Efficacy of Tacrolimus in the Treatment of Refractory Rejection in Heart and Lung Transplant Recipients David R. Onsager, MD, Charles C. Canver, MD, M. Salik Jahania, MD, Debbie Welter, RN, Mary Michalski, RN, Anne Marie Hoffman, RN, Robert M. Mentzer, Jr., MD, a and Robert B. Love, MD Background: Refractory acute cellular rejection may occur despite triple-drug immunosuppression (cyclosporine A, steroids, azathioprine/mycophenolate mofetil). The purpose of this study was to determine the efficacy of tacrolimus rescue therapy in patients maintained on cyclosporine-based immunosuppression (CBI). Methods: Between December 1993 and October 1996, 208 patients underwent thoracic organ transplantation at the Hospital of the University of Wisconsin at Madison. One hundred forty-nine patients underwent heart replacement; 59 underwent lung transplantation. One hundred thirty-nine of the heart transplant cohort received CBI preceded by induction therapy with OKT3. Forty-six of the lung transplant cohort received CBI without induction cytolytic therapy. Refractory rejection was defined as failure to respond to high-dose steroids (500 mg to 1 g IV methylprednisolone for 3 days) and/or monoclonal antibody therapy (OKT3, 5 to 10 mg IV/day for 7 to 14 days). In patients with refractory rejection, cyclosporine was replaced with tacrolimus. Results: Overall, 16% (30/185) of patients receiving CBI experienced refractory rejection. Thirty-one episodes of grade IIIa or greater rejection occurred in 11% (15/139) of heart transplant recipients. Twenty episodes of grade II to IV rejection occurred in 33% (15/46) of lung transplant recipients. After tacrolimus rescue therapy, 93% (14/15) of patients in the heart transplant group converted to grade II or less rejection. Refractory rejection was reversed in 73% (11/15) of the lung transplant group. Reversal was documented at biopsy in all (8/8) lung recipients in whom it had been histologically identified. FEV 1 values of 3 additional patients stabilized. Conclusions: The incidence of refractory rejection in thoracic organ transplant recipients on CBI is significant. Reversal of refractory rejection follows rescue immunotherapy with tacrolimus. J Heart Lung Transplant 1999;18:448–455. Improved survival after thoracic organ transplan- tation followed the introduction of cyclosporine- based immunotherapy into clinical practice. 1,2 This cyclosporine-based immunotherapy commonly in- cludes cyclosporine in conjunction with corticoste- roids and azathioprine. At the University of Wiscon- sin in Madison, since 1984, the overall 1-year survival for heart transplant recipients is 85% and the 5-year survival is 69%. For lung transplant recipients the overall 1-year survival is 83%, while the 5-year survival is 69%. 3 As a result of this improved survival, heart and lung transplantation are viable options for appropriate candidates with end-stage heart or lung failure. Although cyclosporine-based immunotherapy has reduced the incidence of rejection in thoracic organ transplant recipients when compared with previous immunosuppression regimens, there are some pa- From the Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin. Submitted June 5, 1998; accepted February 15, 1999. Corresponding author: David R. Onsager, MD, Division of Cardiothoracic Surgery, Clinical Science Center, H4/376, 600 Highland Avenue, Madison, Wisconsin 53792. Work tele- phone: 608-263-6311. Home telephone: 608-833-4937. Fax: 608-263-0454. Reprint requests: Robert B. Love, MD, Division of Cardiotho- racic Surgery, Clinical Science Center, H4/358, 600 Highland Avenue, Madison, Wisconsin 53792. Current address: Department of Surgery, University of Kentucky, Lexington, Kentucky. a Copyright © 1999 by the International Society for Heart and Lung Transplantation. 1053-2498/99/$–see front matter PII S1053-2498(99)00016-9 448