New Hodgkin’s lymphoma regimen is more effective with less pulmonary toxicity

By Robyn Boyle, RPh, for MDLinx
Published March 9, 2018

Key Takeaways

A study published in the New England Journal of Medicine found that replacing bleomycin with brentuximab vedotin in the standard treatment regimen for Hodgkin’s lymphoma is more effective and causes less pulmonary-related toxicity. Brentuximab vedotin is an anti-CD30 antibody drug conjugate.

The ECHELON-1 Study Group, led by Joseph M. Connors, MD, FRCPC, from the University of British Columbia in Vancouver, Canada, evaluated progression-free survival in a randomized, open-label, multicenter, phase 3 trial in previously untreated patients with stage III or IV classic Hodgkin’s lymphoma.

Since 1975, the most commonly used regimen for treating advanced-stage Hodgkin’s lymphoma has been doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Efforts are being made to incorporate new drugs in the regimen, as up to 30% of patients with stage III or IV Hodgkin’s lymphomas relapse after treatment with ABVD. In addition, bleomycin is often dropped from later cycles due to pulmonary toxicity.

The ECHELON-1 study was designed to compare ABVD to a regimen with brentuximab vedotin plus AVD (A+AVD) as frontline therapy in stage III or IV classic Hodgkin’s lymphoma.

The A+AVD regimen consisted of brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2. The ABVD regimen included doxorubicin 25 mg/m2, bleomycin 10 U/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2.

Participants were randomly assigned 1:1 to receive A+AVD or ABVD intravenously on days one and 15 of each 28-day cycle for up to six cycles.

Patients were stratified based on region (Americas, Europe, Asia) as well as International Prognostic Score (IPS), a value that indicates the risk of treatment failure (range 0-7; 0=low risk, 7=highest risk).

The results of positive-emission tomography (PET) imaging conducted at the end of the second cycle, along with other factors, guided the decision to switch to an alternative frontline therapy.

Patients 18 years of age or older with histologically confirmed advanced classic Hodgkin’s lymphoma who had not previously received treatment were included in the study. Patients were required to be ambulatory with limited disability based on the Eastern Cooperative Oncology Group (ECOG) Performance Status scale. In addition, participants were to have satisfactory absolute neutrophil and platelet counts, as well as satisfactory markers of liver and renal function.

The primary end point of the study was modified progression-free survival defined as time to disease progression, death, or modified progression (non-complete response after completing frontline therapy followed by subsequent treatment).

A total of 1,334 patients at 218 sites in 21 countries were assigned to receive A+AVD (n=664) or ABVD (n=670).

Baseline characteristics were similar between the groups; 58% were men, 64% had stage IV disease, and 62% had extranodal involvement at diagnosis. The median age was 36 years.

After a median follow-up of 24.9 months, the modified progression-free survival was significantly higher in the A+AVD group than in the ABVD group—82.1% vs 77.2% in 2-year progression-free survival rate in A+AVD vs ABVD groups, respectively.

Overall survival was the secondary endpoint. It was defined as the time from randomization to death from any cause, and was to be performed if the result of the primary analysis was statistically significant. The interim 2-year overall survival rate was 96.6% vs 94.9% in the A+AVD vs ABVD groups, respectively, which corresponded to a reduction in the risk of death of 28% in favor of the A+AVD group.

Only 15 of the patients receiving A+AVD and nine receiving ABVD switched to alternative chemotherapy for reasons other than disease progression. Fewer participants in the A+AVD group than in the ABVD group received subsequent anticancer therapy.

Certain subgroups appeared to benefit more with A+AVD than with ABVD including men, North Americans, patients with involvement of more than one extranodal site, patients with an IPS indicating high risk of treatment failure, patients with stage IV disease, and patients younger than 60 years of age.

In general, the incidence of neutropenia and febrile neutropenia were higher in participants of the A+AVD group than in the group receiving ABVD, but the rate of discontinuation due to either was 1% or less in both groups.

Similarly, the rate of infections was higher in the A+AVD group and led to the recommendation of primary prophylaxis with granulocyte colony-stimulation factor (G-CSF) for patients yet to be enrolled who were randomized to A+AVD. Rates of neutropenia, febrile neutropenia, and serious infection were reduced in the subset of 83 patients who received G-CSF.

Peripheral neuropathy was more likely to be reported in the A+AVD group, and discontinuation due to peripheral neuropathy was higher in the A+AVD group than in the ABVD group. Peripheral neuropathy was reversible in most patients; it resolved in 43%, and improved by at least one grade in 24% of patients at the time of last follow-up visit.

Pulmonary toxicity, defined as events related to interstitial lung disease, was reported more frequently in patients in the ABVD group than in patients receiving A+AVD.

During the treatment period, there were nine deaths in the A+AVD group (7 associated with neutropenia and 2 due to myocardial infarction) and 13 deaths in the ABVD group (11 associated with pulmonary-related toxicity, 1 due to cardiopulmonary failure, and 1 cause unknown).

“This large, international, randomized phase 3 trial involving patients who had received a recent diagnosis of stage III or IV classic Hodgkin’s lymphoma showed that treatment with brentuximab vedotin plus AVD, as compared with standard treatment with ABVD, resulted in a statistically significant and clinically meaningful improvement in the rate of modified progression-free survival”, concluded the authors.

Furthermore, they stated that the elimination of bleomycin from frontline therapy in the A+AVD regimen lowers the incidence of pulmonary toxicity.

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