“The removal of bleomycin and addition of brentuximab vedotin represents a major step forward for the Hodgkin lymphoma community.”— Joseph M. Connors, MD
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FRONT-LINE TREATMENT of advanced Hodgkin lymphoma with brentuximab vedotin (Adcetris) plus doxorubicin/ vinblastine/dacarbazine (A+AVD) achieved superior outcomes compared with the standard four-drug regimen of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD). The substitution of brentuximab vedotin for bleomycin in the new regimen achieved a 23% reduction in the risk of disease progression, death, or the need for additional therapy compared with standard treatment in the phase III ECHELON-1 study, presented at the Plenary Session during the 59th Annual Meeting and Exposition of the American Society of Hematology (ASH).
This means that the addition of brentuximab vedotin to standard treatment improved the chances of being cured with the first round of treatment, avoiding the need for additional, more intensive therapy. In the study, 33% fewer patients treated with A+AVD required subsequent salvage therapy or high-dose chemotherapy and transplant compared with patients treated with ABVD alone.
Study results were published online at The New England Journal of Medicine website to coincide with the presentation at the ASH meeting.
“Hodgkin lymphoma is a success story in modern oncology. A large percentage of patients are cured with ABVD front-line therapy, but 25% to 33% do not achieve remission and need subsequent therapy, and some patients die of their disease. ABVD has been used for 40 years, and the challenge has been to improve on that combination without adding irreversible toxicity, such as infertility or unpredictable and potentially fatal pulmonary toxicity associated with bleomycin. Many of these patients are younger. Some regimens, although more effective than ABVD, cause sterility in men and compromised fertility in women. The removal of bleomycin and addition of brentuximab vedotin represents a major step forward for the Hodgkin lymphoma community,” said lead author Joseph M. Connors, MD, Clinical Director, Center for Lymphoid Cancer at the British Columbia Cancer Center in Vancouver, Canada.
“About 25% of patients who would otherwise experience failure of primary chemotherapy to cure their lymphoma were successfully treated with the new combination,” Dr. Connors noted. “If this new regimen is widely adopted, it will change first-line treatment of advanced HL.”
Key Study Findings
ECHELON-1 is a randomized, open-label, two-arm, multicenter phase III study conducted at 218 sites in 21 countries. Patients (n = 1,334) with histologically confirmed stage III or IV classical Hodgkin lymphoma were randomized to receive A+AVD (experimental arm) or standard ABVD. The median age
of patients was 35 years in the experimental arm and 37 years in the control arm. Patients were treated on days 1 and 15 for each 28-day cycle for up to 6 cycles.
“There was an excess in treatment-emergent peripheral neuropathy in the experimental arm, but with appropriate changes in schedule and doses, two-thirds of patients reported peripheral neuropathy resolved or improved.”— Joseph M. Connors, MD
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The study achieved its primary endpoint, with a statistically significant 5% improvement in modified progression-free survival (including disease progression, death, or need for subsequent therapy) in the A+AVD arm vs ABVD (P = .035). Two-year modified progression-free survival was 82.2% vs 77.2%, respectively, per independent review.
Secondary endpoints also favored the experimental arm numerically. The complete response rate was 73% vs 70%, respectively. The objective response rate was 86% vs 83%, respectively. In addition, 33% fewer patients in the experimental arm needed salvage chemotherapy or high-dose chemotherapy and transplant.
THE MOST FREQUENT and clinically relevant adverse events of any grade were neutropenia (58% in the experimental arm vs 45% with ABVD); constipation (42% vs 37%, respectively), vomiting (33% vs 28%, respectively), fatigue (32% in both arms), peripheral sensory neuropathy (29% vs 17%, respectively), diarrhea (27% vs 18%, respectively), abdominal pain (21% vs 10%, respectively), and stomatitis (21% and 16%). The most common grade 3 and 4 events were neutropenia and febrile neutropenia.
When simple measures were used, some adverse events were reduced. For example, the use of granulocyte colony-stimulating factor (G-CSF) reduced the rate of febrile neutropenia from 21% to 11%, Dr. Connors noted. “Primary prophylaxis with G-CSF is now recommended with A+AVD,” he said. Use of G-CSF resulted in an overall comparable safety profile to that of ABVD.
“There was an excess in treatment-emergent peripheral neuropathy in the experimental arm (67% vs 43%, respectively), but with appropriate changes in schedule and doses, two-thirds of patients reported peripheral neuropathy resolved or improved,” he added. Pulmonary toxicity was reported in 2% of the experimental arm vs 7% of the ABVD arm. Less than 1% of patients on the A+AVD arm but 3% of those given ABVD reported grade 3 or higher pulmonary toxicity.
Deaths occurring on study were reported in 9 patients in the A+AVD arm (7 in those with neutropenia not treated with G-CSF) and 13 in the ABVD arm (11 due to or associated with pulmonary toxicity).
“The experimental combination with brentuximab vedotin more frequently got rid of all of the disease, and this was achieved with acceptable levels of adverse effects,” said Dr. Connors. “Treatment with brentuximab vedotin was modestly more toxic, but when we added simple measures to improve their blood cell counts, [patients] were able to take it successfully.”
At a formal ASH press conference, Dr. Connors was asked about the escalated BEACOPP (bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine) regimen used in Europe. He replied: “Escalated BEACOPP is not appropriate for patients over age 50, who comprise about 20% of patients with Hodgkin lymphoma. In Germany, they are also studying how to integrate brentuximab vedotin into that regimen to reduce toxicity. Here in North America, we want to integrate it into the ABVD recipe. We are all moving toward the same goal: to treat advanced Hodgkin lymphoma with a regimen that is less toxic and maintains a high level of cure.”
Laurie Sehn, MD
Peter Hillmen, MD
“PATIENTS WITH HODGKIN LYMPHOMA are often very young, and delayed treatment toxicities are a major concern,” said Laurie Sehn, MD, who moderated a press conference where these data were discussed. “The treatment regimen of ABVD was developed 40 years ago. It is astounding that we are still using that platform for this common hematologic malignancy. It is logical to move forward with more targeted agents that could be more effective with minimal toxicities.” She added: “I want to underscore that 25% of patients who otherwise would have failed [to respond to] ABVD can now achieve complete remission with this new regimen.” Dr. Sehn is a medical oncologist at the BC Cancer Agency and Clinical Associate Professor at the University of British Columbia, Vancouver, Canada.
“It is much too early to say this is practice-changing, with only a small progression-free survival difference and a short duration of follow-up.”— George Canellos, MD
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Weighing in on the discussion at the press conference, Peter Hillmen, MD, noted: “Bleomycin is the most toxic drug in ABVD. It is desirable to have a therapy that replaces bleomycin. Overall survival is the most important endpoint. We will have to follow salvage therapies to see relapses and whether this treatment will translate to improved survival.” Dr. Hillmen is a consultant hematologist at the Leeds Teaching Hospitals NHS Trust and is based at St. James University Hospital, Leeds, UK.
George Canellos, MD, of Dana-Farber Cancer Institute, Boston, and a pioneer in developing chemotherapy for Hodgkin lymphoma, introduced Dr. Connors’ presentation at the ASH Plenary Session. Dr. Canellos expressed some caution. “Should we now consider A+AVD as the new standard of care in advanced classical Hodgkin lymphoma? Not so quick! It is much too early to say that this is practice-changing, with only a small progression-free survival difference and a short duration of follow-up.”
Dr. Canellos pointed out that the need for growth factor support with the addition of brentuximab vedotin will escalate treatment costs of the new regimen. It is not clear whether these data will lead to approval of brentuximab vedotin for front-line treatment of advanced Hodgkin lymphoma.
Funding for this study was provided by Seattle Genetics and Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical. ■
DISCLOSURE: Dr. Connors’ institution, the British Columbia Cancer Agency, receives research funding from Amgen, Bayer, Bristol-Myers Squibb, Cephalon, F. Hoffmann-La Roche, Genentech, NanoString Technologies, Janssen, Lilly, Merck, Seattle Genetics, Inc., and Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. Dr. Sehn reported no conflicts of interest.
1. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin plus doxorubicin, vinblastine, dacarbazine (A+AVD) as frontline therapy demonstrates superior modified progression-free survival versus ABVD in patients with previously untreated stage III or IV Hodgkin lymphoma: The phase 3 Echelon-1 study. 2017 ASH Annual Meeting. Abstract 6. Presented December 10, 2017.
2. Connors JM, Jurczak W, Straus DJ, et al: Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma. N Engl J Med. December 10, 2017 (early release online).