FDA Approves First Antibody-Targeted Chemotherapy Agent

The US Food and Drug Administration recently approved gemtuzumab ozogamicin (Mylotarg) for the treatment of patients 60 years of age and older who are in first relapse with CD33-positive acute myeloid leukemia (AML) and are not considered candidates for cytotoxic chemotherapy. Designated an orphan drug in November 1999, gemtuzumab is the first drug specifically approved to treat relapsed AML patients and the first targeted chemotherapy agent using monoclonal antibody technology.

Manufactured by American Home Products, gemtuzumab will be marketed by the company’s pharmaceutical division, Wyeth-Ayerst Laboratories. “We anticipate Mylotarg being an important treatment option for older patients with relapsed CD33-positive AML who frequently cannot tolerate conventional combination chemotherapy,” said L. Patrick Gage, phd, President, Wyeth-Ayerst Research. “Mylotarg can be administered in outpatient settings. This may be desirable to many patients.”

Accelerated Approval, Limited Studies

Gemtuzumab was approved under accelerated approval provisions. Its safety and efficacy in AML patients with poor performance status and organ dysfunction has not been established. Its effectiveness is based on objective response rates. Moreover, there are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival, compared to any other treatment.

In three multinational phase II trials involving 142 patients, gemtuzumab as a single agent produced a 26% overall remission rate in patients 60 years of age and older with CD33-positive AML in first relapse. Median duration of overall survival was 5.9 months. A 4% incidence of severe mucositis was observed. Hair loss, a common side effect of cancer chemotherapy, was not associated with treatment, which is consistent with its targeted design.

Potential Side Effects

Gemtuzumab should be administered under the supervision of a physician experienced in cancer chemotherapeutic agents. Severe myelosuppression occurs when used at recommended doses. The most commonly reported adverse events associated with gemtuzumab therapy are fever, chills, nausea, vomiting, thrombocytopenia, neutropenia, asthenia, diarrhea, abdominal pain, headache, stomatitis, dyspnea, epistaxis, and hypokalemia.

Patients being treated for leukemia are at increased risk of developing opportunistic infections and bleeding. In clinical studies, 47% of patients have experienced anemia; 98%, severe neutropenia; and 99%, severe thrombocytopenia. Careful hematologic monitoring is required.

During the first 24 hours after administration, gemtuzumab can produce a postinfusion symptom complex of fever and chills and, less commonly, hypotension and dyspnea. Vital signs should be monitored during infusion and for 4 hours thereafter.

Some patients given gemtuzumab have developed severe liver function abnormalities, which were generally transient and reversible. In light of this potential for adverse effects on the liver, caution should be exercised when administering the drug to patients with hepatic impairment.

More About Gemtuzumab

Gemtuzumab is the first of a new class of anticancer agents developed for antibody-targeted chemotherapy. This treatment strategy is based on a proprietary “linker” technology that combines a potent antitumor antibiotic with an antibody that binds to the CD33 antigen, a glycoprotein commonly found on leukemic cells. This antigen is also found on other bone marrow hematopoietic cells, but not on pluripotent progenitor cells.

Gemtuzumab is a recombinant humanized antibody linked with a potent antitumor antibiotic called calicheamicin, which was isolated from a bacterium in a Texas soil sample. The antibody portion binds specifically to the CD33 antigen, a glycoprotein commonly expressed by myeloid leukemic cells.

This antibody was developed by investigators at Fred Hutchinson Cancer Research Center in Seattle, and subsequently licensed to Wyeth-Ayerst. The anti-CD33 antibody was humanized by Celltech Group.