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Gemtuzumab Receives New FDA Approval for Acute Myeloid Leukemia

, by NCI Staff

A bone marrow smear from a patient with acute myeloid leukemia.

Credit: Armed Forces Institute of Pathology

On September 1, the Food and Drug Administration (FDA) approved gemtuzumab ozogamicin (Mylotarg™) for some patients with acute myeloid leukemia (AML).

The approval covers the use of gemtuzumab in adults with newly diagnosed AML that expresses a protein called CD33 (CD33-positive AML). The approval also covers the treatment of patients aged 2 and older with CD33-positive AML who have experienced a relapse or whose disease has not responded to initial treatment.

The approval marks a return to the US market for gemtuzumab. The drug initially received accelerated approval in 2000 as a stand-alone therapy for older patients with CD33-positive AML whose disease had returned after initially successful treatment.

However, confirmatory clinical trials showed that the drug did not improve survival and was linked with excess risks of serious side effects and early death. In 2010, the drug was voluntarily removed from the market by its manufacturer, Pfizer Inc.

Gemtuzumab’s new approval includes “a totally different clinical scenario—combination therapy with induction chemotherapy for newly diagnosed patients,” said Roland Walter, M.D., Ph.D., an AML specialist at Fred Hutchinson Cancer Research Center in Seattle. “The data for gemtuzumab benefiting at least some patients when used as part of induction treatment are really pretty good.”

FDA’s decision on gemtuzumab was the result of “a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk,” explained Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence.

“[The drug’s] history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment," Dr. Pazdur added.

As Part of Induction Therapy, Gemtuzumab Reduces Relapse Risk

Gemtuzumab is a type of targeted therapy called an antibody–drug conjugate. It consists of an antibody, which recognizes the CD33 protein on tumor cells, that is chemically linked to a toxin.

The CD33 protein is expressed on normal blood cells and on some AML cells in the majority of AML patients. When infused into patients, gemtuzumab locates and attaches itself to CD33, which then facilitates uptake of the toxic payload into the cells.

In the clinical trial that led to the new approval of gemtuzumab as part of induction treatment, which was funded by Pfizer, patients with newly diagnosed AML were randomly assigned to receive treatment with a standard induction chemotherapy regimen alone or in combination with gemtuzumab.

Median event-free survival was 17.3 months for patients in the gemtuzumab group and 9.5 months for patients who received chemotherapy alone. (Event-free survival was defined as the time from the date of randomization until failure of the disease to respond to induction therapy, relapse, or death by any cause.) Deaths related to treatment did not increase with the addition of gemtuzumab.

Rare but serious side effects of gemtuzumab include liver damage, allergic reactions to the infusion, and hemorrhage. The drug’s current label contains a boxed warning about the risk of severe or fatal liver disease, and recommends frequent monitoring of liver function during treatment.

Gemtuzumab as a Single Agent for AML

The reapproval also includes the limited use of gemtuzumab as a single drug. That approval was based on findings from two small clinical trials.

In the first of the trials, 237 patients who were older than 75, or between the ages of 61 and 75 but who refused intensive induction chemotherapy, were randomly assigned to receive either gemtuzumab or best supportive care (which could include palliative chemotherapy).

Patients in the gemtuzumab group had a median overall survival of 4.9 months, compared with 3.6 months for patients who received best supportive care. Deaths related to treatment did not increase with use of gemtuzumab.

In the other trial, which was not randomized, 57 patients experiencing their first relapse received gemtuzumab followed by consolidation chemotherapy with cytarabine. The median length of survival without a relapse was 11.6 months.  

For the approval of gemtuzumab as a single agent in some patients with relapsed AML, “the data is much weaker,” said Dr. Walter.

“There hasn’t been a well-controlled, randomized study that shows that gemtuzumab [alone] provides any kind of survival benefit in [this] setting” compared with standard chemotherapy, he added.

How Best to Use Gemtuzumab in the Clinic?

“Now that [gemtuzumab] is reapproved, I think we have to learn how best to use it, because the data suggest that it doesn’t benefit everybody,” said Dr. Walter.

Research has shown that patients who have AML with genetic features suggesting a low risk of relapse appear to benefit the most from induction therapy that includes gemtuzumab, whereas patients with high-risk genetic features derive almost no benefit, he continued. But many other traits of individual patients’ leukemia may also influence treatment response, and these need to be better understood.

“It will be important to optimize its use and give it to people who are predicted to have a response to the drug, and not to people who don’t have a chance of responding, because the drug does have some toxicities,” Dr. Walter explained.

More research is also needed to determine which patients with AML should receive gemtuzumab and which should receive one of the other recently approved drugs for this disease or consider participating in a clinical trial, he continued.

The other recently approved drugs for AML are midostaurin (Rydapt®), enasidenib (Idhifa®), and liposomal cytarabine-daunorubicin CPX-351 (Vyxeos™), which, like gemtuzumab, are approved for some but not all patients with AML.

“For 40 years, we had just a few approved drugs [for AML], and now within a year we have four,” said Dr. Walter. “In some ways, it’s nice to be in this position, but it’s also a difficult position, because we now have to figure out how—or if—these new drugs should be combined.”

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