DACLIZUMAB (ZENAPAX) IN PEDIATRIC RENAL ALLOGRAFTS: FINAL DATA

Abstract

469 According to NAPRTCS data, acute rejection episodes(ARE) occur in 41% to 58% of pediatric (ped) renal transplant (Tx) patients(pt) by 6 months after Tx. ARE jeopardize graft outcome but the toxicity associated with agents that dramatically reduce AREs may make such agents impractical in ped Tx. We conducted an open label single-arm multicenter study of the safety and pharmacokinetics (PK) of adding daclizumab, a humanized monoclonal antibody with specificity for the α subunit of the IL-2 receptor (IL-2R) on activated T cells, to center-specific maintenance immunosuppression. Patients and Methods: In addition to center-specific immunosuppression, pts received daclizumab, 1 mg./kg IV prior to Tx and bi-weekly for a total of 5 doses. Clinical results are available for 54 pts. The median age of the pts was 10 yrs; 16 were <1-5 yrs., 13 were 6-12 yrs., and 25 were 13-17yrs. 36 received living donor Txs. 18 (33%) were CMV seronegative and received Txs from CMV seropositive donors. 44% have been followed for ≥1 yr. and 87% have been followed for ≥6 months. 74% received cyclosporine, 26% received tacrolimus and 87% received mycophenolate mofetil. Serum daclizumab levels and CD25 expression on pts' T cells were followed monthly for the first 4 post-Tx months and again at 6 months post-Tx. Results: No Tx was lost to rejection; 2 grafts were lost- one to vascular thrombosis and one to recurrent focal sclerosis. Only 3pt (5%) experienced AREs at a mean of Day 22. The AREs were mild and resolved with anti-rejection treatment. No symptoms of cytokine release or anaphylaxis were observed. Infectious serious adverse events were uncommon: 11% developed urinary tract infections, 6% developed bacteremia, and only 7% had CMV viremia. One pt developed atypical lymphoid hyperplasia, but none developed lymphoproliferative syndrome. PK studies of daclizumab serum levels showed that predose levels ranged from 2-6 μg/ml and were not significantly different than in adult Tx pts. At the time of Tx, levels of CD25+ T cells were lower than those observed in adults. Daclizumab levels were sufficient to block the IL-2R α subunit without significantly modulating CD25 from the T cell surface. Saturation of the relevant CD25 epitope was present after the first daclizumab dose and remained complete for ≥ 1 month after the last dose. Compared to pts who did not experience ARE, pts with ARE had no difference in CD25 saturation, pretreatment levels of CD25+ T cells, or trough serum levels of daclizumab. Conclusions: The addition of daclizumab to current protocols can reduce ARE in Ped Tx pts without a significant increase in adverse events or infections. The results of this trial suggest that the serum levels of daclizumab achieved with the current regimen are sufficient to achieve the desired immunological effect without additional toxicity.