ArticlesBrentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study
Introduction
Advances such as radiotherapy and combination chemotherapy in the first-line treatment of Hodgkin's lymphoma have contributed to improved outcomes for these patients in the past decades. More recently, the introduction of more dose-intense chemotherapy regimens for advanced stage Hodgkin's lymphoma has been associated with treatment success.1 For patients with advanced stage Hodgkin's lymphoma multiple first-line and second-line treatments, including the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)—internationally, the most widely used regimen in Hodgkin's lymphoma—is expected to cure about 70–80% of patients.2, 3, 4, 5, 6, 7 However, in addition to treatment failures noted for ABVD, the regimen is often associated with unpredictable bleomycin-induced lung-related toxic effects that can be life-threatening.8, 9, 10
Brentuximab vedotin (Seattle Genetics Inc, Bothell, WA, USA) is an antibody–drug conjugate composed of a CD30-targeted chimeric monoclonal antibody covalently linked, via a protease-cleavable linker, to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In a phase 2 single-arm study11 of patients with relapsed or refractory Hodgkin's lymphoma treated with brentuximab vedotin after failure of high-dose chemotherapy and postautologous stem-cell transplant, 76 (75%) of 102 patients achieved an objective response, and 35 patients (34%) achieved complete remission. Adverse events were manageable with dose reduction or delay.
Brentuximab vedotin was also tested preclinically in combination with chemotherapy. In the L450cy Hodgkin's lymphoma xenograph model, administration of ABVD plus brentuximab vedotin in tumour-bearing mice showed significantly increased antitumour activity than in mice treated with ABVD or brentuximab vedotin alone, suggesting a potentially synergistic effect.12 We aimed to assess the safety of brentuximab vedotin in combination with standard, or modified standard chemotherapy, for the treatment of patients with advanced, treatment-naive, Hodgkin's lymphoma.
Section snippets
Study design
We did a phase 1, open-label, dose-escalation safety study of brentuximab vedotin in combination with standard therapy (ABVD), or a modified standard that omitted bleomycin (AVD) at four study sites (three in the USA and one in Canada; appendix). Our primary objectives were to assess the safety profile of treatment with brentuximab vedotin plus ABVD or AVD, and to establish the maximum tolerated dose in combination with each. Our secondary objectives were to assess the incidence of
Results
Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. Figure 1 shows the study profile and table 1 lists the patients' baseline characteristics. A greater proportion of patients were men, and most patients were white. Most patients had characteristics indicative of high-risk disease; nearly half the patients treated in the study had stage IV disease, and many patients presented at baseline with bulky disease.
15 (60%) of 26
Discussion
Our findings show that brentuximab vedotin should not be given with bleomycin in general or specifically in newly diagnosed advanced stage Hodgkin's lymphoma; however, when combined with AVD given every 2 weeks, this combination was generally well tolerated and resulted in 96% of evaluable patients who completed first-line therapy achieving complete remission. The maximum tolerated dose did not exceed the maximum planned dose of 1·2 mg/kg brentuximab vedotin, in combination with either ABVD or
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2022, Blood ReviewsCitation Excerpt :The combinations elicited similar complete remission rates of 95% and 96%, respectively. However, patients receiving BV plus ABVD had severe pulmonary toxic effects [42]. Furthermore, patients receiving BV plus AVD had an estimated 5-year failure-free survival rate of 79% and an overall survival (OS) rate of 92% [43].