Mylotarg

Approved Uses

Mylotarg is indicated for the treatment of acute myeloid leukemia (AML) that expresses the CD33 antigen. It is used in the following clinical situations:

• Newly Diagnosed AML: It is used for adults and pediatric patients 1 month of age and older who have been recently diagnosed with CD33-positive AML.
• Relapsed or Refractory AML: It is used for adults and pediatric patients 2 years of age and older whose CD33-positive AML has returned or did not respond to previous treatments.

This medication may be used alone or in combination with other chemotherapy drugs, depending on the specific diagnosis and the patient's age. Before starting treatment, healthcare providers typically perform a test to confirm the presence of the CD33 protein on the surface of the leukemia cells.

Mechanism of Action

Mylotarg works by targeting a specific protein called CD33. This protein is found on the surface of most myeloblasts (immature white blood cells) in patients with acute myeloid leukemia (AML).

The medication is an antibody-drug conjugate, which means it is composed of two main parts linked together:

• A monoclonal antibody: This part acts like a homing device to find and attach to the CD33 protein on the surface of the cancer cells.
• A cytotoxic agent: This is a powerful anti-cancer drug called calicheamicin.

How it destroys cancer cells

The process of how Mylotarg works inside the body involves several steps:

• Binding and Entry: The antibody portion of the drug attaches to the CD33 protein on the leukemia cell. Once attached, the cell pulls the drug complex inside itself.
• Release: Inside the cell, the link between the antibody and the chemotherapy drug is broken, releasing the calicheamicin.
• DNA Damage: The chemotherapy drug travels to the cell's nucleus and causes double-strand breaks in the DNA.
• Cell Death: This severe DNA damage prevents the cancer cell from growing or multiplying and eventually causes it to die.

Because Mylotarg specifically targets cells with the CD33 protein, it is designed to focus its effects on leukemia cells while potentially sparing some types of healthy cells that do not carry this marker.

Common Side Effects

Many people receiving Mylotarg experience side effects. Some of the most frequently reported include:

• Fever and chills
• Nausea and vomiting
• Mouth sores or inflammation (mucositis)
• Constipation or diarrhea
• Headache
• Skin rash
• Fatigue
• Bleeding or bruising
• Low blood cell counts, which can increase the risk of infection or anemia

Serious Side Effects

Mylotarg can cause severe or life-threatening reactions that require immediate medical attention. These include:

• Liver Toxicity: A serious liver condition called veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), which can cause rapid weight gain, right-sided abdominal pain, and yellowing of the skin or eyes (jaundice).
• Infusion Reactions: Severe reactions may occur during or shortly after the infusion, including fever, chills, low blood pressure, or difficulty breathing.
• Severe Bleeding: Increased risk of fatal or life-threatening bleeding (hemorrhage) due to low platelet counts.
• Severe Infections: A significant drop in white blood cells can lead to serious bacterial, fungal, or viral infections.
• Heart Rhythm Changes: Some patients may experience changes in the electrical activity of the heart (QT prolongation).

Hepatotoxicity

Mylotarg includes a boxed warning regarding the risk of severe, life-threatening, or fatal liver toxicity, including hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS). This condition involves the blockage of small blood vessels in the liver. The risk is significantly higher in patients who have undergone or are planning to undergo a hematopoietic stem cell transplant. Monitoring for symptoms such as jaundice, rapid weight gain, and liver enlargement is standard practice during and after treatment.

Infusion-Related Reactions

Severe and potentially fatal infusion reactions can occur during or within 24 hours of receiving the medication. Symptoms may include fever, chills, rash, low blood pressure, and respiratory distress. Patients are typically monitored closely during the infusion and receive premedication, such as corticosteroids and antihistamines, to help prevent these reactions.

Hemorrhage and Myelosuppression

Treatment can cause a significant decrease in blood cell counts, including white blood cells (neutropenia) and platelets (thrombocytopenia). Severe or fatal bleeding episodes (hemorrhage) have been reported. Regular blood tests are required to monitor for these conditions, and treatment may need to be delayed or discontinued if counts do not recover.

QT Interval Prolongation

There is a risk of QT interval prolongation, which affects the heart's electrical activity and can lead to dangerous heart rhythms. This risk is higher in patients with existing heart conditions, electrolyte imbalances, or those taking other medications that affect the QT interval.

Embryo-Fetal Toxicity

Mylotarg can cause fetal harm when administered to pregnant women. Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during treatment and for several months following the last dose. Breastfeeding is generally not recommended during treatment and for at least one month after the final dose.

Contraindications

Mylotarg is contraindicated in patients with a known history of severe hypersensitivity to gemtuzumab ozogamicin or any of its components.

Pregnancy

Mylotarg may cause fetal harm when administered to a pregnant woman. Because of these risks, healthcare providers usually confirm a negative pregnancy status before starting the medication.

Patients who are able to become pregnant should use effective contraception during treatment and for at least 6 months after the final dose. Males with female partners of reproductive potential should use effective birth control during treatment and for at least 3 months after the last dose.

If a patient becomes pregnant or thinks they might be pregnant while receiving this medication, they should contact their healthcare provider immediately to discuss the potential risks to the fetus.

Breastfeeding

It is currently unknown if Mylotarg passes into breast milk. Because the drug could cause serious adverse reactions in a nursing infant, it is recommended that patients do not breastfeed during treatment and for at least 1 month after the final dose.

Available Forms

Mylotarg is supplied in the following form:

• Lyophilized powder for injection: This is a sterile, preservative-free powder provided in a single-dose vial.

A healthcare professional prepares the medication by reconstituting the powder and diluting it before it is administered into a vein through an intravenous infusion.

FDA Approval and Indications

Mylotarg (gemtuzumab ozogamicin) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of CD33-positive acute myeloid leukemia (AML). Its approved indications include:

• Newly diagnosed CD33-positive AML: For use in adults and pediatric patients 1 month and older.
• Relapsed or refractory CD33-positive AML: For use in adults and pediatric patients 2 years and older.

The medication was originally approved in 2000 under the accelerated approval pathway but was voluntarily withdrawn from the market in 2010. It was re-approved by the FDA in 2017 with a lower recommended dose, a different schedule, and a new patient population.

Boxed Warning

Mylotarg carries a boxed warning for hepatotoxicity. Severe, life-threatening, or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in patients receiving this drug. VOD is a condition where the small blood vessels in the liver become blocked.

The risk of developing VOD is higher in patients who have undergone a hematopoietic stem cell transplant (HSCT), those who receive Mylotarg after a transplant, or those who proceed to a transplant after treatment. Healthcare providers must monitor patients for signs of liver injury, such as jaundice, rapid weight gain, and liver enlargement.

Biomarker Testing

The FDA requires confirmation of CD33 expression on leukemia cells before starting treatment with Mylotarg. This is typically determined using a validated test to ensure the patient is a candidate for this targeted therapy.

Approval History

Mylotarg was originally granted accelerated approval by the FDA in 2000. It was later voluntarily withdrawn from the market in 2010 after a clinical trial failed to confirm clinical benefit and raised safety concerns regarding toxicity. Following the submission of new data and a revised dosing regimen, the FDA re-approved Mylotarg in September 2017.

Current Indications

The FDA has approved Mylotarg for the following specific uses:

• Newly diagnosed AML: For the treatment of newly diagnosed CD33-positive acute myeloid leukemia in adults and pediatric patients 1 month and older.
• Relapsed or refractory AML: For the treatment of CD33-positive acute myeloid leukemia that has returned or did not respond to previous treatments in adults and pediatric patients 2 years and older.

In June 2020, the FDA expanded the indication for newly diagnosed CD33-positive AML to include pediatric patients 1 month and older, based on clinical evidence showing the drug's safety and efficacy in this younger population.