Gemtuzumab Ozogamicin Approved in Europe for CD33+ AML

Sylvie Castaigne, MD

The European Commission has approved the antibody-drug conjugate gemtuzumab ozogamicin (Mylotarg) for use in combination with daunorubicin and cytarabine for the treatment of patients aged 15 years and older with newly diagnosed, CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia.

Up to 90% of patients with AML have CD33 expression on their AML cells, according to Pfizer, the manufacturer of gemtuzumab ozogamicin. The approval is based on the multicenter, open-label phase III ALFA-0701 trial, which 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; 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).

“I am thrilled that Mylotarg will be available soon in Europe as a first-line treatment for patients with acute myeloid leukemia,” lead ALFA-0701 investigator Doctor Sylvie Castaigne, MD, professeur des universités, Université de Versailles, Saint Quentin, Praticien Hospitalier, Centre Hospitalier de Versailles, said in a statement.

“This important milestone is a result of close collaboration between Pfizer and clinical investigators around the world, particularly the ALFA investigators in France, who believed in the promise of this therapy. We thank all of the investigators, nurses and patients who participated in these studies,” added Castaigne.

In September 2017, the FDA approved gemtuzumab ozogamicin for the treatment of adults with newly diagnosed CD33-positive AML, as well as the treatment of patients aged 2 years and older with CD33-positive relapsed/refractory AML. Beyond the ALFA-0701 trial, the FDA approval was also based on data from the AML-19 and MyloFrance-1.1 trials.

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.

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 US 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&mdash;could be combined safely with daunorubicin and cytarabine.