Brentuximab: is it time for a new “B” in ABVD?

In this issue of Blood, Connors et al report promising 5-year outcomes that support the replacement of bleomycin with brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (AVD) for the front-line treatment of patients with advanced-stage Hodgkin lymphoma.¹ 

Fortunately, most patients with advanced-stage Hodgkin lymphoma are cured with front-line standard chemotherapy.^2,3  In the United States, the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is generally considered the preferred regimen to treat these patients secondary to multiple large phase 3 studies that have demonstrated significant efficacy of the regimen combined with fewer toxicities when compared with more aggressive regimens.^2,3  Although treatment with ABVD has cured a majority of patients, we have been left with at least 2 pressing issues:

1. Relapsed/refractory disease. Up to 30% of patients are not cured with initial ABVD therapy, as evidenced by a reported 10-year progression-free survival (PFS) rate of 69%.²  These patients with relapsed/refractory disease require treatment with aggressive therapy, often including salvage chemotherapy and stem-cell rescue. Even with these therapies, only ∼50% of these patients are alive and disease free 10 years after treatment.⁴  An improved front-line treatment strategy is needed to improve the cure rate for these patients.

2. Bleomycin-induced pulmonary toxicity. Although ABVD has relatively limited toxicities, one of particular concern is bleomycin-related pulmonary toxicity. This adverse event can be seen in 10% to 50% of patients with Hodgkin lymphoma treated with bleomycin, with ∼20% of these cases considered to be severe (grade ≥3) toxicity.⁵  This pulmonary damage has been reported to be fatal in ∼4% of those with mild/moderate (grade 1 or 2) toxicity and up to 25% of those with severe toxicity.⁵  Additionally, long-term respiratory compromise has been reported in ∼15% of those who develop the toxicity.⁵  Clearly, this long-term adverse effect can be detrimental to quality of life, especially in patients who are cured from their Hodgkin lymphoma. In response to these concerns and retrospective data that suggest no decrease in response or survival after stopping bleomycin at time of detection of pulmonary toxicity, efforts have been made to identify patients in whom bleomycin can be safely discontinued.⁵  A large phase 3 study randomly assigned patients with advanced Hodgkin lymphoma who had a negative positron emission tomography scan (Deauville score ≤3) after 2 cycles of ABVD to omit or continue bleomycin therapy for the remaining 4 cycles.⁶  The study found that patients had a similar 3-year PFS rate in both arms and less pulmonary toxicity if bleomycin was stopped.⁶  These data support the limitation of bleomycin therapy, and one strategy is to replace bleomycin with a more effective and less toxic agent.

Several novel therapeutic agents have been developed for Hodgkin lymphoma, and one of the most promising therapies is brentuximab vedotin. This compound is an antibody-drug conjugate designed to deliver the cytotoxic agent monomethyl auristatin E directly to CD30-expressing cells. Because CD30 is reliably expressed on Hodgkin lymphoma Reed-Sternberg cells, it has shown considerable efficacy in this disease. In relapsed/refractory Hodgkin lymphoma, brentuximab vedotin demonstrated an impressive overall response rate of 75%, leading to US Food and Drug Administration approval of the drug in this setting.⁷  In addition to the efficacy of the drug, toxicities of brentuximab vedotin are somewhat limited, most notably with reversible neuropathy.

On the basis of the clinical efficacy and safety of brentuximab vedotin and the goal of improving efficacy of ABVD, the authors initially embarked on a phase 1 study of front-line therapy in patients with advanced Hodgkin lymphoma (n = 51) to determine the safety of adding brentuximab vedotin (1.2 mg/kg IV every 2 weeks) to either ABVD or AVD.⁸  Initial safety data showed an increased rate of pulmonary toxicity in the brentuximab vedotin plus ABVD arm (44%) that was not seen in the brentuximab vedotin plus AVD arm, indicating that brentuximab vedotin and bleomycin cannot safely be combined.⁸  Secondary to high efficacy (complete response rate of 95%), the authors initiated a long-term follow-up study of these patients, which is described in this issue of Blood.^1,8 

Connors et al report the primary outcomes of failure-free and overall survival in these patients, which demonstrate the durability of the initial responses noted in the phase 1/2 study: impressive rates of 5-year failure-free and overall survival of 79% and 92%, respectively, for the brentuximab vedotin plus ABVD arm (n = 25) and 92% and 100%, respectively, for the brentuximab vedotin plus AVD arm (n = 26). No unexpected toxicities were detected in the brentuximab vedotin plus AVD arm; only 2 of the patients relapsed, and both have since achieved second remission.¹ 

Although these phase 1/2 data are limited by the small number of patients (n = 51), they have spurred significant interest in brentuximab vedotin plus AVD as front-line therapy for advanced Hodgkin lymphoma. Because of the potential of enhanced efficacy and the elimination of bleomycin-induced pulmonary toxicity, could brentuximab vedotin replace bleomycin in ABVD as the standard of care for these patients? To definitively answer this question, a large phase 3 study (ECHELON-1) is ongoing, in which treatment-naive patients with advanced Hodgkin lymphoma have been randomly assigned to ABVD versus brentuximab vedotin plus AVD. The primary end point of the trial is 2-year PFS, and preliminary press releases from the trial sponsors indicate that this end point has been reached, with a statistically significant benefit in the brentuximab plus AVD arm. The official release of the data is expected at the American Society of Hematology annual meeting in December 2017. Although no official data have been released, the available evidence certainly predicts a change in the standard of care in the front-line setting for patients with advanced Hodgkin lymphoma. In the near future, the “B” of ABVD may stand for brentuximab vedotin.