Abstract HuM195, a humanized anti-CD33 monoclonal antibody, targets myeloid leukemia cells and has single-agent activity against acute myeloid leukemia (AML). To enhance the potency of native HuM195 and avoid nonspecific cytotoxicity seen with β-emitting radioimmunoconjugates, the α-emitting radiometal 213Bi was conjugated to HuM195. The feasibility, safety, and antileukemic activity of 213Bi-HuM195 were shown in a phase I trial (Jurcic et al. Blood 2002). Because of the short-range (50–80 μm) and high linear energy transfer (8400 keV) of α particles, radioimmunotherapy with 213Bi is ideally suited for the treatment of residual disease. To determine the effects of 213Bi-HuM195 against cytoreduced disease, we treated 31 patients (median age, 67 years; range, 37–80) with cytarabine 200 mg/m2/day for 5 days followed by 213Bi-HuM195 in a phase I/II trial. Thirteen patients had untreated AML (5 with de novo AML; 8 with secondary AML). Eight patients had AML in untreated first relapse, and ten patients had heavily pretreated relapsed AML (n=7) or primary refractory AML (n=3). Nine patients had poor-risk cytogenetics. During the phase I portion of the study, cohorts of 3–6 patients were treated with 18.5, 27.75, 37, and 46.25 MBq/kg. Prolonged myelosuppression with grade 4 leukopenia > 35 days was the most common dose-limiting toxicity. The maximum tolerated dose (MTD) was 37 MBq/kg. Extramedullary toxicity was primarily limited to ≤ grade 2 events, including infusion-related reactions; however, grade 3/4 liver function abnormalities were seen in four patients (13%). Treatment-related deaths occurred in two of 21 patients (10%) who received the MTD. Significant reductions in marrow blasts were seen at all dose levels, and clinical responses were observed in 6 of the 25 patients (24%) who received doses of at least 37 MBq/kg (2 CR, 2 CRp, 2 PR). The median response duration was 7.7 months (range, 2–12). Pharmacokinetic and biodistribution studies suggested that saturation of all available CD33 sites by 213Bi-HuM195 was possible after cytoreduction with cytarabine. Sequential administration of cytarabine and 213Bi-HuM195 is tolerable and can produce complete remissions in patients with AML.