Advances in LLM: Brentuximab vedotin in relapsed/refractory Hodgkin lymphoma.

Although the majority of patients with Hodgkin lymphoma attain a complete response with initial combination chemotherapy and/or radiotherapy, 20–40% of patients with newly diagnosed, advanced-stage Hodgkin lymphoma are refractory to initial therapy or relapse following a response.1,2 The optimal second-line treatment approach for these patients is high-dose chemotherapy followed by autologous stem cell transplantation (SCT).3 However, autologous SCT induces durable long-term remission in approximately half of patients. For the remaining patients, outcomes are poor, with a median survival of 28 months.4 The lack of effective therapies for this relatively young population has been a key unmet need in cancer therapy. Hodgkin lymphoma is characterized by the presence of Reed-Sternberg cells that express CD30, a tumor necrosis factor superfamily member. Expression of CD30 on normal cells is limited to a small proportion of activated lymphocytes and eosinophils. The highly restricted expression pattern of CD30 makes it an attractive therapeutic target in Hodgkin lymphoma and other CD30-positive malignancies, such as systemic anaplastic large-cell lymphoma (ALCL). The antibody-drug conjugate (ADC) brentuximab vedotin (Adcetris, Seattle Genetics) was developed to selectively deliver cytotoxic therapy to CD30-expressing cells. Brentuximab vedotin consists of an anti-CD30 antibody conjugated to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease cleavable linker. Binding of brentuximab vedotin to CD30 triggers internalization of the ADC-CD30 complex. In the lysosomal compartment, MMAE is proteolytically cleaved, enabling it to bind tubulin. The binding of MMAE to tubulin disrupts the microtubule network, prevents cell cycle progression, and causes cell death.5 Brentuximab vedotin was initially evaluated in a phase I study in 45 patients with relapsed or refractory CD30-positive lymphomas.6 In that study, brentuximab vedotin demonstrated significant antitumor activity and was fairly well tolerated, with primary adverse events including fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy. The study identified the maximum tolerated dose as 1.8 mg/kg administered intravenously every 3 weeks; this dosing schedule was selected for further study. Based on the promising activity and acceptable safety profile in the phase I study, 2 pivotal phase II studies were undertaken to further evaluate the efficacy and safety of brentuximab vedotin: one in patients with Hodgkin lymphoma and the other in patients with systemic ALCL. Both studies showed high response rates and acceptable toxicity, resulting in the FDA approval of brentuximab vedotin for both indications in 2011. The pivotal trial in Hodgkin lymphoma is described here.7,8