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Executive Summary

ORTHOCLONE OKT3 HEART TRANSPLANT PATIENTS EXPERIENCE LYMPHOMA INCIDENCE OF 9% according to a study presented by Lode Swinnen, MD, Loyola University Medical Center of Chicago, at a recent meeting of the American Society of Clinical Oncology. Swinnen et al. found that the incidence of the malignancy called post-transplant lymphoproliferative disorder rose from 1.4% at the Loyola center to 9% following introduction of OKT3 as a therapy for transplant rejection. The study will be published in a major medical journal, Swinnen said. The study tracked 149 patients receiving a cardiac transplant between 1984 and 1989; OKT3 was approved in June 1986. Of 72 patients who were transplanted before OKT3 became available, only one (1.4%) developed a lymphoma. In comparision, among the 77 patients treated with OKT3, lymphomas appeared in seven (9%). Patients treated with the drug had an average cumulative dose of 75 mg administered intravenously. "We examined all identifiable factors that could potentially be significant in a patient's risk for PTLD following a heart transplant," Swinnen said. "Only the use of OKT3 was a statistically significant predictive factor." The findings suggest particularly that risks may outweigh benefits for prophylactic use of OKT3, Swinnen indicated. OKT3 is approved for the treatment of acute renal allograft rejection. The drug also has become widely used for treatment and prevention of cardiac transplant rejection, although, Swinnen said, this use is still controversial among cardiac transplant specialists. The risk of using OKT3 at the time of transplant, rather than only when organ rejection occurs, is that patients may require a second course of the drug, thus increasing the cumulative dose. Patients receiving a normal single course of OKT3 at a cumulative dose of less than 75 mg had a lower incidence of lymphoma compared to those receiving more than 75 mg, the study found. Among 64 transplant patients who received 75 mg or less of OKT3, three developed lymphomas (4.7%), whereas lymphomas occurred in the four of 13 patients (31%) who received higher cumulative doses of OKT3. The recommended approved dosing regimen for OKT3 for renal graft rejection is 5 mg/day for 10 to 14 days. Ortho said it is reviewing the findings of the Loyola study, but pointed out that the OKT3 dose used in this study was greater than recommended, and that use in cardiac transplants is not yet an approved indication. In addition, Orthoclone OKT3 labeling bears a boxed warning that states: "Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Orthoclone OKT3." The labeling also notes that "lymphomas have been reported following immunosuppressive therapy, and data suggest that their occurrence is related to the intensity and duration of immunosuppression rather than the use of specific agents." Ortho filed supplemental submissions with FDA for the use of OKT3 in cardiac and liver transplant rejection in March 1989 ("The Pink Sheet" March 26, T&G-2). In the past, the company has expressed interest in exploring the prophylactic use of OKT3 in transplantation and in Type I diabetes.

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