Brentuximab

Introduction to Brentuximab Vedotin

Brentuximab vedotin (trade name: Adcetris) is an antibody-drug conjugate consisting of an anti-CD30 monoclonal antibody linked to the antimicrotubule agent monomethyl auristatin E (MMAE). It was developed by Seattle Genetics and Takeda Oncology, receiving FDA approval in 2011. Brentuximab vedotin is used in the treatment of various CD30-positive lymphomas, including Hodgkin lymphoma and certain types of T-cell lymphomas.

Mechanism of Action

Brentuximab vedotin's mechanism of action involves several steps:

  1. Binding: The antibody component selectively binds to CD30, a cell membrane protein expressed on certain lymphoma cells.
  2. Internalization: After binding, the antibody-drug conjugate is internalized by the cell.
  3. Release of MMAE: Inside the cell, lysosomal enzymes cleave the linker, releasing the active MMAE.
  4. Cytotoxic effect: MMAE disrupts the microtubule network within the cell, inducing cell cycle arrest and apoptosis.

This targeted approach allows for the delivery of the cytotoxic agent specifically to CD30-expressing tumor cells, potentially reducing systemic toxicity compared to traditional chemotherapy.

Indications

Brentuximab vedotin is approved for use in several hematologic malignancies:

  1. Classical Hodgkin Lymphoma (cHL):
    • Previously untreated Stage III/IV cHL in combination with chemotherapy
    • cHL at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT) consolidation
    • cHL after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not auto-HSCT candidates
  2. Systemic Anaplastic Large Cell Lymphoma (sALCL):
    • Previously untreated sALCL or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with chemotherapy
    • sALCL after failure of at least one prior multi-agent chemotherapy regimen
  3. Primary Cutaneous Anaplastic Large Cell Lymphoma (pcALCL) or CD30-expressing Mycosis Fungoides (MF): Adult patients who have received prior systemic therapy

Notably, Brentuximab vedotin has shown efficacy in pediatric patients with relapsed or refractory classical Hodgkin lymphoma or systemic anaplastic large cell lymphoma, making it an important option in pediatric oncology.

Dosage and Administration

Brentuximab vedotin is administered as an intravenous infusion. The recommended dosage varies based on the indication and patient population:

  • Adults:
    • Monotherapy: 1.8 mg/kg up to a maximum of 180 mg every 3 weeks
    • Combination therapy for previously untreated cHL or PTCL: 1.2 mg/kg up to a maximum of 120 mg every 2 weeks
  • Pediatric patients (≥12 years with body weight ≥40 kg):
    • Monotherapy: 1.8 mg/kg up to a maximum of 180 mg every 3 weeks
    • Combination therapy for previously untreated cHL: 1.2 mg/kg up to a maximum of 120 mg every 2 weeks
  • Pediatric patients (<12 years or body weight <40 kg): 1.4 mg/kg up to a maximum of 140 mg every 3 weeks

The infusion is typically given over 30 minutes. Dose modifications may be necessary based on adverse reactions or renal/hepatic impairment.

Adverse Effects

Common adverse effects of Brentuximab vedotin include:

  • Peripheral neuropathy
  • Fatigue
  • Nausea
  • Diarrhea
  • Neutropenia
  • Anemia
  • Upper respiratory tract infection
  • Fever

Serious adverse reactions can occur, including:

  • Progressive multifocal leukoencephalopathy (PML)
  • Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Anaphylaxis and infusion reactions
  • Pulmonary toxicity
  • Hepatotoxicity
  • Serious infections and opportunistic infections
  • Tumor lysis syndrome
  • Increased risk of complications in patients receiving allogeneic stem cell transplantation following Brentuximab vedotin

Embryo-fetal toxicity can occur, and females of reproductive potential should use effective contraception during treatment and for at least 6 months after the last dose.

Monitoring and Follow-up

Patients receiving Brentuximab vedotin require close monitoring for adverse effects and treatment response:

  1. Pre-treatment evaluation:
    • Complete blood count, liver function tests, renal function tests
    • Baseline neurological examination
    • Screening for hepatitis B virus infection
    • Baseline imaging studies
  2. During treatment:
    • Regular clinical assessments for signs and symptoms of adverse reactions, particularly peripheral neuropathy
    • Monitoring of vital signs during and after infusions for infusion-related reactions
    • Periodic laboratory tests (CBC, LFTs, renal function)
    • Imaging studies to assess treatment response
  3. Post-treatment:
    • Continued monitoring for delayed adverse effects, particularly peripheral neuropathy
    • Long-term follow-up for treatment efficacy and potential late-onset complications

Healthcare providers should educate patients about potential side effects, particularly the symptoms of peripheral neuropathy, and the importance of reporting any new or worsening symptoms promptly. Special attention should be given to monitoring pediatric patients, as they may have different tolerability profiles compared to adults.



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