For the front-line treatment of advanced Hodgkin lymphoma, ABVD is a standard treatment, but not all patients have good outcomes with this regimen. The addition of brentuximab vedotin (Adcetris), or its substitution for bleomycin, produces high complete response rates but with a moderate increase in toxicity, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic, Rochester, Minnesota.

At the 9th International Symposium on Hodgkin Lymphoma, held recently in Cologne, Germany, Dr. Ansell discussed ways to improve upon ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).

In an interview with The ASCO Post, Dr. Ansell provided some context for the study of brentuximab. “Over the years, there has been significant debate about what’s the best front-line treatment for advanced Hodgkin lymphoma. In Europe, they use escalated BEACOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane], prednisone), a more intense regimen than ABVD, which is what is commonly used in North America,” Dr. Ansell noted.

BEACOPP vs ABVD

A number of head-to-head comparisons have shown that escalated BEACOPP produces higher complete response rates and improved progression-free survival over ABVD, but this comes at the price of more infertility and hematologic toxicity as well as long-term toxicities, he pointed out.

“For complete response and progression-free survival, BEACOPP has an edge, but toxicity is the problem,” Dr. Ansell said.

The most recent studies, however, have suggested that these two regimens may have similar long-term outcomes when subsequent salvage therapy is also included in the analysis. “At the end of the day, the roads seem to converge,” he said.

With ABVD as the initial therapy, approximately 75% of advanced-stage Hodgkin lymphoma patients obtain a complete response, and the 5-year failure-free survival rate is 75%. “If you are in this 75% group, you can get away with less therapy and far less long-term toxicity,” Dr. Ansell noted.

Improving Upon ABVD

A problem with routine acceptance of ABVD, he acknowledged, is that it is less successful in certain patient subgroups, including:

• Elderly patients (> 60 years old), who have a 5-year failure-free survival rate of approximately 55%
• Patients with stage III/IV disease, who have a 5-year failure-free survival rate of approximately 65%
• Patients with an International Prognostic Score (IPS) of 3 to 7, who have a 5-year failure-free survival rate of approximately 65%

Much of the problem is the result of bleomycin-related toxicity. In a subset analysis of the recent E2496 trial of ABVD, 24% of older patients developed bleomycin-related lung toxicity and 18% died.¹ Escalated BEACOPP is also not acceptable for patients over 60, creating a large population with an unmet need, Dr. Ansell emphasized.

A number of modifications of ABVD have been attempted in an effort to make ABVD less toxic and more suitable for the subgroup of patients who are older, have poor performance status, are at high risk for progression, or have more advanced disease, but these approaches have been unsuccessful. They have included intensification of therapy (which proved too toxic to older patients), omission of dacarbazine (which reduced progression-free survival) and substitution of bleomycin and dacarbazine with gemcitabine (which led to inferior outcomes).

“You can shave 10% to 15% off your enthusiasm for ABVD based on these groups,” he commented.

Adding Brentuximab

Perhaps the best way to modify ABVD is to add or substitute a novel agent, Dr. Ansell suggested. At the Cologne symposium, Dr. Ansell discussed the results from a phase I study of brentuximab by the Mayo Clinic, the British Columbia Cancer Research Centre, The University of Texas MD Anderson Cancer Center, and The University of North Carolina.²

The study evaluated brentuximab in addition to ABVD or as a substitute for bleomycin (AVD plus brentuximab). The substitution was made after the observation that adding brentuximab created more bleomycin toxicity. “In the second half of the study we eliminated the bleomycin, and the results were very encouraging,” Dr. Ansell told The ASCO Post.

Complete responses after the conclusion of front-line therapy were achieved by 21 (95%) of the 22 patients receiving ABVD plus brentuximab and by 24 (96%) of the 25 receiving AVD plus brentuximab. Only one patient, who was receiving AVD with brentuximab, had disease progression. One patient in the ABVD/brentuximab cohort developed grade 5 pulmonary toxicity during treatment and was not evaluable.

ECHELON-1

“This was a very high response rate, and the addition of the drug was well tolerated, so we initiated the large randomized ECHELON-1 trial,” he said.

ECHELON-1 is an international study enrolling more than 1,000 treatment-naive patients with stage IIA bulky or stage IIB–IV disease. Patients will be randomly assigned to two cycles of ABVD or AVD plus brentuximab, and upon response assessment based on Deauville score, they will either continue the protocol-assigned therapy for four additional cycles or switch to an alternative treatment.

“If positive, this study will define the practice of front-line therapy in advanced Hodgkin lymphoma patients,” Dr. Ansell predicted. ■

Disclosure: Dr. Ansell receives research funding from Seattle Genetics and is a member of the steering committee for the ECHELON-1 trial.

References

1. Evens AM, Hong F, Gordon LI, et al: The efficacy and tolerability of adriamycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: A comprehensive analysis from the North American intergroup trial E2496. Br J Haematol 161:76-86, 2013.

2. Ansell SM, Conors JM, Park SI, et al: Front-line therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. 9th International Symposium on Hodgkin Lymphoma. Abstract P005. Presented October 15, 2013.