EPIDEMIOLOGY AND CLINICAL OUTCOMES

L. Tracy¹, L. Tracy², P. Archdeacon³, E. Messersmith^4
1Office Of Biostatistics, Division Of Biometrics Vii, Food and Drug Administration, CDER, Silver Spring/UNITED STATES OF AMERICA, ²Office Of Biostatistics, Division Of Biometrics Vii, Food and Drug Administration, CDER, Silver Spring/MD/UNITED STATES OF AMERICA, ³Division Of Special Pathogen And Transplant Products, Food and Drug Administration, CDER, Silver Spring/MD/UNITED STATES OF AMERICA, ⁴Arbor Research Collaborative For Health, Scientific Registry of Transplant Recipients, Ann Arbor/MI/UNITED STATES OF AMERICA

Body: Introduction Post-transplant lymphoproliferative disorder (PTLD) is a rare, yet serious, complication of post-transplant immunosuppression in renal transplantation. Prospective randomized clinical trials (RCTs) to evaluate an immunosuppressive regimen post-transplant are generally not powered to demonstrate a difference between treatment groups with respect to rare events such as PTLD, particularly among EBV+ patients. For that reason, establishing estimates of expected PTLD rates associated with commonly used immunosuppressive regimens could help inform safety evaluation of immunosuppressive agents used in kidney transplantation. Using information from previous clinical trials which included control regimens consisting of induction with an IL-2R antagonist and maintenance with cyclosporine-based immunosuppression, we calculated the observed PTLD rates among kidney transplant recipients. Through data from the Organ Procurement and Transplant Network (OPTN) registry, we also calculated estimates of the expected PTLD rate among kidney transplant recipients who receive induction with an IL-2R antagonist and maintenance with a calcineurin-inhibitor based immunosuppressive regimen. Methods We performed retrospective analyses of RCTs and of the OPTN transplant registry to estimate the 2-year incidence and corresponding exact 95% confidence interval (CI) of PTLD by EBV-status among renal transplant recipients receiving a maintenance regimen including a calcineurin-inhibitor (cyclosporine or tacrolimus), MMF, corticosteroids (CS) and antibody induction with an IL-2R antagonist (basilixamab or daclizumab).
Results We identified three RCTs that collected information on patients for at least 12-months post-transplant and that included a cyclosporine, MMF, corticosteroid with either basiliximab or daclizumab induction treatment group. Out of 896 total patients (534 EBV+, 121 EBV- and 201 EBV unknown), we identified one (1) case of PTLD, which was in a patient who was EBV- at baseline. Therefore, the estimated overall incidence of PTLD among all three trials was 0.112% (1/896) and by EBV status: 0% (0/534), 95% exact CI (0, 0.0069) among EBV+ patients, 0.621% (1/161), 95% exact CI (0.0002, 0.0341) EBV-, and 0% (0/201), 95% exact CI (0, 0.0182) EBV status unknown. Additionally, registry data from OPTN was analyzed by the FDA and independently by the Scientific Registry of Transplant Recipients (SRTR) to determine a rate of PTLD by EBV status among kidney transplant recipients receiving induction immunosuppression with an IL-2R antagonist and maintenance immunosuppression with a combination of a calcineurin inhibitor (tacrolimus or cyclosporine), MMF, and corticosteroids. Both FDA and SRTR found 2-year PTLD incidence rates to be 0.05 per 100 person-years among EBV+ kidney recipients with a 95% CI of (0.02, 0.09). Conclusion The evaluation of incidence rates of PTLD observed in randomized clinical trials of immunosuppressive agents used in kidney transplantation may be augmented by using data from previous RCTs and registry data to increase the power to detect a possible safety signal for this rare event.

Disclosure: All authors have declared no conflicts of interest.