Gemtuzumab ozogamicin – Uses, Dosage, Side Effects, Interation

Marketing approval of gemtuzumab ozogamicin was granted on May 17, 2000, by FDA as a treatment for patients with CD33-positive AML in first relapse? who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy? ^[rx]. However, it was voluntarily withdrawn from the market in 2010 due to safety concerns, increased patient deaths, and insufficient evidence of clinical? benefit during confirmatory trials ^[rx]. On September 1, 2017, gemtuzumab ozogamicin was again approved for the treatment of adults with newly diagnosed CD33-positive acute myeloid leukemia but with a lower dosing regimen and a different schedule in combination with chemotherapy or on its own ^[rx]. It is also indicated 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?) ^[rx].

Mechanism of action

Mylotarg is directed against the CD33 antigen expressed by hematopoietic cells. 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 site-specific DNA double-strand breaks via the formation of a p-benzene diradical ⁴. Eventually, cell death is induced.

Used for the treatment of acute myeloid leukemia (AML), Mylotarg binds to the CD33 antigen, which is expressed on the surface of leukemic cells in more than 80% of patients with AML. The CD33 antigen is not expressed on pluripotent hematopoietic stem cells or nonhematopoietic cells. This gives Mylotarg the selectivity needed to target leukemic cells.

or

Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). The antibody portion (hP67.6) recognizes human CD33 antigen. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumor? cells, followed by internalization of the ADC-CD33 complex, and the 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, subsequently inducing cell cycle arrest and apoptotic cell death.

Indications

• Indicated for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. Indicated 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).
• Acute Myeloid Leukemia (AML)
• Refractory Acute Myeloid Leukemia (AML)
• Relapsed Acute Myelogenous Leukemia (AML)

Use in Cancer

Gemtuzumab ozogamicin is approved to treat:

• Acute myeloid leukemia that is CD33 positive.
  • It is used in adults and children aged 1 month and older with the newly-diagnosed diseases.
  • It is used in adults and children aged 2 years and older whose disease has relapsed or is refractory (does not respond to treatment).

Gemtuzumab ozogamicin is also being studied in the treatment of other types of cancer.

Contraindications

• low amount of magnesium in the blood
• low amount of calcium in the blood
• low amount of potassium in the blood
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• abnormal EKG with QT changes from birth
• hepatic veno-occlusive disease, a type of liver? disease
• liver problems
• pregnancy
• a patient who is producing milk and breastfeeding

Dosage?

Strengths: 4.5 mg

Acute Myeloid Leukemia

Newly diagnosed CD33-positive acute myeloid leukemia (AML):
COMBINATION REGIMEN (therapy consists of 1 induction cycle and 2 consolidation cycles in combination with chemotherapy):

• Induction: 3 mg/m2 (maximum 4.5 mg/dose) IV over 2 hours on Days 1, 4, and 7 in combination with daunorubicin and cytarabine (for patients who require a second induction cycle, gemtuzumab is NOT given during the second induction cycle)
• Consolidation (2 cycles): 3 mg/m2 (maximum 4.5 mg/dose) IV over 2 hours on Day 1 in combination with daunorubicin and cytarabine

Newly diagnosed CD33-positive acute myeloid leukemia (AML):
SINGLE AGENT REGIMEN (MONOTHERAPY) (therapy consists of 1 induction cycle and up to 8 continuation cycles):

• Induction: 6 mg/m2 IV over 2 hours on Day 1 and 3 mg/m2 IV on Day 8
• Continuation: 2 mg/m2 IV over 2 hours on Day 1 every 4 weeks

Relapsed or Refractory CD33-positive AML:
SINGLE-AGENT REGIMEN (MONOTHERAPY):

• 3 mg/m2 (maximum 4.5 mg/dose) IV over 2 hours on Days 1, 4, and 7
• Treatment in the relapsed or refractory setting consists of a single course of gemtuzumab.
• Premedicate with acetaminophen 650 mg orally and diphenhydramine 50 mg orally or IV one hour prior to infusion, and methylprednisolone (or equivalent) 1 mg/kg orally or IV within 30 minutes prior to infusion. Repeat the same dose of methylprednisolone (or equivalent) for any sign of an infusion reaction (e.g., fever?, chills?, hypotension?, dyspnea?) during the infusion or within 4 hours of the infusion.
• Monitor vital signs? during infusion and for 4 hours following infusion.
• For patients with hyperleukocytosis (leukocyte? count greater than or equal to 30 Gi/L), cytoreduction is recommended prior to the administration of this drug.
• For newly diagnosed CD33-positive acute myeloid leukemia (AML)
• For relapsed or refractory CD33-positive AML

Acute Myeloid Leukemia

Newly Diagnosed De Novo CD33-positive AML (Combination Regimen):
ONE MONTH AND OLDER:

• Body surface area (BSA) less than 0.6 m2: 0.1 mg/kg IV over 2 hours
• BSA 0.6 m2 or greater: 0.3 mg/m2 IV over 2 hours

INDUCTION 1:

• For Induction 1, gemtuzumab is given once in combination with standard chemotherapy; no gemtuzumab is given in the second induction cycle.

INTENSIFICATION:

• No gemtuzumab is given in the first or third intensification cycles; for Intensification 2, gemtuzumab is given once in combination with standard chemotherapy; consider the risks and potential benefits before giving gemtuzumab during Intensification 2.

Relapsed or Refractory CD33-positive AML:
SINGLE-AGENT REGIMEN (MONOTHERAPY):
2 YEARS AND OLDER:
3 mg/m2 (maximum 4.5 mg/dose) IV over 2 hours on Days 1, 4, and 7

• Treatment in the relapsed or refractory setting consists of a single course of gemtuzumab.
• Premedicate children 1 month and older with acetaminophen 15 mg/kg (maximum of 650 mg) orally and diphenhydramine 1 mg/kg (maximum of 50 mg) orally or IV within 1 hour of infusion, and methylprednisolone 1 mg/kg orally or IV within 30 minutes of infusion. Additional doses of acetaminophen and diphenhydramine may be administered every 4 hours if needed. Repeat with the same dose of methylprednisolone (or equivalent) for an infusion reaction (e.g., fever, chills, hypotension, dyspnea) during the infusion or within 4 hours of the infusion.
• Monitor vital signs during infusion and for 4 hours following infusion.
• For patients with hyperleukocytosis (leukocyte count greater than or equal to 30 Gi/L), cytoreduction is recommended prior to the administration of this drug.
• For the treatment of newly diagnosed CD33-positive acute myeloid leukemia in pediatric patients 1 month and older
• For relapsed or refractory CD33-positive acute myeloid leukemia (AML) in pediatric patients 2 years and older

Dose Adjustments

FOR PATIENTS RECEIVING GEMTUZUMAB IN COMBINATION THERAPY:
PERSISTENT THROMBOCYTOPENIA?:

• ADULTS: If platelet? count does not recover to greater than or equal to 100 Gi/L within 14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following the previous cycle), discontinue gemtuzumab (do not administer gemtuzumab in the consolidation cycles).
• PEDIATRICS: Patients should have a platelet count of 75 Gi/L before the next cycle (induction or intensification).

PERSISTENT NEUTROPENIA?:

• ADULTS: If the neutrophil? count does not recover to greater than 0.5 Gi/L within 14 days following the planned start date of the consolidation cycle (14 days after hematologic recovery following the previous cycle), discontinue gemtuzumab (do not administer gemtuzumab in the consolidation cycles).
• PEDIATRICS: Patients should have a neutrophil count of 1 Gi/L before the next cycle (induction or intensification).

FOR ALL PATIENTS RECEIVING GEMTUZUMAB (MONOTHERAPY OR COMBINATION THERAPY:
VENO-OCCLUSIVE LIVER DISEASE (VOD):

• Manage hepatic toxicity by dose interruption or discontinuation of therapy.
• In patients who experience VOD, discontinue therapy and treatment according to standard medical practice.

INFUSION-RELATED REACTIONS:

• Interrupt the infusion and manage medically.
• Administer acetaminophen, diphenhydramine, and/or methylprednisolone, if needed. Provide supportive care as needed.
• For mild?, moderate?, or severe? infusion-related reactions, once symptoms resolve, consider resuming the infusion at no more than one-half the rate at which the reaction occurred.
• Repeat the procedure in the event of a recurrence? of symptoms.
• Permanently discontinue therapy upon the occurrence of a severe infusion reaction or for any life-threatening infusion reaction.

OTHER SEVERE OR LIFE-THREATENING NONHEMATOLOGIC TOXICITIES:

• Delay therapy until recovery to a severity of no more than mild.
• Omit scheduled dose if delayed more than 2 days between sequential infusions.

Administration advice:

• Use an in-line 0.2-micron polyethersulfone (PES) filter for infusion.
• Protect the IV bag from light using a light-blocking cover during the infusion. The infusion line does not need to be protected from light.
• Infuse the diluted solution over 2 hours.

Side Effects

The Most Common

• rash?
• diarrhea?
• constipation?
• nausea?
• vomiting
• headache
• pain
• pain, swelling, or sores in mouth or throat
• unusual or severe bleeding or bruising
• cough, shortness of breath, or difficulty breathing
• fast heartbeat
• fever, chills, sore throat, or other signs of infection

More common

• Bleeding gums
• blood in the urine or stools
• blurred vision
• bone pain
• chest pain
• chills
• confusion
• cough
• coughing up blood
• decreased urine output
• difficulty in breathing or swallowing
• dizziness, lightheadedness, or fainting
• dry mouth
• fast or irregular heartbeat
• fever
• flushed, dry skin
• fruit-like breath odor
• headache
• hoarseness
• increased hunger
• increased menstrual flow or vaginal bleeding
• increased thirst
• increased urination
• irregular heartbeat
• loss of appetite
• loss of consciousness
• lower back or side pain
• mood changes
• muscle pain or cramps
• nausea
• nosebleeds
• numbness or tingling in the hands, feet, or lips
• painful or difficult urination
• paralysis
• pinpoint red spots on the skin
• prolonged bleeding from cuts
• rapid, shallow breathing
• rash
• red or black, tarry stools
• red or dark brown urine
• seizures
• sore throat
• stomach pain and bloating
• sweating
• swelling of the face, ankles, or hands
• tightness in the chest
• unexplained weight loss
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting

Rare

• Blue lips and fingernails
• coughing that sometimes produces a pink frothy sputum
• difficult, fast, noisy breathing
• fast, pounding, or irregular heartbeat or pulse
• increased sweating
• pale skin
• ulcers, sores, or white spots in the mouth
• Stomach cramps
• watery or bloody diarrhea

Drug Interactions

Pregnancy and Lactation

US FDA pregnancy category Not Assigned

Pregnancy

Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1)], MYLOTARG can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on MYLOTARG use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In rat embryo-fetal development studies, gemtuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were greater than or equal to 0.4 times the
exposure in patients at the maximum recommended dose, based on AUC (see Data). If MYLOTARG is used during pregnancy, or if the patient becomes pregnant while taking MYLOTARG, advise the patient of the potential risk to a fetus.

Lactation

There are no data on the presence of gemtuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for adverse reactions in breastfed infants, women should not breastfeed during treatment with MYLOTARG and for at least 1 month after the final dose.

References