General Information

Mylotarg is a chemotherapy agent approved for the treatment of CD33 positive acute myeloid leukemia (AML) in first relapse. It is indicated in patients who are 60 years old or older and who are not considered candidates for other cytotoxic chemotherapy. Mylotarg was withdrawn in 2010 and reapproved in 2017. The new drug approval is for the treatment of adults with newly diagnosed acute myeloid leukemia whose tumors express the CD33 antigen (CD33-positive AML). The FDA also approved Mylotarg for the treatment of patients aged 2 years and older with CD33-positive AML who have experienced a relapse or who have not responded to initial treatment (refractory).

The recommended dose is a follows:

Newly-Diagnosed De Novo CD33-positive AML (combination regimen)

A treatment course including Mylotarg in combination therapy for adults with newly-diagnosed de novo CD33-positive AML consists of 1 induction cycle and 2 consolidation cycles.
For the induction cycle, the recommended dose of Mylotarg 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, do NOT administer Mylotarg during the second induction cycle.

For the consolidation cycles, the recommended dose of Mylotarg is 3 mg/m2 on Day 1 (up to one 4.5 mg vial) in combination with daunorubicin and cytarabine.
Newly-Diagnosed CD33-positive AML (single-agent regimen)
A treatment course of Mylotarg as a single agent for adults with newly-diagnosed CD33-positive AML consists of 1 cycle of induction and up to 8 cycles of continuation therapy.
For the induction cycle, the recommended dose of Mylotarg is 6 mg/m2 (not limited to one 4.5 mg vial) as a single agent on Day 1, and 3 mg/m2 (not limited to one 4.5 mg vial) on Day 8.
For continuation, the recommended dose of Mylotarg is 2 mg/m2 (not limited to one 4.5 mg vial) as a single agent on Day 1 every 4 weeks.
Relapsed or Refractory CD33-positive AML (single-agent regimen)
The recommended dose of Mylotarg as a single agent for treatment of relapsed or refractory CD33-positive AML is 3 mg/m2 (up to one 4.5 mg vial) on Days 1, 4, and 7. Treatment in the relapsed or refractory setting consists of a single course of Mylotarg.

Clinical Results

In three trials with Mylotarg, 142 subjects were evaluated in a treatment regimen of two 9mg/m2 doses separated by 14 days and a 28-day follow-up after the last dose. In the first two studies, the subects were 18 years of age or older, and the third study included subjects 60 years of age or older. All subjects had CD33 positive AML in first relapse. The primary endpoint of the studies was the rate of complete remission (CR), defined using the following criteria: 1. leukemic blasts absent from the peripheral blood; 2. 5% or fewer blasts in the bone marrow; 3. Hgb greater than or equal to 9 g/dL, platelates greater than or equal to 100,000/µL, ANC greater than or equal to 1,500/µL; 4. red cell and platelet-transfusion independence.

A second response category, CRp, was also evaluated. CRp is defined using the same criteria as CR, excluding platelate recovery greater than or equal to 100,000/µL. This category was added, because Mylotarg seems to delay platelet recovery in some patients.

Results showed that the overall response rate for the three studies was 30%, with 16% of subjects achieving CR and 13% achieving CRp. For both categories, the median time to remission was 60 days.

Of the subjects acheiving CR or CRp, the median months of relapse-free survival was 6.8. Six subjects had a relapse-free survival of >12 months. Median duration of overall survival for the 142 subjects was 5.9 months.

Side Effects

The following infusion-related adverse events were experienced by two percent or more of patients receiving Mylotarg during clinical trials:

Chills

Fever

Nausea

Vomiting

Headache

Hypotension

Hypertension

Hypoxia

Dyspnea

Hyperglycemia

The prescribing information for Mylotarg includes a boxed warning that severe or fatal liver damage (hepatotoxicity), including blockage of veins in the liver (veno-occlusive disease or sinusoidal obstruction syndrome), occurred in some patients who took Mylotarg.

Mechanism of Action

Gemtuzumab ozogamicin binds to the CD33 antigen. This antigen is expressed on the surface of leukemic blasts in more than 80% of patients with acute myeloid leukemia. Binding of the anti-CD33 antibody portion of Mylotarg with the CD33 antigen results in the formation of a complex that is internalized. Upon internalization, the calicheamicin derivative is released inside the lysosomes of the myeloid cell. The released calicheamicin derivative binds to DNA in the minor groove resulting in DNA double strand breaks and cell death. [From the FDA approved product-label.]