Study Overview
Objective. To compare the efficacy of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) with that of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage III or IV classic Hodgkin’s lymphoma.
Design. The ECHELON-1 trial, an international, openlabel, randomized phase 3 trial.
Setting and participants. In this multicenter international trial, a total of 1334 patients underwent randomization from November 2012 through January
2016. Eligible patients were 18 years of age older and had newly diagnosed and histologically proven classic Hodgkin’s lymphoma, Ann Arbor stage III or IV. Patients were eligible only if they had not received prior systemic chemotherapy or radiotherapy. All patients were required to have an ECOG performance status of ≤ 2 and adequate hematologic parameters (hemoglobin ≥ 8, ANC ≥ 1500, and platelet count ≥ 75,000). Patients with nodular lymphocyte predominant Hodgkin’s lymphoma, pre-existing peripheral sensory neuropathy, or known cerebral or meningeal disease were excluded.
Intervention. Patients were randomized in a 1:1 fashion to receive A+AVD (brentuximab vedotin 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2 and dacarbazine 375 mg/m2) IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. A PET scan was done at the end of the second cycle (PET2) and if this showed increased uptake at any site or uptake at a new site of disease (Deauville score 5) patients could be switched to an alternative frontline therapy at the treating physician’s discretion.
Main outcome measures . The primary endpoint of this study was modified progression-free survival (mPFS), defined as time to disease progression, death, or modified progression (noncomplete response after completion of frontline therapy—Deauville score 3, 4, or 5 on PET). Modified progression was incorporated as an endpoint in order to assess the effectiveness of frontline therapy. A secondary endpoint of the study was overall survival (OS).
Results. The baseline characteristics were well balanced between the treatment arms. 58% of the patients were male and 64% had stage IV disease. The median age was 36 years and 9% in each group were over the age of 65. After a median follow-up of 24.9 months, the independently assessed 2-year mPFS was 82.1% and 77.2% in the A+AVD and ABVD groups, respectively (hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.6–0.98). The 2-year mPFS rate according to investigator assessment was 81% and 74.4% in the A+AVD and ABVD groups, respectively. Modified progression (failure to achieve a complete response after completion of frontline therapy resulting in treatment with subsequent therapy) occurred in 9 and 22 patients in the
A+AVD and ABVD groups, respectively. A pre-specified subgroup analysis showed that patients from North America, male patients, patients with involvement of more than 1 extranodal site, patients with a high IPSS score (4–7), patients < 60 years old and those with stage IV disease appeared to benefit more from A+AVD. The rate of PET2 negativity was 89% with A+AVD and 86% with ABVD. The 2-year overall survival was 96.6% in the A+AVD group and 94.9% in the ABVD group (HR 0.72; 95% CI 0.44–1.17). Fewer patients in the A+AVD group received subsequent cancer-directed therapy.
Neutropenia was more commonly reported in the A+AVD group (58% vs. 45%). Moreover, febrile neutropenia was reported in 19% and 8% of patients in the A+AVD and ABVD groups, respectively. Discontinuation rates in either arm for febrile neutropenia was ≤ 1%. The rate of infections was 55% in the A+AVD group and 50% in the ABVD group (grade 3 or higher: 18% and 10%, respectively). After review of the rates of febrile neutropenia, the safety monitoring committee recommended that primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) be used for patients who were yet to be enrolled. The rate of febrile neutropenia in the 83 patients in the A+AVD group who received primary prophylaxis was lower than those who did not (11% vs. 18%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and 42% in the ABVD group (grade 3 or higher: 11% vs 2%, respectively). Neuropathy lead to discontinuation of a study drug in 10% of patients in the A+AVD group. 67% of patients with peripheral neuropathy in the A+AVD group had resolution or improvement by one grade of their neuropathy at the time of last follow up. Pulmonary toxicity was reported in 2% of patients in the A+AVD group and 7% of the ABVD group (grade 3 or higher: < 1% vs. 3%, respectively). During treatment, 9 deaths were reported in the A+AVD group and 13 deaths in the ABVD group. Of the deaths in the ABVD group, 11 were associated with pulmonary toxicity.
Conclusion. A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma.
Commentary
Hodgkin’s lymphoma (HL) accounts for approximately 10% of all lymphomas in the world annually [1]. While outcomes with frontline therapy for patients with HL have dramatically improved with ABVD, up to 30% of patients have either refractory disease or relapse after initial therapy [2,3]. One particular area of concern in the current treatment of HL with ABVD is the associated pulmonary toxicity of bleomycin. Pulmonary toxicity from bleomycin occurs in approximately 20%–30% of patients and can lead to long-term morbidity [4,5]. In addition, approximately 15% or more of HL patients are elderly and may have co-existing pulmonary disease. In the previously published E2496 trial, the risk of bleomycin lung toxicity in the elderly was 24% [3]. Although the risk of clinically relevant lung toxicity remains low, there is considerable concern about this amongst clinicians. Recent data has challenged the benefit of bleomycin as a component of ABVD. For example, Johnson and colleagues have shown that in patients with a negtive PET scan after 2 cycles of ABVD, the omission of bleomycin (ie, continuation of AVD) resulted in only a 1.6% reduction in 3-year progression-free survival with a decrease in pulmonary toxicity [6].
Recently, there have been notable advances in the treatment of patients with relapsed or refractory HL, including the incorporation of the PD-1 inhibitor
nivolumab as well as the immunotoxin conjugated CD30 monoclonal antibody brentuximab vedotin (BV). Given the activity of such agents in relapsed and refractory patients, there has been much enthusiasm about incorporation of such agents into the frontline setting. In the current ECHELON-1 trial, Connors and colleagues present the results of a randomized phase 3 trial comparing ABVD, the current standard of care, to A+AVD, which replaces bleomycin with BV. The trial used a primary endpoint of modified progression-free survival, where a noncomplete response and after primary therapy and subsequent treatment with anticancer therapy was considered disease progression. Notably, this trial did meet its primary endpoint of improved
modified PFS, with a 4.9% lower risk of progression, death, or noncomplete response and subsequent need for treatment at 2 years. Overall survival was not significantly different at the time of analysis.
There are some noteworthy findings in addition to this. First, A+AVD was associated with a higher risk of febrile neutropenia and infectious complications; however, following the incorporation of G-CSF prophylaxis this risk was lowered. The pulmonary toxicity was lower in the A+AVD group (2% vs. 7%). A+AVD was associated with an increased risk of peripheral neuropathy, which appeared to improve or resolve following discontinuation of therapy. The neuropathy was mainly low grade with only 11% being grade 3 or higher. Although it remains early and follow-up short, A+AVD did appear to have superior efficacy with a decrease in the risk of pulmonary toxicity in this study. It is worth noting that the risk of neurotoxicity was higher, albeit reversible with drug discontinuation. Given these results, A+AVD warrants consideration as frontline therapy in newly diagnosed patients with advanced stage classic Hodgkin’s lymphoma.
Applications for Clinical Practice
The results of this trial suggest that A+AVD with G-CSF support compares favorably to ABVD and may represent an acceptable first-line treatment strategy, particularly for patients at higher risk for pulmonary toxicity, although follow-up remains short at this time.
—Daniel Isaac, DO, MS