection episode, another surveillance biopsy revealed mild-acute cellular rejection (ISHLT grade 2). Again, the patient remained asymptomatic, with a stable FEV1 (2.82, 68% predicted). For this rejection episode he received IV rabbit antithymocyte globulin, 1.5 mg/kg every 24 hr for 3 days. Two months after the previous rejection episode, another surveillance biopsy revealed mild-acute cellular rejection (ISHLT grade 2). The patient’s FEV1 had declined at that point from baseline (2.38L, 57%) resulting from the development of a right middle-lobe pneumonia. Because of infection, additional antilymphocyte therapy was not given. Instead, IV immunoglobulin-G,was administered at a total dose of 2 g/kg over 4 days. One month later, a transbronchial biopsy demonstrated mild-acute cellular rejection (ISHLT grade 2). FEV1 remained lower than baseline (2.31L, 55% predicted), and the patient was admitted to the hospital for treatment with alemtuzumab (Campath 1H). Baseline laboratory parameters were remarkable for an elevated serum creatinine (2.4 mg/dL), elevated blood urea nitrogen (45 mg/dL), a decreased white blood cell count (1.9 cells/mm3), and decreased platelets (56 cells/mm3). The abnormalities in renal function were stable compared with earlier renal-function studies and thought to be secondary to calcineurin inhibitor-associated nephrotoxicity. The hematologic abnormalities were attributed to prolonged prophylactic ganciclovir therapy that was instituted during the patient’s numerous rejection therapies. Alemtuzumab therapy began on day 1 with 3 mg administered IV. Doses on days 2, 3, and 4 were 10 mg, 30 mg, and 30 mg, respectively. The patient tolerated the infusion well, with the premedications methylprednisolone, diphenhydramine, and acetaminophen. Filgrastim 300 mcg by subcutaneous injection was begun to support white blood cells. Antiviral and antifungal prophylaxis consisted of ganciclovir and inhaled amphotericin, respectively. After the alemtuzumab treatment, the patient has been followed for 8 months (as of the time of the manuscript preparation). The patient’s platelet counts have risen slightly, and white blood cell counts have remained stable with the support of weekly filgrastim injections. Lymphocyte count on day 3, before the first 30-mg dose of alemtuzumab, was zero and has remained less than 0.5 since then. CD3 and CD4 counts 1 week after dose 4 were undetectable and, to date, remain below normal. Follow-up biopsies on day 11, 3 months, and 6 months after the last alemtuzumab infusion showed no evidence of acute cellular rejection (ISHLT grade 0), as shown in Figure 1. R.T.’s pulmonary function tests remain slightly below baseline (2.28L, 56% predicted), and he has not experienced any significant toxicity related to the alemtuzumab therapy. Bronchial alveolar lavage cultures are negative thus far for bacteria, fungus, Pneumocystis carinii pneumonia, and cytomegalovirus. Figure 1: Time course of rejection therapies after lung transplantation.Alemtuzumab is a humanized monoclonal antibody against the CD52 antigen that is expressed on the surface of normal and malignant B cells, T lymphocytes, natural killer (NK) cells, monocytes, macrophages, and platelets. Treatment with alemtuzumab has been investigated as a method for the reduction of T cells and B cells during transplantation in renal transplant recipients and in the treatment of acute renal allograft rejection (3,4). The method by which it induces cytotoxicity is unknown, but complement-mediated and antibody-direct cellular cytotoxicity are thought to play a role (5). Acute rejection is orchestrated primarily by T-cell recognition of donor major histocompatibility antigens and later by the stimulation and activation of inflammatory cytokines and cytolytic T-helper cells that mediate graft dysfunction. Histologic analysis of lung biopsy material suggests that unresponsive acute rejection may involve a broader range of immunologic effector cells (e.g., B lymphocytes, monocytes, and NK cells) (6). Use of an agent such as alemtuzumab, which involves binding and elimination of multiple cell types may prove to be a more successful approach to refractory acute rejection. We describe the first use of alemtuzumab for refractory acute rejection found in a lung transplant recipient. Although follow-up is relatively short, the lack of rejection on multiple biopsies after administration of alemtuzumab is significant given the earlier failures of multiple therapies. Lack of serious complications and infections associated with the drug are encouraging. The absence of significant improvement in FEV1 thus far may indicate the development of BOS. Careful follow-up of FEV1 and radiographic studies will be necessary, as will further studies to define the role of alemtuzumab in acute rejection. B. Diane Reams R. Duane Davis Julia Curl Scott M. Palmer