Complete Remissions Observed in Acute Myeloid Leukemia Following Prolonged Exposure to SGN-33 (lintuzumab), a Humanized Monoclonal Antibody Targeting CD33.

Blood - Tập 110 - Trang 159 - 2007
Azra Raza1, Joseph G. Jurcic2, Gail J. Roboz3, Michael Maris4, Joseph Stephenson5, Brent L. Wood6, Bhaskar Rege7, Laurie E. Grove7, Jonathan G. Drachman7, Eric L. Sievers7
1Division of Hematology/Oncology, University of Massachusetts, Worcester, MA, USA
2Department of Medicine, Memorial Sloan Kettering, New York City, NY, USA
3Department of Medicine, Weill Medical College of Cornell University, New York City, NY, USA
4Blood and Marrow Transplant, Rocky Mountain Cancer Center, Denver, CO, USA
5Cancer Center of the Carolinas, Greenville, SC, USA
6Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
7Seattle Genetics, Inc, Bothell, WA, USA

Tóm tắt

Abstract CD33 is a sialoglycan protein expressed on the vast majority of myeloid malignancies as well as normal myeloid and monocytic progenitors. SGN-33 is a humanized antibody that specifically binds CD33, inducing antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. In prior clinical testing at lower dose levels, this antibody elicited antitumor activity and objective responses in patients with relapsed and refractory acute myeloid leukemia (AML) without dose-limiting toxicity. To further characterize a dose-response relationship, a phase I single-arm dose-escalation trial was performed at 5 trial sites to assess the safety, immunogenicity, pharmacokinetics, and antileukemic activity of SGN-33. Entry criteria included CD33 expression on >50% of marrow blasts as determined by flow cytometry. Cohorts of 3–6 patients with advanced myeloid malignancies received intravenous SGN-33 at weekly doses of 1.5 to 8 mg/kg for 5 weeks as outpatients. Clinical response was assessed by bone marrow morphology and hematologic improvement. Patients demonstrating clinical benefit were eligible for additional every other week outpatient infusions. A total of 31 patients [AML (18), MDS (10), and CMML (3)] with a median age of 75 years (range: 52 to 89) were treated with escalating doses of SGN-33. Among AML patients, 6 had antecedent hematologic disorder. Dosing cohorts included 1.5 (6), 2.5 (4), 4 (4), and 8 mg/kg (17). Dose limiting toxicity has not been observed; the most common drug-related adverse event was chills associated with the first infusion (11/31 patients). Infusion reactions were uncommon during subsequent doses. Among adverse events considered related to antibody, none were Grade 4 and two were Grade 3: tumor lysis syndrome documented at 4 mg/kg that resolved swiftly with hydration, and febrile neutropenia observed at 8 mg/kg dose level. No anti-SGN-33 immune responses were detected among the first 15 patients tested. Exposure (AUC) to SGN-33 increased relative to dose and accumulation was documented with repeat dosing. The median time on study was 33 days (range 1–407) and 9 patients have received treatment for more than 56 days. Among 18 patients with AML, 4 have achieved CR and 1 CR with incomplete platelet recovery. To date, stable disease has been observed in 6 MDS patients. In summary, SGN-33 has been well tolerated at doses up to 8 mg/kg/wk, achieving serum SGN-33 exposures approximately twenty times higher than in prior studies. Complete remissions were observed in older patients with AML who were not candidates for intensive therapies. Given the responses observed in the context of an excellent tolerability profile, SGN-33 holds promise, as single agent or as part of combination therapy, for the treatment of patients with myeloid malignancy who are ineligible for aggressive therapy.

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Blood

Tập 110

159

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