Pharmacokinetics and Clinical Activity of Very Low Dose (10mg) Alemtuzumab In Transplantation for Acute Leukemia.

Abstract 1275

The impressive safety and efficacy demonstrated with the in vivo use of the rat Campath-1G led to the introduction of the commercially available humanized Campath-1H (alemtuzumab) with the same schedule, i.e. total dose (TD) 100mg and later the TD was reduced to 50mg. However, studies with such high doses of alemtuzumab revealed increased incidence of relapse and severe viral infections. The most probable explanation for the untoward effects seen turned out to be the prolonged half-life of alemtuzumab (15-21 days) as compared to rat Campath-1G (13 hours). Pharmacokinetic studies showed that the peak serum alemtuzumab levels with the 100mg and 50mg schedule were 13700 ng/ml and 2500 ng/ml, respectively. Concentrations remained at high levels >1000 ng/ml at least 4 weeks (TD 100mg) and >500 ng/ml at least 2 weeks (TD 50mg), and thus far above the lymphotoxic levels of 100ng/ml. We report here for the first time pharmacokinetic studies and clinical activity of very low dose alemtuzumab (TD 10mg) in transplantation for acute leukemia. 18 consecutive pts (median age 38y, 20–65) with acute leukemias (AML 12, ALL 6 pts) underwent sibling (39%) or unrelated (61%) allogeneic transplantation and received a TD of only 10 Campath-1H (5mg/d at d-2 and d-1) as part of the conditioning and post-transplant cyclosporine (Cya) without methotrexate. 39% of patients had advanced disease (>CR1) at tranpslant. Conditioning was BuCy=7, TBI/VP16/Cy=4, Flu/BCNU/Thiotepa +/− HD-ARA-C=10. All pts except one received peripheral blood stem cells. All pts engrafted promptly (WBC>1.000/μl on d+14, 11–21 and PLT> 20.000/μl on d+12, 7–27). 17% pts developed grade I skin acute GVHD, 11% VUD-recipients developed steroid-sensible grade II acute GvHD and further 2 (11%) VUD-recipients, who had refractory AML at transplant, developed GvHD III after early Cya discontinuation (d+43, d+95). TRM on d+100 was 0. Cya was stopped at median on d+109 (30-202). Chronic GvHD observed in only 2 patients (1 limited, 1 fulminant and fatal liver GvHD on d+143 in a HbsAg +/+ pair). 72% seropositive patients revealed CMV reactivation but no CMV disease occurred. A median absolute CD4 count higher than 200/μL was reached at 9 months. After a median follow up of 200 days (71-486), 14/18 pts are alive and in CR (Karnofsky 100%) and 4 died (relapse n=1, TRM n=3). Causes of death were liver GvHD, H1N1 infection and post-DLI GvHD. We measured serum alemtuzumab levels in 8 patients (5 AML, 3 ALL) with a sensitive (limit of detection 31.25 ng/ml) ELISA technique (performed at BioAnaLab Ltd, Oxford, UK). A total of 54 samples (median 7 samples/patient) were tested from d-2 (15 minutes after the end of the first infusion of 5mg Campath-1H) up to d+30 after transplantation. The median serum peak level was 176 ng/ml (range 135–281) and was found at day of transplantation (day 0). Alemtuzumab levels declined slowly thereafter reaching a median serum level at d+7 of 78 ng/ml (41-114) and at d+20 just above the detection limit (median 42 ng/ml). Alemtuzumab was still detected only in 1 out of 4 patients at day+30. Campath levels were not influenced by disease (AML vs ALL), body weight or body surface area (r² test). Taken together, with our administration dose and timing (5mg/d at d-2 and d-1) we achieve the maximum peak level at day of stem cell infusion which is lymphotoxic but still 1–2 log lower as compared with the 100mg and the 50mg schedules. Levels decline fast thereafter and at the time of engraftment nearly no Campath antibody remains in the patient's serum. Such fast clearance of the low dose alemtuzumab may prove beneficial regarding safety and GvL efficacy. Though the follow-up period is still relatively short, the clinical results reported here are very encouraging.