On September 1, 2017, gemtuzumab ozogamicin (Mylotarg) was approved for treatment for newly diagnosed CD33-positive acute myeloid leukemia (AML) in adults and for treatment of relapsed or refractory CD33-positive AML in adults and pediatric patients aged ≥ 2 years.^1,2 It may be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML or as stand-alone therapy for certain adult and pediatric patients.

The current approval includes a different patient population and a lower recommended dose and schedule than did the previous approval in 2000. Gemtuzumab ozogamicin was voluntarily withdrawn in 2010 after trials failed to confirm a benefit and identified safety concerns, including early mortality and veno-occlusive disease.

Supporting Efficacy Data

The approval of gemtuzumab ozogamicin in combination with chemotherapy for adults was based on an open-label phase III trial (ALFA-0701), in which 271 patients with newly diagnosed de novo AML aged 50 to 70 years were randomized to receive induction therapy with daunorubicin (60 mg/m² on days 1–3) and cytarabine (200 mg/m² on days 1–7) with (n = 135) or without (n = 136) gemtuzumab ozogamicin at 3 mg/m² (up to a maximum of 1 vial) on days 1, 4, and 7.² Median event-free survival was 17.3 months in the gemtuzumab ozogamicin group vs 9.5 months in the chemotherapy-alone group (hazard ratio [HR] = 0.56, P < .001)

Approval of single-agent gemtuzumab ozogamicin was based on findings in two clinical trials. In an open-label phase III trial (AML-19), 237 patients with newly diagnosed AML who were aged > 75 years, 61 to 75 years of age with World Health Organization (WHO) performance status > 2, or unwilling to receive intensive chemotherapy were randomized to receive gemtuzumab ozogamicin (n = 118) or best supportive care (n = 119). Gemtuzumab ozogamicin was given at 6 mg/m² on day 1 and at 3 mg/m² on day 8 for induction; patients with no evidence of disease progression or significant toxicities received continuation therapy with up to 8 courses of gemtuzumab ozogamicin at 2 mg/m² on day 1 every 4 weeks. Median overall survival was 4.9 months in the gemtuzumab ozogamicin group vs 3.6 months in the best supportive care group (HR = 0.69, P = .005).

In the second trial (phase II, MyloFrance-1), 57 patients with a first relapse received a single course of gemtuzumab ozogamicin at 3 mg/ m² on days 1, 4, and 7. Consolidation therapy consisted of intravenous cytarabine every 12 hours for 3 days. Complete response was observed in 15 patients (26%) after a single course; median relapse-free survival from the first documentation of complete response was 11.6 months.

How It Works

Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate. The antibody portion recognizes human CD33 antigen, and the small-molecule portion, N-acetyl gamma calicheamicin, is a cytotoxic agent covalently bound to the antibody via a linker.

Preclinical data indicate that gemtuzumab ozogamicin acts via the binding of the antibody-drug conjugate to CD33-expressing tumor cells, followed by internalization of the antibody-drug conjugate–CD33 complex and intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-strand DNA breaks, resulting in cell-cycle arrest and apoptotic cell death.

How It Is Used

Adults should be premedicated with acetaminophen at 650 mg and diphenhydramine at 50 mg at 1 hour before and 1 mg/ kg of methylprednisolone or the equivalent within 30 minutes before infusion. Children should be premedicated with acetaminophen at 15 mg/kg (maximum 650 mg), diphenhydramine at 1 mg/kg (maximum 50 mg), and 1 mg/kg of methylprednisolone; additional doses of acetaminophen and diphenhydramine may be administered every 4 hours after the initial pretreatment dose. The same dose of methylprednisolone or equivalent should be repeated for any sign of infusion reaction. Appropriate measures should be taken to prevent tumor-lysis syndrome. Cytoreduction is recommended prior to gemtuzumab ozogamicin administration for patients with hyperleukocytosis (leukocyte count ≥ 30 Gi/L).

A treatment course of gemtuzumab ozogamicin in combination therapy for adults with newly diagnosed disease consists of one induction cycle and two consolidation cycles. For the induction cycle, the recommended dose is 3 mg/m² (up to one 4.5 mg vial) on days 1, 4, and 7 in combination with daunorubicin and cytarabine. For patients requiring a second induction cycle, gemtuzumab ozogamicin should not be given during the second cycle. For consolidation cycles, the recommended dose is 3 mg/m² on day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.

A treatment course as a single agent for adults with newly diagnosed disease consists of 1 cycle of induction and up to 8 cycles of continuation therapy. The recommended dose for the induction cycle is 6 mg/m² on day 1 and 3 mg/m² on day 8. For continuation, the recommended dose is 2 mg/m² on day 1 every 4 weeks. For use as a single agent in relapsed or refractory disease, the recommended dose is 3 mg/m² (up to one 4.5 mg vial) on days 1, 4, and 7.

Specific instructions for the management of gemtuzumab ozogamicin-related toxicities are provided in product labeling, including treatment modifications for persistent thrombocytopenia, persistent neutropenia, veno-occlusive disease, hepatic toxicity (total bilirubin > 2 × upper limit of normal [ULN], or aspartate transaminase (AST) and/or alanine transaminase (ALT) > 2.5 × ULN), infusion-related reactions, and other severe or life-threatening nonhematologic toxicities.

Safety Profile

Overall, the most common adverse events (> 15%) in patients receiving gemtuzumab ozogamicin in clinical trials were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis. Serious adverse events associated with treatment included hepatotoxicity, infusion-related reactions, and hemorrhage.

Gemtuzumab ozogamicin carries a boxed warning for hepatotoxicity, including severe and fatal hepatic veno-occlusive disease. The drug also carries warnings/precautions for infusion-related reactions, hemorrhage, and embryofetal toxicity. Patients must be premedicated with a corticosteroid, acetaminophen, and diphenhydramine and monitored during and for at least 1 hour after the end of infusion for infusion-related reaction. In case of infusion-related reaction, infusion should be interrupted, steroids or antihistamines administered, or treatment permanently discontinued, as necessary. Platelet counts must be frequently monitored.

REFERENCES

1. U.S. Food and Drug Administration: FDA approves gemtuzumab ozogamicin for CD33-positive AML. Available at www.fda.gov. Accessed December 20, 2017.

2. Mylotarg (gemtuzumab ozogamicin) for injection prescribing information, Pfizer Inc, September 2017. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf. Accessed December 20, 2017.