Brentuximab – Uses, Dosage, Side Effects, Interaction

Brentuximab vedotin is a CD30-directed antibody-drug conjugate used to treat various types of lymphoma. 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 [rx].

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 [rx].

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 [rx].

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 [rx].

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 [rx].

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.[rx]

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

Indications

  • Brentuximab vedotin is indicated in adult patients for the treatment of previously untreated stage III or IV classical Hodgkin’s lymphoma (cHL) in combination with doxorubicinvinblastine, 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.[rx]
  • 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.[rx]
  • 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.[rx]
  • 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

Brentuximab vedotin is an anti-neoplastic agent used in the treatment of Hodgkin’s lymphoma [PMID:25796459] and systemic anaplastic large-cell lymphoma. Several clinical trials are evaluating the combination of brentuximab vedotin with immune checkpoint inhibitors, to assess any synergistic effects as a result of dual targeting. Checkpoint inhibitors being investigated in this way include nivolumab and pembrolizumab (both anti-PD-1), and ipilimumab (anti-CTLA4). Brentuximab vedotin + pembrolizumab (NCT02684292) and brentuximab vedotin + nivolumab (NCT03138499) are both Phase 3 studies in patients with relapsed/refractory classical Hodgkin’s lymphoma. Expanded approvals:In November 2017, the FDA approved brentuximab vedotin for the treatment of adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy, following review of results from the Phase 3 ALCANZA trial (NCT01578499) . In March 2018, the FDA approved the use of brentuximab vedotin for the treatment of patients with previously untreated stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy. This expansion was based on results from the ECHELON-1 clinical trial (NCT01712490). November 2018 saw further expansion of approval for the use of brentuximab vedotin plus chemotherapy for adult patients who are newly diagnosed with CD30-expressing peripheral T-cell lymphomas.

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 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

  • 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
  • The dose for patients weighing more than 100 kg should be calculated based on a weight of 100 kg.
  • In patients with previously untreated Stage III or IV cHL who are treated with this drug plus doxorubicin/ vinblastine/dacarbazine (AVD), administer G-CSF beginning with Cycle 1.
  • For previously untreated Stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy
  • For adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation
  • For adults with cHL after the failure of auto-HSCT or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
  • For adults with systemic anaplastic large cell lymphoma (sALCL) after the failure of at least one prior multi-agent chemotherapy regimen
  • For adults with pcALCL or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy

Mycosis Fungoides

  • Previously Untreated Stage 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
  • The dose for patients weighing more than 100 kg should be calculated based on a weight of 100 kg.
  • In patients with previously untreated Stage III or IV cHL who are treated with this drug plus doxorubicin/ vinblastine/dacarbazine (AVD), administer G-CSF beginning with Cycle 1.
  • For previously untreated Stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy
  • For adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation
  • For adults with cHL after the failure of auto-HSCT or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
  • For adults with systemic anaplastic large cell lymphoma (sALCL) after the failure of at least one prior multi-agent chemotherapy regimen
  • For adults with pcALCL or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy

Lymphoma

  • Previously Untreated Stage 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
  • The dose for patients weighing more than 100 kg should be calculated based on a weight of 100 kg.
  • In patients with previously untreated Stage III or IV cHL who are treated with this drug plus doxorubicin/ vinblastine/dacarbazine (AVD), administer G-CSF beginning with Cycle 1.
  • For previously untreated Stage III or IV classical Hodgkin lymphoma (cHL) in combination with chemotherapy
  • For adult patients with cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation
  • For adults with cHL after the failure of auto-HSCT or after failure of at least 2 prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
  • For adults with systemic anaplastic large cell lymphoma (sALCL) after the failure of at least one prior multi-agent chemotherapy regimen
  • For adults with pcALCL or CD30-expressing mycosis fungoides (MF) who have received prior systemic therapy

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
  • Moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment: Not recommended.

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

  • constipation
  • mouth sores
  • decreased appetite
  • weight loss
  • tiredness
  • dizziness
  • weakness
  • difficulty falling asleep or staying asleep
  • anxiety
  • dry skin
  • hair loss
  • night sweats
  • joint, bone, muscle, back, arm, or leg pain
  • muscle spasms

More Common

  • unusual bleeding or bruising
  • numbness, burning, or tingling in the hands, arms, feet, or legs
  • muscle weakness
  • peeling or blistering skin
  • hives
  • rash
  • itching
  • nausea
  • vomiting
  • diarrhea
  • cough or shortness of breath
  • decreased urination
  • swelling of the hands, feet, ankles, or lower legs
  • difficult, painful, or frequent urination
  • fever, chills, cough, or other signs of infection
  • ongoing pain that begins in the stomach area but may spread to the back
  • pale skin
  • yellowing of the skin or eyes
  • pain or discomfort in the right upper stomach area
  • dark urine
  • clay-colored bowel movements
  • stomach pain
  • unusual bleeding or bruising
  • black and tarry stools
  • red blood in stools

Rare

  • 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.

Interaction

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Pregnancy and Lactation

Pregnancy

May cause fetal harm.

Lactation

Not known whether distributed into milk. Effects on nursing infants and on milk production also unknown. Discontinue nursing.

How should this medicine be used?

Brentuximab vedotin injection comes as a powder to be mixed with fluid and injected over 30 minutes intravenously (into a vein) by a doctor or nurse in a medical office or hospital. When brentuximab vedotin is given to treat Hodgkin’s lymphoma, sALCL, or PTCL, it is usually injected once every 3 weeks for as long as your doctor recommends that you receive treatment. When brentuximab vedotin is used in combination with chemotherapy to treat Hodgkin lymphoma as a first treatment, it is usually injected once every 2 weeks for as long as your doctor recommends that you receive treatment.

Brentuximab vedotin injection may cause serious allergic reactions, which usually occur during the infusion of the medication or within 24 hours of receiving a dose. You may receive certain medications before your infusion to prevent an allergic reaction if you had a reaction with previous treatment. Your doctor will watch you carefully while you are receiving brentuximab vedotin. If you experience any of the following symptoms, tell your doctor immediately: fever, chills, rash, hives, itching, or difficulty breathing.

Your doctor may need to delay your treatment, adjust your dose, or stop your treatment if you experience certain side effects. Be sure to tell your doctor how you are feeling during your treatment with brentuximab vedotin injection.

Other uses for this medicine

This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.

What special precautions should I follow?

Before receiving brentuximab vedotin injection,

  • tell your doctor and pharmacist if you are allergic to brentuximab vedotin, any other medications, or any of the ingredients in brentuximab vedotin injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor if you are receiving bleomycin. Your doctor will probably tell you not to use brentuximab vedotin injection if you are receiving this medication.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: clarithromycin (Biaxin, in PrevPac), indinavir (Crixivan), itraconazole (Sporanox), ketoconazole, nefazodone, nelfinavir (Viracept), rifampin (Rifadin, Rimactane, in Rifamate, in Rifater), and ritonavir (Norvir, in Kaletra). 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 liver or kidney disease.
  • tell your doctor if you are pregnant or plan to become pregnant. If you are a woman who is able to become pregnant, you must take a pregnancy test before starting treatment and use effective birth control during your treatment and for 6 months after your final dose. If you are male with a female partner who is pregnant or could become pregnant, you must use effective birth control during your treatment and for 6 months after your final dose. Talk to your doctor about birth control methods that you can use. If you or your partner become pregnant while receiving brentuximab vedotin injection, call your doctor immediately. Brentuximab vedotin injection may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are receiving brentuximab vedotin injection.
  • you should know that this medication may decrease fertility in men. Talk to your doctor about the risks of receiving brentuximab vedotin injection.

References