Ofatumumab – Uses, Dosage, Side Effects, Interaction

Ofatumumab is an anti-CD20 antibody used for the treatment of chronic lymphocytic leukemia (CLL) in selected patients with certain treatment histories and responsiveness to anticancer medications.

Ofatumumab is a novel anti-CD20 monoclonal antibody that targets B-cells. It is an IgG1κ human monoclonal antibody produced from a recombinant murine cell line (NS0) via transgenic mouse and hybridoma technology.[rx] Ofatumumab works by recognizing antigens that are expressed on the tumor cells in certain cancers; however, the antigen is not tumor-specific and can also be found in normal B-cells.[rx] Ofatumumab was first approved by the FDA in 2009.[rx] It is used in treating recurrent, progressive, or recurrent chronic lymphocytic leukemia (CLL) or CLL in treatment-naive patients in whom fludarabine-based therapy is considered inappropriate. Ofatumumab is used as monotherapy or in combination with other medications, depending on the patient’s profile and previous treatment history.[rx] Although it has a similar molecular mechanism of action as rituximab, another CD-20 monoclonal antibody used in the treatment of rheumatoid arthritis and B-cell non-Hodgkin’s lymphoma, ofatumumab has a higher affinity towards CD20.[rx]

Ofatumumab is available for intravenous administration and is marketed as Arzerra. In Phase III clinical trials consisting of subjects with relapsing forms of multiple sclerosis (RMS), subcutaneous administration of ofatumumab reduced the number of relapses and delayed disease progression. In February 2020, FDA and EMA approved Supplemental Biologics License Application (sBLA) and Marketing Authorization Application (MAA), respectively, for ofatumumab for the treatment of RMS in adults.[rx] The FDA subsequently approved ofatumumab for the treatment of RMS on August 20, 2020.[rx] The potential therapeutic use of ofatumumab in various lymphomas and rheumatoid arthritis has also been investigated.[rx]

Mechanism of action

CD20 is expressed on normal pre-B lymphocytes and mature B lymphocytes, as well as malignant B lymphocytes. Numerous studies demonstrate that the depletion of B-cells can significantly alleviate symptoms of many forms of leukemia and lymphoma, which are malignancies associated with B-cell dysfunctions and high expression of CD20.[rx]

Ofatumumab is an anti-CD20 monoclonal antibody that binds to the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab binds to CD20, and this drug-target interaction does not result in immediate shedding and internalization of CD20 from the plasma membrane of B lymphocytes.[rx,rx] This allows ofatumumab to persist on the B lymphocyte cell surface for an extended period and recruit immunological molecules or FcR-expressing innate effectors, such as macrophages, that mediate immune effector functions with strong cytotoxic effects. These immune effector functions include complement-dependent cytotoxicity (CCD) and antibody-dependent cellular cytotoxicity (ADCC), which promote the lysis of malignant B-cells. Complement-dependent cytotoxicity (CDC) involves the translocation of the CD20 molecule into lipid rafts, which are involved in cell signaling and receptor trafficking.[rx]

The mechanism by which ofatumumab exerts a therapeutic effect in multiple sclerosis patients is unknown but is presumed to still occur as a consequence of its ability to bind CD20.[rx]

Indications

  • Ofatumumab is indicated, in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate.[rx]
  • In patients with recurrent or progressive CLL, ofatumumab is indicated for extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL.[rx]
  • Ofatumumab is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab.[rx]
  • Ofatumumab is also indicated for the treatment of adult patients with relapsing forms of multiple sclerosis, including active secondary progressive disease, clinically isolated syndrome, and relapsing-remitting disease.[rx]
  • Chronic Lymphocytic Leukemia (CLL)
  • Chronic Lymphocytic Leukemia (CLL) – Refractory
  • Clinically Isolated Syndrome (CIS)
  • Multiple Sclerosis, Relapsing Forms of Multiple Sclerosis
  • Relapsing-Remitting Multiple Sclerosis (RRMS)
  • Active Secondary Progressive Multiple Sclerosis (SPMS)
  • Progressive Chronic Lymphocytic Leukaemia (CLL)
  • Recurrent Chronic Lymphocytic Leukaemia (CLL)

 

Use in Cancer

Ofatumumab is approved to be used alone or with other drugs to treat:

  • Chronic lymphocytic leukemia (CLL).
    • It is used alone as extended treatment in patients with recurrent or progressive disease who are in complete or partial response after at least two other types of treatment.
    • It is used with fludarabine phosphate and cyclophosphamide in patients with relapsed disease.
    • It is used alone in patients who have not gotten better with other drugs.
    • It is used with chlorambucil in patients who have never been treated and cannot receive specific chemotherapy.

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

Contraindications

The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:

  • a bad infection
  • anemia
  • decreased blood platelets
  • low levels of a type of white blood cell called neutrophils
  • angina, a type of chest pain
  • pregnancy
  • chronic obstructive pulmonary disease
  • resolved hepatitis B
  • reactivation of hepatitis B infection
  • progressive multifocal leukoencephalopathy, a type of brain infection
  • are allergic to ofatumumab or any ingredients of the medication
  • have active hepatitis B infection
  • have any severe infection
  • have or have had progressive multifocal leukoencephalopathy (PML)
  • have a severely reduced immune system
  • have active cancer

Dosage

Strengths: 20 mg/mL; 20 mg/0.4 mL

Chronic Lymphocytic Leukemia

ARZERRA:
PREVIOUSLY UNTREATED CLL:

  • 300 mg IV on Day 1 followed by 1000 mg IV on Day 8 (Cycle 1) followed by 1000 mg IV on Day 1 of subsequent 28-day cycles for a minimum of 3 cycles until the best response or a maximum of 12 cycles

RELAPSED CLL:
In combination with fludarabine and cyclophosphamide:

  • 300 mg IV on Day 1 followed by 1000 mg IV on Day 8 (Cycle 1), followed by
  • 1000 mg IV on Day 1 of subsequent 28-day cycles for a maximum of 6 cycles

EXTENDED TREATMENT IN CLL:
As a single agent:

  • 300 mg IV on Day 1 followed by 1000 mg IV on Day 8 followed by 1000 mg IV 7 weeks later and every 8 weeks thereafter for up to a maximum of 2 years

REFRACTORY CLL:

  • 300 mg IV on Day 1 followed by 2000 mg IV weekly for 7 doses (infusions 2 through 8), followed 4 weeks later by 2000 mg IV every 4 weeks for 4 doses (infusions 9 through 12)
PREMEDICATION:

Patients should receive premedication 30 minutes to 2 hours before each infusion:
Previously Untreated CLL, Relapsed CLL, or Extended Treatment in CLL:

  • Infusions 1 and 2: IV corticosteroid (prednisolone or equivalent) 50 mg AND oral acetaminophen 1000 mg AND oral or IV antihistamine (diphenhydramine 50 mg or cetirizine 10 mg [or equivalent])
  • Infusions 3 and beyond (up to 13 infusions in previously untreated CLL; up to 14 infusions in extended treatment in CLL): IV corticosteroid (prednisolone or equivalent) 0 to 50 mg (the corticosteroid may be reduced or omitted for subsequent infusions if a Grade 3 or greater infusion-related adverse event did not occur with the preceding infusion) AND oral acetaminophen 1000 mg AND oral or IV antihistamine (diphenhydramine 50 mg or cetirizine 10 mg [or equivalent])

Refractory CLL:

  • Infusions 1, 2, and 9: IV corticosteroid (prednisolone or equivalent) 100 mg AND oral acetaminophen 1000 mg AND oral or IV antihistamine (diphenhydramine 50 mg or cetirizine 10 mg [or equivalent])
  • Infusions 3 to 8: IV corticosteroid (prednisolone or equivalent) 0 to 100 mg (the corticosteroid may be reduced or omitted for subsequent infusions if a Grade 3 or greater infusion-related adverse event did not occur with the preceding infusion) AND oral acetaminophen 1000 mg AND oral or IV antihistamine (diphenhydramine 50 mg or cetirizine 10 mg [or equivalent])
  • Infusions 10 to 12: IV corticosteroid (prednisolone or equivalent) 50 to 100 mg (the corticosteroid may be given at a reduced dose of 50 mg to 100 mg if a Grade 3 or greater infusion-related adverse event did not occur with Infusion 9) AND oral acetaminophen 1000 mg AND oral or IV antihistamine (diphenhydramine 50 mg or cetirizine 10 mg [or equivalent])
ADMINISTRATION:

PREVIOUSLY UNTREATED CLL AND EXTENDED TREATMENT IN CLL:

  • Initiate the first 300 mg dose IV at 3.6 mg/hr (12 mL/hr) for 30 minutes
  • For subsequent infusions of 1000 mg, initiate at 25 mg/hr (25 mL/hr); initiate infusion at 12 mg/hour if a Grade 3 or greater infusion-related reaction was experienced during the previous infusion
  • In the absence of an infusion-related reaction, the rate of infusion may be increased every 30 minutes:

Infusion rates for this drug in previously untreated CLL relapsed CLL, and extended treatment in CLL:

  • 300 mg IV at 12 mL/hr for the first 30 minutes; if tolerated, increase to 25 mL/hr for 30 minutes; if tolerated increase to 50 mL/hr for 30 minutes; if tolerated increase to 100 mL/hr for 30 minutes; if tolerated increase to 200 mL/hr for 30 minutes; if tolerated increase to 300 mL/hr for 30 minutes; if tolerated increase to 400 mL/hr for the remainder of the infusion. The median duration of infusion is 4.2 to 4.4 hours.

REFRACTORY CLL:

  • Infusion 1 (300 mg dose): Initiate infusion at 3.6 mg/hr (12 mL/hour)
  • Infusion 2 (2000 mg dose): Initiate infusion at 24 mg/hr (12 mL/hour)
  • Infusions 3 through 12 (2000 mg doses): Initiate infusion at 50 mg/hr (25 mL/hour)

In the absence of an infusion-related adverse event, the rate of infusion may be increased every 30 minutes:

  • 300 mg IV at 12 mL/hr for the first 30 minutes; if tolerated, increase to 25 mL/hr for 30 minutes; if tolerated increase to 50 mL/hr for 30 minutes; if tolerated increase to 100 mL/hr for 30 minutes; if tolerated increase to 200 mL/hr for 30 minutes; if tolerated increase to 300 mL/hr for 30 minutes; if tolerated increase to 400 mL/hr for the remainder of the infusion. The median duration of infusion is 4.2 to 4.4 hours.

Multiple Sclerosis

KESIMPTA:

  • 20 mg subcutaneously at Weeks 0, 1, and 2, followed by 20 mg subcutaneously once a month starting at Week 4
    NOTE: If a dose is missed, administer it as soon as possible without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals.

Dose Adjustments

INFUSION RATE DOSE MODIFICATION FOR INFUSION REACTIONS:

  • Interrupt infusion for infusion reactions of any severity.
  • Therapy may be resumed at the discretion of the physician.
  • The following infusion rate modifications can be used as a guide: if the infusion reaction resolves or remains less than or equal to Grade 2, resume infusion with the following modifications according to the initial Grade of the infusion reaction:
  • Grade 1 or 2: Infuse at one-half of the previous infusion rate.
  • Grade 3 or 4: Infuse at a rate of 12 mL/hour.
  • After resuming the infusion, the infusion rate may be increased according to the standard schedule, based on patient tolerance.
  • Consider permanent discontinuation of therapy if the severity of the infusion reaction does not resolve to less than or equal to Grade 2 despite adequate clinical intervention.
  • Permanently discontinue therapy for patients who develop an anaphylactic reaction.

Side Effects

The Most Common

  • signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)
  • muscle spasms
  • stuffy or runny nose
  • diarrhea
  • headache
  • difficulty sleeping
  • difficulty breathing or swallowing
  • heavy sweating
  • swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or lower legs
  • hoarseness
  • sudden reddening of the face, neck, or upper chest
  • weakness
  • unusual bleeding or bruising
  • pale skin
  • pinpoint, flat, round, red spots under the skin
  • rash
  • hives
  • fever, chills, cough, sore throat, or other signs of infection
  • pain in arms, back, neck, or jaw
  • chest pain,
  • fast heartbeat
  • fainting

More Common

  • low blood cell counts–fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands, and feet, feeling light-headed or short of breath; or
  • signs of tumor cell breakdown–tiredness, weakness, muscle cramps, nausea, vomiting, diarrhea, fast or slow heart rate, tingling in your hands and feet or around your mouth.
  • chills
  • headache
  • increased frequency of cold symptoms or sinus infections (e.g., sore throat, runny nose, nasal congestion, or facial pain)
  • muscle pain
  • redness, pain, itching, or swelling at the injection site
  • tiredness
  • fever
  • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)

Rare

  • pain, redness, swelling, or itching where the medicine was injected;
  • right-sided upper stomach pain, vomiting, loss of appetite, yellowing of your skin or eyes, and not feeling well;
  • a lung infection–fever, chills, cough with mucus, chest pain, feeling short of breath;
  • side effects during an infusion;
  • irritation where an injection was given;
  • fever, low blood cell counts;
  • cold symptoms such as stuffy nose, sneezing, and sore throat;
  • cough, chest tightness, trouble breathing, lung infection;
  • diarrhea, nausea;
  • rash; or
  • headache, tiredness.

Drug Interaction

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Pregnancy and Lactation

FDA Pregnancy Category C 

Pregnancy

This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.

Women who may become pregnant should use effective birth control when receiving ofatumumab and for at least 6 months after treatment has ended.

Breast-feeding

It is not known if ofatumumab passes into breast milk. If you are breastfeeding and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.

Children: The safety and effectiveness of using this medication have not been established for children.

Seniors: The safety and effectiveness of using this medication have not been established for adults older than 55 years of age.

Hepatitis B reactivation: People who have a hepatitis B infection that is dormant may experience the infection returning, causing further liver dysfunction or liver failure. If you have a history of hepatitis B infection, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

If you experience symptoms of worsening liver function, such as fatigue, feeling unwell, loss of appetite, nausea, yellowing of the skin or whites of the eyes, dark urine, pale stools, abdominal pain or swelling, and itchy skin, contact your doctor immediately.

Infections: Ofatumumab can affect the way your body’s natural defenses work to fight infection. This makes the body more likely to develop infections due to bacteria, viruses, and fungi. This effect is increased if you are taking ofatumumab with other medications that reduce the body’s ability to fight infection. If you have a history of chronic or frequent infections, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Contact your doctor right away if you notice symptoms of a serious infection, such as fever, chills, headache, flu-like symptoms, feeling tired, cough, blood in the sputum, shortness of breath, night sweats, weight loss, nausea, vomiting, diarrhea, frequency or burning while passing urine, redness or swelling of skin or joints, cold sores, tooth pain, or new or worsening pain in any part of the body.

Progressive multifocal leukoencephalopathy (PML): There have been reports of PML after using ocrelizumab. PML is a rare disorder that causes nerve damage in the brain. If you experience memory loss, vision loss, trouble thinking, or difficulty walking, contact your doctor immediately.

Vaccinations: This medication may interfere with the effectiveness of certain vaccines. Before starting treatment with this medication, check with your doctor to ensure your immunizations are up to date. Any required vaccinations with live vaccines should be completed at least 4 weeks before starting and vaccinations with inactivated vaccines completed at least 2 weeks before starting treatment with ofatumumab.

What special precautions should I follow?

Before receiving an ofatumumab injection,

  • tell your doctor and pharmacist if you are allergic to ofatumumab, any other medications, or any of the ingredients in the ofatumumab injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had the chronic obstructive pulmonary disease (COPD; a group of diseases that affect the lungs and airways)
  • tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while receiving an ofatumumab injection, call your doctor.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving an ofatumumab injection.
  • ask your doctor whether you should receive any vaccinations before you begin your treatment with ofatumumab. Do not have any vaccinations during your treatment without talking to your doctor.

References