On September 1, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (Mylotarg, Pfizer Inc.) for the treatment of newly-diagnosed CD33-positive acute myeloid leukemia (AML) in adults and for treatment of relapsed or refractory CD33-positive AML in adults and in pediatric patients 2 years and older. Gemtuzumab ozogamicin may be used in combination with daunorubicin and cytarabine for adults with newly-diagnosed AML, or as a stand-alone treatment for certain adult and pediatric patients.
Approval of gemtuzumab ozogamicin in combination with chemotherapy for adults was based on ALFA-0701 (NCT00927498), a multicenter, randomized, open-label phase 3 study of 271 patients with newly-diagnosed, de novo AML aged 50 to 70 years. Patients were randomized (1:1) to receive induction therapy consisting of daunorubicin (60 mg/m2 on days 1 to 3) and cytarabine (200 mg/m2 on days 1 to 7) with (n=135) or without (n=136) gemtuzumab ozogamicin 3 mg/m2 (up to maximum of one vial) on days 1, 4, and 7. Using the per protocol definition of event-free survival (EFS), estimated median EFS was 17.3 months for patients receiving gemtuzumab ozogamicin vs. 9.5 months for those receiving chemotherapy alone, with hazard ratio of 0.56 (95% CI: 0.42, 0.76).
Gemtuzumab ozogamicin was evaluated in two clinical trials for use as a single agent. The first trial, AML-19, was a multicenter, randomized (1:1), open-label phase 3 study in 237 patients comparing gemtuzumab ozogamicin monotherapy to best supportive care (BSC). Eligible patients had newly-diagnosed AML and were 1) greater than 75 years of age or 2) 61 to 75 years of age with a WHO performance status greater than 2 or were unwilling to receive intensive chemotherapy. During induction, gemtuzumab ozogamicin 6 mg/m2 was given on day 1 and gemtuzumab ozogamicin 3 mg/m2 was given on day 8. Patients with no evidence of disease progression or significant toxicities after induction received continuation therapy as outpatients with up to 8 courses of treatment including gemtuzumab ozogamicin 2 mg/m2 on day 1, every 4 weeks. BSC included standard supportive care measures and hydroxyurea or other anti-metabolites for palliative purposes. Estimated median overall survival (OS) was 4.9 months for patients receiving gemtuzumab ozogamicin vs. 3.6 months for those receiving BSC, with hazard ratio of 0.69 (95% CI: 0.53, 0.90).
The second trial, MyloFrance-1, a phase 2, single-arm, open-label study, included 57 patients with CD33-positive AML in first relapse. Patients received a single course of gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7. Consolidation therapy consisted of cytarabine intravenously every 12 hours for 3 days. Fifteen (26%; 95% CI: 16% - 40%) patients achieved complete response (CR) following a single course of gemtuzumab ozogamicin. Median relapse-free survival, measured from the first documentation of CR to the date of relapse or death, was 11.6 months.
The label contains a box warning for hepatotoxicity. The most common adverse reactions (>15%) were hemorrhage, infection, fever, nausea, vomiting, constipation, headache, increased AST, increased ALT, rash, and mucositis. Serious adverse reactions associated with gemtuzumab ozogamicin are hepatotoxicity (including veno-occlusive disease), infusion-related reactions (including anaphylaxis), and hemorrhage.
This approval includes a lower recommended dose and schedule of gemtuzumab ozogamicin than what FDA approved previously in 2000, as well as a different patient population. Gemtuzumab ozogamicin was voluntarily withdrawn in 2010 after trials failed to confirm benefit and demonstrated safety concerns, including early mortality and VOD.
The full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761060lbl.pdf.
FDA previously granted orphan drug designation to gemtuzumab ozogamicin. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
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