A humanized unconjugated antibody targeting CD33 (SGN-33; huM195) is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)

Abstract

16500 Background: CD33 is a sialoglycan protein expressed on normal myeloid and monocytic cells as well as the vast majority of myeloid malignancies. A humanized antibody has been developed that recognizes CD33 and induces antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In prior clinical testing, this antibody led to significant reductions in blasts in patients with relapsed and refractory AML. Methods: A phase I single-arm dose escalation trial was initiated at multiple sites to assess the safety, immunogenicity, pharmacokinetics, and activity of SGN-33 at higher doses than previously tested. Cohorts of 3–6 patients with advanced MDS or AML will receive intravenous SGN-33 at weekly doses of 1.5 to 8 mg/kg over 5 weeks. Clinical response will be determined by bone marrow morphology and hematologic improvement. Responding patients will be eligible for 4 additional infusions. Results: Treatment of 6 patients at 1.5 mg/kg/wk has been well-tolerated, with no dose-limiting toxicity or related adverse events > grade 2. The median age is 79.5 years (range 52–88), and all patients were previously untreated. One patient discontinued treatment because of refractory thrombocytopenia, unrelated to SGN-33. CD33 saturation of the bone marrow blasts after 2 infusions ranged from 27% to 84% with an average of 55%. The mean change in bone marrow blasts by flow cytometry after 2 weeks was −9% (range −68% to +44%; N = 5), and the marrow monocytes changed by −39% (range −90% to +86%; N = 5). Two patients have completed re-staging after cycle 1. Blasts decreased from 29% to 12% in an 88 year-old woman with AML and from 11% to 9% in a 79 year-old man with RAEB. Conclusions: SGN-33 is well tolerated at 1.5 mg/kg/wk, and dose escalation is ongoing. Antitumor activity was seen in elderly patients with previously untreated AML and MDS. Incomplete saturation of the CD33 on bone marrow blasts suggests that higher doses may improve efficacy. SGN-33 holds promise for the treatment of patients with myeloid malignancy who are ineligible for aggressive therapy. [Table: see text]