The addition of fractionated doses of gemtuzumab ozogamicin (GO) to a standard chemotherapy regimen improved both event-free, and overall survival (OS) of newly diagnosed patients with acute myeloid leukemia (AML), aged 50 to 70 years, according to results from a Phase III trial reported at the 53rd Annual Meeting of the American Society of Hematology.
“With this research we are encouraged that gemtuzumab may be able to deliver better overall outcomes for these AML patients with limited alternatives,” said lead investigator, Sylvie Castaigne, MD, professor, Department of Hematology at Hôpital de Versailles,Versailles, France.
Gemtuzumab ozogamicin (GO), a humanized monoclonal antibody linked to a cytotoxic agent, is targeted to the CD33 cell surface antigen that is present on roughly 90% of blast cells in AML. When the drug was first developed it was seen as a promising agent in treating AML; however, studies performed after the drug’s approval in 2000 raised questions about excess toxicity. These concerns persisted, and in June of 2010, the manufacturer voluntarily withdrew GO from the US market.
“In its initial development, gemtuzumab was dosed 9 mg/m2
,” said Castaigne, “but this dose was so toxic we were unable to combine it with standard chemotherapy.” This led Castaigne and her colleagues to develop a new fractionated regimen. “We give 3 mg/m2
on day 1, 4, and 7, which allows us to combine it with chemotherapy. Using it this way we were able to demonstrate more efficacy,” and with less toxicity than that observed with the 9-mg bolus dose. The approach was validated in 2 previous Phase II trials.
In the current investigation, the research team at the Acute Leukemia French Association designed a Phase III, prospective, open-label, randomized trial, enrolling treatment naïve, de novo
patients with AML, ages 50 to 70 years. Study participants were randomized to 1 of 2 treatment arms — either standard chemotherapy with daunorubicin/ara-C (DC: n=134) or DC plus GO (DCGO, n=137). Study endpoints were event-free survival (EFS), disease-free survival (DFS), OS, and safety over a 3-year follow-up period.
Response rates to treatment were as follows: overall, CR+CRp was achieved in 220/271 patients (77%): 100/134 (75%) in the DC arm (control) versus 110/137 (80%) in the DCGO arm (P
=0.31). Significantly, primary resistant AML rate was 29/134 (22%) after DC versus 18/137 (13%) after DCGO (P
=0.08). Regarding safety at induction, there were 5/134 (4%) induction deaths in the DC arm and 9/137 (6%) in the DCGO arm (P
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