A New Combination as First-Line Regimen in Advanced Hodgkin Lymphoma?
Atlanta, GA—Adding brentuximab vedotin (Adcetris) to doxorubicin, vinblastine, and dacarbazine (A+AVD) instead of the standard regimen with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for advanced Hodgkin lymphoma reduced the risk for disease progression, death, or the need for additional therapy by 23%, according to new data presented at ASH 2017.
Lead investigator Joseph M. Connors, MD, FRCPC, Clinical Director, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, Canada, reported the results of the phase 3 ECHELON-1 clinical trial, which were also published online (Connors JM, et al. N Engl J Med. 2018;378:331-344) to coincide with the ASH meeting.
The A+AVD regimen improved the chances of cure with the first round of chemotherapy, obviating the need for additional, more intensive therapy, and reducing the odds of toxicity. Overall, 33% fewer patients who received A+AVD as frontline therapy required subsequent salvage therapy or high-dose chemotherapy and transplant compared with those who received standard therapy with ABVD.
ABVD has been the standard-of-care regimen for approximately 40 years. Although the majority of patients with Hodgkin lymphoma are cured, an estimated 25% to 33% require additional therapy. The new regimen replaces bleomycin with brentuximab vedotin.
“Many of these patients are younger. Bleomycin can cause life-threatening pulmonary toxicity, and causes sterility in males and compromised fertility in females. The removal of bleomycin and addition of brentuximab vedotin represents a major step forward for the Hodgkin lymphoma community,” said Dr Connors.
“About 25% of patients who would otherwise fail [treatment] were successfully treated with the new combination,” he said. “If this new regimen is widely adopted, it will change first-line treatment of advanced Hodgkin lymphoma,” added Dr Connors.
ECHELON-1 was a randomized, open-label, multicenter, phase 3 clinical trial that was conducted at 218 sites in 21 countries. Overall, 1334 patients with histologically confirmed stage III or IV Hodgkin lymphoma were randomized to receive A+AVD (experimental arm) or standard treatment with ABVD. All patients received treatment for up to 6 cycles.
For the primary end point, A+AVD achieved a significant 23% improvement in modified progression-free survival (PFS; including disease progression, death, or need for subsequent therapy) versus ABVD (P = .035); the 2-year modified PFS was 82.2% versus 77.2%, respectively, per independent review.
The secondary end points also favored A+AVD over ABVD. The complete response rate was 73% in the A+AVD arm versus 70% in the ABVD arm, and the objective response rate was 86% versus 83%, respectively.
Reduced Pulmonary Toxicity
The most common grade 3 or 4 adverse events with A+AVD were neutropenia, febrile neutropenia, and a reduction in neutrophil count. The use of growth factor support with granulocyte colony-stimulating factor (G-CSF) reduced the rate of febrile neutropenia from 21% at baseline to 11% in the A+AVD arm. Primary prophylaxis with G-CSF is now recommended with A+AVD.
“There was an excess in treatment-emergent peripheral neuropathy in the experimental arm [67% with A+AVD vs 43% with ABVD], but with appropriate changes in schedule and doses, two-thirds of patients reported peripheral neuropathy resolved or improved,” Dr Connors said.
Pulmonary toxicity, which is a major concern with bleomycin therapy, was reported in 2% of patients in the A+AVD arm versus 7% of patients in the ABVD arm. Fewer than 1% of patients in each arm reported grade ≥3 pulmonary toxicity.
Overall, 9 patients died in the A+AVD arm (7 in patients with neutropenia not treated with G-CSF) and 13 patients in the ABVD arm (11 in association with pulmonary toxicity).
George P. Canellos, MD, Medical Director, Network Development, Dana-Farber Cancer Institute, Boston, MA, was cautious about endorsing A+AVD as a new standard of care. “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,” said Dr Canellos.
He noted that the need for growth factor support will escalate treatment costs of the new regimen. “It is not clear whether these data will lead to approval of brentuximab vedotin for frontline treatment of advanced Hodgkin lymphoma,” stated Dr Canellos.