Brentuximab Vedotin – Uses, Dosage, Side Effects, Interactions

Brentuximab vedotin, also known as Adcetris®, is an antibody-drug conjugate that combines an anti-CD30 antibody with the drug monomethyl auristatin E (MMAE). It is an anti-neoplastic agent used in the treatment of Hodgkin’s lymphoma and systemic anaplastic large-cell lymphoma. Brentuximab vedotin was initially approved in 2011. In January 2012, the drug label was revised with a boxed warning of a condition known as progressive multifocal leukoencephalopathy and death due to opportunistic JC virus infection post-treatment 5.

The U.S. Food and Drug Administration approved Adcetris in March 2018 to treat adult patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy 5.

Adcetris has also been previously approved by the FDA to treat Hodgkin’s lymphoma after relapse, Hodgkin’s lymphoma after stem cell transplantation when a patient has a high risk of relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after the failure of other treatment regimens, and primary cutaneous ALCL after the failure of other treatment regimens 5.

Lymphoma is a malignancy that begins in the lymphatic system, which helps to combat infection and disease. Lymphoma may begin anywhere in the body and can spread to nearby lymph nodes. The two main types of lymphoma are Hodgkin lymphoma (also called Hodgkin disease) and non-Hodgkin lymphoma. Most individuals with Hodgkin’s lymphoma have the classical type. In this type of lymphoma, large, abnormal lymphocytes (a type of white blood cell) are found in the lymph nodes called Reed-Sternberg cells. With early diagnosis and intervention, patients with Hodgkin lymphoma normally experience long-term remission 5.

The ECHELON-1 study results demonstrated the superior efficacy of the drug combined with a chemotherapy regimen when it is compared to the previous standard of care. Importantly, removing the drug bleomycin, a highly toxic agent, was completely removed from the regimen. This demonstrates meaningful progress in treatment for patients affected by this disease 6.

Mechanism of action

Brentuximab vedotin is composed of 3 parts: a chimeric human-murine IgG1 that selectively targets CD30, monomethyl auristatin E (MMAE), which is a microtubule-disrupting agent, and a protease-susceptible linker that links the antibody and MMAE. The IgG1 antibody enables Brentuximab vedotin to target tumor cells expressing CD30 on their surface. Following this Brentuximab vedotin enters the cell. Once inside, the linker is cleaved releasing MMAE which binds and disrupts the microtubule network.13

The antibody component of this drug is a chimeric IgG1 directed against CD30. The small molecule, MMAE, is a microtubule-disrupting particle. MMAE is covalently attached to the antibody by a linker. Data suggest that the anticancer activity of Adcertris is due to the binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex, and the subsequent release of MMAE by proteolytic cleavage. The binding of MMAE to tubulin disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptosis of the malignant cells

Brentuximab vedotin causes apoptosis of tumor cells by preventing cell cycle progression of the G2 to M phase through disruption of the cytosolic microtubule network, thus preventing tumor growth and proliferation.13

Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30, a marker of large-cell lymphoma.4 Until March 2018, USA National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens.7

Indications

  • Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or IV classical Hodgkin’s lymphoma (NHL) in combination with doxorubicin, vinblastine, and dacarbazine. It is also indicated for the treatment of cHL post-autologous hematopoietic stem cell transplantation (auto-HSCT) in patients at high risk of relapse or progression. Finally, it may be used in the treatment of adult patients with cHL who have previously failed either auto-HSCT or at least two prior multi-agent chemotherapy regimens if they are not candidates for auto-HSCT.13
  • Brentuximab vedotin is additionally indicated in the treatment of previously untreated systemic anaplastic large cell lymphoma (sALCL), or other CD30-expressing peripheral T-cell lymphomas (PTCL), in combination with cyclophosphamide, doxorubicin, and prednisone. It may also be used as monotherapy in sALCL after the therapeutic failure of a least one prior multi-agent chemotherapy regimen.13
  • Brentuximab vedotin is also indicated in the treatment of primary cutaneous large anaplastic large cell lymphoma, or CD30-expressing mycosis fungoides, who have received prior systemic therapy.13
  • CD30-expressing Mycosis Fungoides (MF)
  • Classical Hodgkin’s Lymphoma
  • Peripheral T Cell Lymphoma (PTCL)
  • Primary Cutaneous Anaplastic Large Cell Lymphoma
  • Systemic Anaplastic Large Cell Lymphoma
  • Stage 3 Classical Hodgkin’s Lymphoma

Use in Cancer

Brentuximab vedotin is approved for use in adults to treat:

  • Anaplastic large cell lymphoma. Brentuximab vedotin is used in:
    • Patients whose cancer is systemic (affects the whole body) and has not gotten better after treatment with combination chemotherapy.
    • Patients whose cancer has not been treated. is given with cyclophosphamide, doxorubicin hydrochloride, and prednisone.
  • Cutaneous anaplastic large cell lymphoma is primary. Brentuximab vedotin is used in patients who have received other systemic therapy.
  • Hodgkin lymphoma. Brentuximab vedotin is used:
    • After an autologous stem cell transplant (ASCT) patients who have a high risk that the cancer will recur (come back) or get worse.
    • In patients whose cancer has not gotten better after an ASCT. Brentuximab vedotin is also used in patients whose cancer has not gotten better after at least two treatments with combination chemotherapy and who cannot receive an ASCT.
    • With chemotherapy in patients with stage III or stage IV Hodgkin lymphoma whose cancer has not been treated.
  • Mycosis fungoides (a type of cutaneous T-cell lymphoma). Brentuximab vedotin is used in patients whose cancer has the CD30 protein and who have received other systemic therapy.
  • Peripheral T-cell lymphoma that has the CD30 protein. Brentuximab vedotin is given with cyclophosphamide, doxorubicin hydrochloride, and prednisone.

Brentuximab vedotin is also being studied in the treatment of other conditions and 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
  • a painful condition that affects the nerves in the legs and arms called peripheral neuropathy
  • a type of inflammation of the lung called interstitial pneumonitis
  • pregnancy
  • a patient who is producing milk and breastfeeding
  • a rupture in the wall of the stomach or intestine
  • progressive multifocal leukoencephalopathy, a type of brain infection
  • chronic kidney disease stage 4 (severe)
  • chronic kidney disease stage 5 (failure)
  • kidney disease with likely reduction in kidney function
  • Child-Pugh class B liver impairment
  • Child-Pugh class C liver impairment

Dosage

Strengths: 50 mg

Hodgkin’s Disease

  • Previously Untreated State III or IV Classical Hodgkin Lymphoma: 1.2 mg/kg (maximum 120 mg) IV over 30 minutes in combination with chemotherapy; administer every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity
  • Classical Hodgkin Lymphoma Consolidation: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; initiate therapy within 4 to 6 weeks post-auto-HSCT or upon recovery from auto-HSCT; administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity
  • Relapsed Classical Hodgkin Lymphoma: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until disease progression or unacceptable toxicity
  • Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma or DC30-Expressing Mycosis Fungoides (MF): 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity
  • Relapsed Systemic Anaplastic Large Cell Lymphoma: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until disease progression or unacceptable toxicity

Mycosis Fungoides

  • Classical Hodgkin Lymphoma Consolidation: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; initiate therapy within 4 to 6 weeks post-auto-HSCT or upon recovery from auto-HSCT; administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity
  • Relapsed Classical Hodgkin Lymphoma: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until disease progression or unacceptable toxicity
  • Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma or DC30-Expressing Mycosis Fungoides (MF): 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity
  • Relapsed Systemic Anaplastic Large Cell Lymphoma: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until disease progression or unacceptable toxicity

Lymphoma

  • Previously Untreated State III or IV Classical Hodgkin Lymphoma: 1.2 mg/kg (maximum 120 mg) IV over 30 minutes in combination with chemotherapy; administer every 2 weeks until a maximum of 12 doses, disease progression, or unacceptable toxicity
  • Classical Hodgkin Lymphoma Consolidation: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; initiate therapy within 4 to 6 weeks post-auto-HSCT or upon recovery from auto-HSCT; administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity
  • Relapsed Classical Hodgkin Lymphoma: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until disease progression or unacceptable toxicity
  • Relapsed Primary Cutaneous Anaplastic Large Cell Lymphoma or DC30-Expressing Mycosis Fungoides (MF): 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until a maximum of 16 cycles, disease progression, or unacceptable toxicity
  • Relapsed Systemic Anaplastic Large Cell Lymphoma: 1.8 mg/kg (maximum 180 mg) IV over 30 minutes; administer every 3 weeks until disease progression or unacceptable toxicity

Liver Dose Adjustments

Mild hepatic impairment (Child-Pugh A):

  • If the recommended dose is 1.2 mg/kg (maximum 120 mg) IV over 30 minutes every 2 weeks, reduce the dose to 0.9 mg/kg (maximum 90 mg) IV over 30 minutes every 2 weeks; the dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg
  • If the recommended dose is 1.8 mg/kg (maximum 180 mg) IV over 30 minutes every 3 weeks, reduce the dose to 1.2 mg/kg (maximum 120 mg) IV over 30 minutes every 3 weeks; the dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg

Dose Adjustments

Peripheral Neuropathy/Neutropenia:
GRADE 3 OR 4:

  • If the recommended dose is 1.2 mg/kg (maximum 120 mg) IV over 30 minutes every 2 weeks, administer G-CSF prophylaxis for subsequent cycles for patients not receiving primary G-CSF prophylaxis.
  • If the recommended dose is 1.8 mg/kg (maximum 180 mg) IV over 30 minutes every 3 weeks, hold dosing until improvement to baseline or Grade 2 or lower and consider G-CSF prophylaxis for subsequent cycles; for recurrent Grade 4 despite G-CSF prophylaxis consider discontinuing therapy or reduce the dose to 1.2 mg/kg up to a maximum of 120 mg every 3 weeks.

Side Effects

The Most Common

  • numbness, weakness, burning pain, tingly feeling, or loss of feeling in your arms or legs;
  • sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;
  • pain or burning when you urinate;
  • high blood sugar–increased thirst, increased urination, dry mouth, fruity breath odor;
  • ketoacidosis (too much acid in the blood)–nausea, vomiting, stomach pain, confusion, unusual drowsiness, or trouble breathing; or
  • 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;
  • signs of tumor cell breakdown–confusion, weakness, muscle cramps, nausea, vomiting, fast or slow heart rate, decreased urination, tingling in your hands and feet or around your mouth;
  • pancreatitis–severe pain in your upper stomach spreading to your back, nausea and vomiting;
  • liver problems–loss of appetite, stomach pain (upper right side), tiredness, dark urine, jaundice (yellowing of the skin or eyes); or
  • stomach problems–severe constipation, new or worsening stomach pain, bloody or tarry stools, coughing up blood or vomit that looks like coffee grounds.

More common

  • Abdominal or stomach pain
  • back pain
  • black, tarry stools
  • bleeding gums
  • blood in the urine or stools
  • blurred vision
  • body aches or pain
  • bone pain
  • burning, numbness, tingling, or painful sensations
  • chills
  • cough
  • difficult or labored breathing
  • dry mouth
  • ear congestion
  • fever
  • flushed, dry skin
  • fruit-like breath odor
  • headache
  • increased hunger
  • increased thirst
  • increased urination
  • loss of voice
  • lower back or side pain
  • nausea
  • pain
  • painful or difficult urination
  • pale skin
  • pinpoint red spots on the skin
  • sneezing
  • sore throat
  • stuffy or runny nose
  • sweating
  • swollen, painful, or tender lymph glands in the neck, armpit, or groin
  • tightness in the chest
  • troubled breathing with exertion
  • unexplained weight loss
  • ulcers, sores, or white spots in the mouth
  • unsteadiness or awkwardness
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • vomiting
  • weakness in the arms, hands, legs, or feet

Less common

  • Anxiety
  • bladder pain
  • blistering, peeling, or loosening of the skin
  • bloating or swelling of the face, arms, hands, lower legs, or feet
  • chest pain
  • cloudy urine
  • confusion
  • diarrhea
  • dizziness or lightheadedness
  • drowsiness
  • fainting
  • fast heartbeat
  • frequent urge to urinate
  • a general feeling of discomfort or illness
  • irregular heartbeat
  • itching
  • joint pain, stiffness, or swelling
  • muscle pain
  • rapid weight gain
  • red skin lesions, often with a purple center
  • red, irritated eyes

Drug Interactions

Pregnancy and Lactation

Pregnancy category D

Pregnancy

(Brentuximab vedotin may be hazardous to the fetus. Women who are pregnant or become pregnant must be advised of the potential hazard to the fetus.) For both men and women: Use contraceptives, and do not conceive a child (get pregnant) while taking brentuximab vedotin.

Lactation

Breastfeeding should be avoided due to the potential for serious adverse reactions in the breastfed child from this drug, including cytopenias and neurologic or GI toxicities.

No information is available on the use of this drug during breastfeeding. Because it is a large protein molecule, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant GI tract.

Brentuximab Vedotin Precautions:

  • This treatment may not be given at the same time as Bleomycin therapy.
  • Before starting brentuximab vedotin treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.). Do not take aspirin, or products containing aspirin unless your doctor specifically permits this.
  • Do not receive any kind of immunization or vaccination without your doctor’s approval while taking brentuximab vedotin.
  • Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment. Pregnancy category D (Brentuximab vedotin may be hazardous to the fetus. Women who are pregnant or become pregnant must be advised of the potential hazard to the fetus.)
  • For both men and women: Use contraceptives, and do not conceive a child (get pregnant) while taking brentuximab vedotin. Barrier methods of contraception, such as condoms, are recommended.
  • Do not breast feed while taking brentuximab vedotin.

Brentuximab Vedotin Self-Care Tips:

  • Drink at least two to three quarts of fluid every 24 hours, unless you are instructed otherwise.
  • You may be at risk of infection so try to avoid crowds or people with colds, and report fever or any other signs of infection immediately to your health care provider.
  • Wash your hands often.
  • To help treat/prevent mouth sores, use a soft toothbrush, and rinse three times a day with 1 teaspoon of baking soda mixed with 8 ounces of water.
  • Use an electric razor and a soft toothbrush to minimize bleeding.
  • Avoid contact sports or activities that could cause injury.
  • To reduce nausea, take anti-nausea medications as prescribed by your doctor, and eat small, frequent meals.
  • Follow regimen of anti-diarrhea medication as prescribed by your health care professional.
  • Eat foods that may help reduce diarrhea (see managing side effects – diarrhea).
  • Acetaminophen or ibuprofen may help relieve discomfort from fever, headache and/or generalized aches and pains. However, be sure to talk with your doctor before taking it.
  • Avoid sun exposure. Wear SPF 15 (or higher) sunblock and protective clothing.
  • In general, drinking alcoholic beverages should be kept to a minimum or avoided completely. You should discuss this with your doctor.
  • Get plenty of rest.
  • Maintain good nutrition.
  • Remain active as you are able. Gentle exercise is encouraged such as a daily walk.
  • If you experience symptoms or side effects, be sure to discuss them with your healthcare team. They can prescribe medications and/or offer other suggestions that are effective in managing such problems.

Monitoring and Testing While Taking Brentuximab Vedotin:

Lab work to check blood counts and liver/kidney functions will be checked regularly by your health care professional while you are taking brentuximab vedotin, to monitor side effects and check your response to therapy.

How Brentuximab Vedotin Works:

Targeted therapy is the result of about 100 years of research dedicated to understanding the differences between cancer cells and normal cells. To date, cancer treatment has focused primarily on killing rapidly dividing cells because one feature of cancer cells is that they divide rapidly. Unfortunately, some of our normal cells divide rapidly too, causing multiple side effects.

Targeted therapy is about identifying other features of cancer cells. Scientists look for specific differences in the cancer cells and the normal cells. This information is used to create a targeted therapy to attack the cancer cells without damaging the normal cells, thus leading to fewer side effects. Each type of targeted therapy works a little bit differently but all interfere with the ability of the cancer cell to grow, divide, repair and/or communicate with other cells.

There are different types of targeted therapies, defined in three broad categories. Some targeted therapies focus on the internal components and function of the cancer cell. The targeted therapies use small molecules that can get into the cell and disrupt the function of the cells, causing them to die. There are several types of targeted therapy that focus on the inner parts of the cells. Other targeted therapies target receptors that are on the outside of the cell. Therapies that target receptors are also known as monoclonal antibodies. Antiangiogenesis inhibitors target the blood vessels that supply oxygen to the cells, ultimately causing the cells to starve.

Brentuximab vedotin has the component of an antibody type of targeted therapy. Antibodies are an integral part of the body’s immune system. Normally the body creates antibodies in response to an antigen (such as a protein or a germ) that has entered the body. The antibodies attach to the antigen in order to mark it for destruction by the immune system. To make anti-cancer antibodies in the laboratory, scientists analyze specific antigens on the surface of cancer cells (the targets). Then using animal and human proteins, they create a specific antibody that will attach to the target antigen on the cancer cells. When given to a patient, these antibodies will attach to matching antigens like a key fits a lock. Since antibodies target only specific cells, they may cause less toxicity to healthy cells. Monoclonal antibody therapy is usually only given for cancers in which antigens and the respective antibodies have been identified already.

Brentuximab vedotin is a CD30-directed Antibody Drug conjugate (ADC); meaning that it consists of a targeted therapy monoclonal antibody and an antineoplastic (chemotherapy) agent. These work together to destroy cancer cells.

The brentuximab portion of the drug is a monoclonal antibody which targets the CD30 antigen on the surface of the cancer cells. When it attaches itself, it allows the ADC to enter the cell and disrupt the microtubule network which is part of the structural network of the cell (skeleton). This disruption stops the cell from dividing and copying itself. This disruption ultimately leads to cell death.

References