Mogamulizumab – Uses, Dosage, Side Effects, Interaction

Mogamulizumab is a CCR4-targeted immuno-oncology drug. It is intended to deplete CCR4-expressing Treg cells in the tumor microenvironment so as to release Teff cells from Treg-mediated suppression and facilitate tumor cell killing. However, it also targets intratumoral Treg cells that serve other vital immune cell functions and can induce serious side effects such as dermatologic toxicity and autoimmune issues.

Mogamulizumab is a humanized monoclonal antibody (mAb) directed against CC chemokine receptor 4 (CCR4) for the treatment of Mycosis fungoides (MF) and Sézary Syndrome (SS), the most common subtypes of cutaneous T-cell lymphoma. Cutaneous T-cell lymphomas occur when certain white blood cells, called T cells, become cancerous; these cancers typically affect the skin, causing various types of skin lesions.^[rx]

On August 8, 2018, the U.S. Food and Drug Administration (FDA) approved mogamulizumab injection (also known as Poteligeo) for intravenous use for the treatment of adult patients with relapsed or refractory mycosis fungoid (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.^[rx] It was approved for the same indications in Canada in June 2022.^[rx]

Mogamulizumab is derived from Kyowa Hakko Kirin’s INTELLIGENT (®) technology, which produces antibodies with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity. Approval in Japan was granted on April 30 2012 by the Japanese Ministry of Health, Labour, and Welfare for patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma.^[rx]

Mechanism of action

Mogamulizumab selectively binds to and inhibits the activity of CCR4, which may block CCR4-mediated signal transduction pathways and, so, chemokine-mediated cellular migration and proliferation of T cells, as well as chemokine-mediated angiogenesis. Additionally, this agent may induce antibody-dependent cell-mediated cytotoxicity (ADCC) against CCR4-positive T cells. CCR4, a G-coupled-protein receptor for C-C chemokines such as MIP-1, RANTES, TARC, and MCP-1, is expressed on the surfaces of some types of T cells, endothelial cells, and certain types of neurons. CCR4, also known as CD194, may be overexpressed on adult T-cell lymphoma (ATL) and peripheral T-cell lymphoma (PTCL) cells ^[rx]. In addition to directly targeting malignant T cells expressing CCR4, mogamulizumab depletes Treg cells, an important therapeutic target in many human cancers because of their role in suppressing host antitumor immunity ^[rx].

This drug is a CC chemokine receptor 4 (CCR4) antagonist. It is a monoclonal antibody that blocks T-cell proliferation, which leads to malignancy.^[rx,rx] CCR4 is a chemokine receptor that is preferentially expressed by Th2 and regulatory T (Treg) cells. In response to its ligands, CCL17 (TARC) and CCL22 (MDC), CCR4 promotes T-cell migration to extranodal sites, including the skin

Indications

• Mogamulizumab is indicated for the treatment of adult patients with relapsed or refractory mycosis fungoid (MF) or Sézary syndrome (SS) after at least one prior systemic therapy.
• Mogamulizumab is a monoclonal antibody used to treat relapsed or refractory mycosis fungoides or Sézary syndrome after attempting one other therapy.
• Refractory Mycosis Fungoides and Sezary Syndrome
• Relapsed Mycosis Fungoides/Sezary Syndrome

Use in Cancer

Mogamulizumab-kpkc is approved to treat:

• Mycosis fungoides or Sezary syndrome (types of cutaneous T-cell lymphoma). It is used to treat the disease that has relapsed (come back) or is refractory (does not respond to treatment) in adult patients who have received at least one other type of systemic therapy.

Mogamulizumab-kpkc is also being studied in the treatment of other types of cancer.

Contraindications

• a bad infection
• inflammation of the middle tissue heart muscle
• a type of inflammation of the lung called interstitial pneumonitis
• inflammation of the liver called hepatitis
• glomerulonephritis, a condition that affects the kidneys
• muscle inflammation

Dosage

Strengths: kpkc 4 mg/mL

Mycosis Fungoides

• 1 mg/kg IV over at least 60 minutes on days 1, 8, 15, and 22 of the first 28-day cycle, then on days 1 and 15 of each subsequent 28-day cycle until disease progression or unacceptable toxicity
• Administer premedication with diphenhydramine and acetaminophen for the first infusion.
• For relapsed or refractory mycosis fungoid’s (MF) or Sezary syndrome (SS) after at least one prior systemic therapy

Dose Adjustments

Dose Modifications for Dermatologic Toxicity:

• If mild (Grade 1) rash occurs, consider topical corticosteroids.
• If a moderate or severe (Grade 2 or 3) rash occurs, interrupt therapy and administer at least 2 weeks of topical corticosteroids; if the rash improves to Grade 1 or less, therapy may be resumed.
• Permanently discontinue therapy for life-threatening (Grade 4) rash or for Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). If SJS or TEN is suspected, discontinue therapy, and do not resume unless SJS or TEN has been excluded and the cutaneous reaction has resolved to Grade 1 or less.

Dose Modifications for Infusion Reactions:

• If an infusion reaction occurs, administer premedication (i.e., diphenhydramine and acetaminophen) for subsequent infusions.
• Temporarily interrupt the infusion for mild to severe (Grades 1 to 3) infusion reactions and treat symptoms. Reduce the infusion rate by at least 50% when restarting the infusion after symptoms resolve. If the reaction recurs and is unmanageable, discontinue infusion.
• Permanently discontinue therapy for a life-threatening (Grade 4) infusion reaction.

Administration advice:

• Premedicate patients with diphenhydramine and acetaminophen for the first infusion.
• Administer within 2 days of the scheduled dose; if a dose is missed, administer the next dose as soon as possible and resume the dosing schedule.
• Do not administer subcutaneously or by rapid IV administration.
• Administer infusion solution over at least 60 minutes through an IV line containing a sterile, low protein binding, 0.22 micron (or equivalent) in-line filter.
• Do not mix this drug with other drugs.
• Do not coadminister other drugs through the same IV line

Reconstitution/preparation techniques:

• Visually inspect drug product solution for particulate matter and discoloration prior to administration. The solution should be clear to slightly colorless opalescent. Discard the vial if cloudiness, discoloration, or particulates are observed.
• Calculate the dose (mg/kg) and the number of vials needed to prepare the solution based on patient weight.
• Aseptically withdraw the required dose into the syringe and transfer it into an IV bag containing 0.9% sodium chloride injection. The final concentration of the diluted solution should be between 0.1 mg/mL to 3 mg/mL.
• Mix diluted solution by gentle inversion. Do not shake.
• Discard any unused portion left in the vial.
• The diluted solution is compatible with polyvinyl chloride (PVC) or polyolefin (PO) infusion bags.

Side Effects

The Most Common

• constipation
• muscle spasms or pain
• tiredness or fatigue
• headache
• swelling of the hands, feet, ankles, or lower legs
• decreased appetite
• changes in weight
• difficulty falling asleep or staying asleep
• depression
• dry skin
• hair loss
• rash, skin pain, itching, blistering, or peeling
• painful sores or ulcers in the mouth, nose, throat, or genital area
• fever, cough, sore throat, chills, flu-like symptoms, or other signs of infection
• nausea, diarrhea, or stomach pain
• painful or frequent urination
• easy bruising or bleeding

More common

• Black, tarry stools
• bladder pain
• bleeding gums
• blood in the urine or stools
• cloudy urine
• blurred vision
• body aches or pain
• burning, dry, or itching eyes
• burning, itching, and pain in hairy areas, pus at the root of the hair
• burning, numbness, tingling, or painful sensations
• chest pain
• chills
• cough
• cracked lips
• decreased frequency or amount of urine
• diarrhea
• difficult or labored breathing
• difficult, burning, or painful urination
• difficulty in swallowing
• discharge, excessive tearing
• dizziness
• drowsiness
• dry mouth
• ear congestion
• fainting
• fast, slow, or irregular heartbeat
• fever
• flushed, dry skin
• frequent urge to urinate
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• increased urination
• itching, skin rash
• joint pain, stiffness, or swelling
• loss of appetite
• loss of voice
• lower back, side, or stomach pain
• mood or mental changes
• muscle and bone pain
• muscle spasms (tetany) or twitching seizures
• nasal congestion
• nausea
• nervousness
• pale skin
• pinpoint red spots on the skin
• pounding in the ears
• redness, pain, or swelling of the eye, eyelid, or inner lining of the eyelid
• runny nose
• skin blisters
• sneezing
• sore throat
• sores, ulcers, or white spots on the lips, tongue, or inside the mouth
• stomach pain
• swelling of the face, fingers, lower legs, or feet
• tenderness
• tightness in the chest
• trembling
• troubled breathing with exertion
• unexplained weight loss
• unsteadiness or awkwardness
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• warmth on skin
• weakness in the arms, hands, legs, or feet
• weight gain

Rare

• Burning or stinging of the skin
• earache
• painful cold sores or blisters on the lips, nose, eyes, or genitals
• redness or swelling in the ear
• Chest discomfort
• dilated neck veins
• extreme tiredness or weakness
• irregular breathing
• pain or discomfort in the arms, jaw, back, or neck
• Dark urine
• general tiredness and weakness
• light-colored stools
• upper right abdominal pain
• yellow eyes and skin
• Constipation
• decreased appetite
• discouragement
• falls
• feeling sad or empty
• irritability
• loss of interest or pleasure
• thinning or loss of hair
• trouble concentrating
• trouble sleeping

Drug Interactions

Pregnancy and Lactation

FDA and TGA pregnancy category C

Pregnancy

There are no available data on POTELIGEO use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In an animal reproduction study, administration of mogamulizumab-kpkc to pregnant cynomolgus monkeys from the start of organogenesis through delivery did not show potential for adverse developmental outcomes at maternal systemic exposures 27 times the exposure in patients at the recommended dose, based on AUC (see Data).

In general, IgG molecules are known to cross the placental barrier and in the monkey reproduction study mogamulizumab-kpkc was detected in fetal plasma. Therefore, POTELIGEO has the potential to be transmitted from the mother to the developing fetus. POTELIGEO is not recommended during pregnancy or in women of childbearing potential not using contraception. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other
adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Lactation

There is no information regarding the presence of POTELIGEO in human milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for POTELIGEO and any potential adverse effects on the breastfed child from POTELIGEO or from the underlying maternal condition.