brentuximab

**Structure/MOA:** Brentuximab vedotin is an antibody-drug conjugate (ADC) made of (1) a chimeric IgG1 monoclonal antibody against CD30 (brentuximab), (2) a protease-cleavable linker, and (3) monomethyl auristatin E (MMAE; "vedotin"), a synthetic antimitotic agent. After binding CD30, the complex is internalized and trafficked to lysosomes. The linker is cleaved by cathepsin and MMAE is released. MMAE binds tubulin and disrupts microtubule polymerization. This causes G2/M cell-cycle arrest and apoptosis. Released MMAE can also diffuse into neighboring cells (bystander effect).

**Target - CD30 (TNFR superfamily member):** Expressed on Reed-Sternberg cells of classical Hodgkin lymphoma (CD15+, CD30+), anaplastic large cell lymphoma (ALCL), and some other T-cell lymphomas (for example, cutaneous T-cell lymphoma/mycosis fungoides). It is also expressed on activated lymphocytes. Expression on normal tissue is limited.

**Indications:** - Classical Hodgkin lymphoma: relapsed/refractory disease, after autologous HSCT as consolidation in high-risk patients, and in newly diagnosed advanced-stage disease combined with AVD (doxorubicin, vinblastine, dacarbazine). In that regimen it replaces bleomycin (BV-AVD). - Systemic ALCL (ALK+ or ALK-): relapsed disease, and in newly diagnosed disease with CHP (cyclophosphamide, doxorubicin, prednisone). - Primary cutaneous ALCL and CD30+ mycosis fungoides after prior systemic therapy. - Other CD30+ peripheral T-cell lymphomas, with CHP.

**Adverse effects (high-yield):** - Peripheral neuropathy, mostly sensory and cumulative, from microtubule disruption (like vinca alkaloids). - Progressive multifocal leukoencephalopathy (PML) from JC virus reactivation. This is a boxed warning. - Neutropenia and other cytopenias. - Infusion reactions and anaphylaxis. - Tumor lysis syndrome. - Stevens-Johnson syndrome/TEN. - Hepatotoxicity. - Pancreatitis. - Pulmonary toxicity. - Fatigue, nausea, and diarrhea. - Embryo-fetal toxicity.

**Key drug interaction/contraindication:** Concomitant bleomycin is contraindicated because of increased pulmonary toxicity. Strong CYP3A4 inhibitors (for example, ketoconazole) raise MMAE exposure, and strong CYP3A4 inducers (for example, rifampin) lower it.

**Board pearls:** - The suffix "-ximab" denotes a chimeric monoclonal antibody. "-vedotin" denotes the MMAE payload. - Think "CD30 = Hodgkin (Reed-Sternberg) and ALCL." - Rituximab targets CD20, alemtuzumab targets CD52, and gemtuzumab ozogamicin targets CD33. Brentuximab targets CD30. - Brentuximab's neuropathy resembles vinca alkaloid toxicity, because both disrupt microtubules. - Dose adjustment is needed in hepatic impairment (avoid in severe impairment).