FDA Approves Gemtuzumab Ozogamicin for Newly Diagnosed CD33+ AML

The FDA has approved gemtuzumab ozogamicin (Mylotarg) for the treatment of adults with newly diagnosed CD33-positive acute myeloid leukemia (AML).

Additionally, the agency approved the antibody-drug conjugate for the treatment of patients aged 2 years and older with CD33-positive relapsed/refractory AML. The decision follows the recommendation of the FDA’s Oncologic Drugs Advisory Committee, which voted 6 to 1 recommending approval during a meeting in July.

“We are approving Mylotarg after a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Mylotarg’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.”

The approval is based on data from several trials, including the ALFA-0701, AML-19, and MyloFrance-1.1 trials.

The multicenter, open-label phase III ALFA-0701 trial randomized 271 patients aged 50 to 70 years old with newly-diagnosed AML to daunorubicin and cytarabine alone (n = 136) or combined with gemtuzumab ozogamicin (n = 135).

Gemtuzumab ozogamicin at 3 mg/m² was administered on days 1, 4, and 7 during induction and day 1 of each of the 2 consolidation chemotherapy courses. The primary endpoint was event-free survival (EFS) with a secondary endpoint of overall survival (OS).

Gemtuzumab ozogamicin was associated with a statistically significant improvement in EFS of 7.8 months (median EFS, 17.3 vs 9.5 months; hazard ratio [HR], 0.56; 95% CI 0.42-0.76; P <.001). However, the drug was not associated with a significant improvement in OS (HR 0.81; 95% CI, 0.60-1.09; P = 0.16).

In the open-label phase III Study AML-19, elderly patients who could not tolerate other AML treatments were randomized to gemtuzumab ozogamicin (n=118) or best supportive care (n=119). Gemtuzumab ozogamicin was initially administered at 6 mg/m² on day 1 and 3 mg/m² on day 8. Patients without evidence of disease progression then received the drug at 2 mg/m² on day 1 every 4 weeks.

Gemtuzumab ozogamicin reduced the risk of death by 31%, with a median OS of 4.9 months versus 3.6 months in the control arm. (HR, 0.69; 95% CI, 0.53-0.90; 2-sided P = .005).

Fifty-seven adult AML patients in first relapse were included in the phase II single-arm, open-label MyloFrance-1 study. Single-agent gemtuzumab ozogamicin was administered at 3 mg/m² on days 1, 4, and 7. Fifteen patients achieved a complete remission and the median relapse-free survival was 11.6 months.

In the trial, 15 patients achieved a complete remission and median relapse-free survival was 11.6 months.

“Today is an important day for patients, their families, and the entire AML community, as the approval of Mylotarg brings forth a long-awaited treatment option that may lead to deeper, more durable remissions for patients with AML,” Jorge Cortes, MD, University of Texas, MD Anderson Cancer Center, said in a statement. “After many years, we are finally seeing progress in the treatment of AML, which has renewed my hope in improving outcomes for my patients. I am pleased that I can now offer many adult and pediatric patients targeted treatment with Mylotarg.”

According to the FDA’s approval statement, common side effects of gemtuzumab ozogamicin include pyrexia, nausea, infection, vomiting, bleeding, thrombocytopenia, stomatitis, constipation, rash, headache, elevated liver function tests, and neutropenia. Severe side effects of the drug include low blood counts, infections, liver damage, hepatic veno-occlusive disease, infusion-related reactions, and hemorrhage.

The label for gemtuzumab ozogamicin includes a boxed warning for hepatotoxicity, including veno-occlusive disease or sinusoidal obstruction syndrome.

The FDA awarded accelerated approval to gemtuzumab in 2000 for the treatment of patients 60 years or older with CD33-positive AML in first relapse who were not considered candidates for cytotoxic chemotherapy. Wyeth, now Pfizer, voluntarily pulled the drug from the market in 2010 after results from the SWOG-S0106 trial showed that gemtuzumab did not improve rate of complete response, disease-free survival, or OS compared with daunorubicin and cytarabine.

Results from subsequent trials suggested that a lower dose—the previous regimen was 2 doses of 9 mg/m² of gemtuzumab administered 14 days apart—could be combined safely with daunorubicin and cytarabine.