Gemtuzumab ozogamicin: is there room for salvage?

To the editor:

On May 17, 2000, gemtuzumab ozogamicin received marketing approval from the US Food and Drug Administration (FDA) under accelerated approval regulations for the treatment of patients with CD33-positive acute myeloid leukemia (AML) in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy.¹  The data supporting this application included 3 open-label studies that enrolled 157 patients at least 60 years of age in whom an overall response rate of 24% (12% CR + 12% CRp) was observed. On June 21, 2010, the FDA and Pfizer announced that this drug would be voluntarily withdrawn from the market due to failure of 2 confirmatory clinical trials to demonstrate clinical benefit. Of note, the confirmatory trials examined gemtuzumab as an addition to standard induction chemotherapy in newly diagnosed patients up to 70 years of age, rather than in a relapsed or refractory older population.

To those familiar with other attempts at improving outcomes in patients with newly diagnosed AML and with the hepatic toxicity of the approved dosing regimen of gemtuzumab, the failure of gemtuzumab to provide survival benefit when combined with anthracycline and cytarabine was not surprising.^2-4  It is, therefore, appropriate for the drug to be withdrawn from the market at this time given the accelerated regulatory pathway agreed upon previously. However, questions remain. Is there a role for this agent in a certain population of patients? Is there a safer method for administering the drug?

Data from uncontrolled studies clearly indicate that the drug has single-agent activity in the setting of relapsed or refractory AML in addition to having activity in acute promyelocytic leukemia.^1,5  In addition, a study of 57 patients with relapsed or refractory AML examined fractionation of the dosing of gemtuzumab by administering 3 mg/m² on days 1, 4, and 7 rather than the FDA-approved 9 mg/m² on days 1 and 8. Administration in this manner was not associated with any grade 3 or 4 hepatotoxicity.⁶  The CR rate of 26% also indicated that efficacy appeared to be maintained when the drug was administered in this manner. In our own small series of 12 relapsed/refractory patients combining gemtuzumab with decitabine, we similarly observed absence of grade 3 or 4 hepatotoxicity with a response rate of 41%.⁷ 

There is a paucity of active agents effective for relapsed or refractory AML, particularly in older individuals. It was our hope that future efforts would examine gemtuzumab in this setting, particularly with modification of the dosing schedule and in combination. However, based upon discussions with the manufacturer, sponsorship of such trials seems unlikely (Mark Shapiro, Oncology Business Unit, Pfizer Inc, oral personal communication, June 23, 2010). If nothing else, given the magnitude of resources required to bring a drug to market, the course of gemtuzumab has hopefully highlighted the importance of careful planning of confirmatory clinical trials. One cannot help but speculate that if these trials had been performed in the relapsed or refractory setting, particularly with a modified dosing schedule, gemtuzumab might have been salvaged.