Increased risk of lymphoproliferative disorders following the use of OKT3 in cardiac transplantation

A sudden increase in the incidence of post-transplant lymphoproliferative disorder (PTLD) in our cardiac transplant program prompted a retrospective study of 154 consecutive patients to identify predictive variables. The increase was found to be temporally and statistically related to the introduction of the immunosuppressive antibody OKT3. While effective in the treatment of refractory rejection, the value of OKT3 used prophylactically at the time of transplantation remains to be clearly established. Among 75 patients who had not received the drug, PTLD developed in 1 (1.3%) compared with 9 of 79 patients who had (11.4%), a ninefold higher incidence (p=0.01). The following factors were assessed in a multivariate model: sex; race; age; weight; reason for transplant; rejection episodes; mean cyclosporine level; use and cumulative dose of OKT3, ATG, and steroids. Only the use of OKT3 was significantly associated with development of PTLD (p=0.001). Increasing risk with increasing dose was evident, in that 4 of 65 patients (6.2%) who received one course of OKT3 (≤75mg) developed PTLD, while 5 of 14 patients (35.7%) who received more than 1 course did so (p<0.001). Over the year since the study was completed, two more cases of PTLD have arisen in the group receiving one course of the drug, resulting in an incidence of 9.2% after a single prophylactic course of OKT3 (p=0.03), and an overall incidence of 13.9%. Withholding cyclosporine during the prophylactic course did not reduce the risk of PTLD. Among patients who had received >75mg OKT3, all but one presented with widespread, rapidly progressive disease resulting in early organ failure and death. Among the 14 patients who had received >75mg, the interval between courses for those who developed PTLD was much shorter (med 13 days, range 0-33) than for those who did not (med 115 days, range 8-884, p=0.02). There was a strong inverse correlation between total OKT3 dose and the time to appearance of PTLD following transplantation; a mean of 11±4.9 mos. for patients who had received one course, compared to a mean of 1.3±0.45 mos. for those who had received two (p<0.001). It can be concluded that the addition of OKT3 to a triple drug immunosuppressive regimen increases the incidence of PTLD after cardiac transplantation, and that both the risk and clinical pattern of disease are dose related. No conclusions regarding the mechanism for this increase can be drawn from these data. It is suggested that the risks and benefits of prophylactic OKT3 administration be reassessed, that short intervals between courses be avoided, and that patients who have received the drug be monitored closely for indications of PTLD.