In a phase-1 study, siplizumab, a humanized anti-CD2 monoclonal antibody, was administered (0.012 or 0.04 mg/kg) to 10 pediatric patients with > or = grade-II newly diagnosed, non-steroid-refractory aGvHD after BMT or PBSCT. SAEs and other AEs including infections, and GvHD staging changes (overall, skin, liver, gut) were evaluated over 364 days. Patients reported a total of 121 AEs (19 grade-3, 5 grade-4 0.012 mg/kg group; 17 grade-3, 17 grade-4 0.04 mg/kg group) and 14 SAEs (five grade-3, three grade-4, 0.012 mg/kg group; three grade-3, 0.04 mg/kg group); 15 AEs in five patients and four SAEs in three patients (fever, PTLD, adenoviral infection, and EBV lymphoma) were considered siplizumab-related. Six deaths occurred (study days 17-267); two were considered siplizumab-related: one from EBV-associated PTLD (0.012 mg/kg) and one from adenoviral infection (0.04 mg/kg); the other four deaths could potentially be attributed in part to study drug Three patients (one, 0.012 mg/kg group; two, 0.04 mg/kg group) developed PTLD. By study day 12, GvHD grade decreased in 3/5 and 2/5 patients in the 0.012 and 0.04 mg/kg groups, respectively; remission (grade 0) occurred in one patient in each group. Four of five patients (0.012 mg/kg group) and one of four patients (0.04 mg/kg group) achieved grade 0 GvHD during the first 100 study days (55.6% response). While treatment with siplizumab was associated with improvement of GvHD and remission in some pediatric patients, the overall high morbidity, mortality, and occurrence of PTLD is of safety concern, not warranting further development of siplizumab for the treatment of aGvHD in children.