Moving Brentuximab Vedotin Into the First-Line Therapy for Hodgkin Lymphoma

In patients with early unfavorable and advanced-stage Hodgkin lymphoma, front-line therapy that includes escalated BEACOPP (eBEACOPP: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) improves survival compared to ABVD therapy (doxorubicin, bleomycin, vinblastine, and dacarbazine). However, this regimen is associated with higher risk of grade 3 and 4 hematologic adverse events (AEs), infections, and potential for secondary malignancies and infertility. The CD30-targeting antibody-drug conjugate (ADC) brentuximab vedotin (BV) has demonstrated impressive single-agent activity in relapsed and refractory Hodgkin lymphoma and is the current standard of care in this setting. Additionally, BV is associated with a much more favorable toxicity profile compared to chemotherapy. Thus, BV is being investigated in combination with multiple chemotherapy regimens in the first-line setting. The German Hodgkin Study Group is currently evaluating if modification of the eBEACOPP regimen with BV can reduce toxicity while maintain the high efficacy of eBEACOPP.

In a randomized phase II trial, newly diagnosed patients with advanced classical Hodgkin lymphoma (N = 104) were treated with one of two BV-based first-line regimens: BrECAPP (BV, etoposide, cyclophosphamide, doxorubicin, procarbazine, and prednisone) or BrECADD (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). Patients received six cycles of therapy followed by localized radiotherapy to residual lymphoma.

At a median follow-up of 17 months, 86% of patients receiving BrECAPP had a complete response after chemotherapy and 94% achieved complete remission as the final treatment outcome. Treatment with BrECADD resulted in both a complete response after chemotherapy and a complete remission as the final treatment outcome in 88% of patients. Positron emission tomography (PET)-guided consolidating radiotherapy after chemotherapy was indicated in 14% of patients receiving BrECAPP and 12% of those receiving BrECADD. The estimated 18-month progression-free survival (PFS) was 95% with BrECAPP and 89% with BrECADD.

Acute grade 3/4 AEs occurred in 94% of patients receiving BrECAPP and in 88% of patients receiving BrECADD. Hematologic AEs were most common, occurring in 92% and 87% of patients, respectively. Grade 3/4 infections occurred in 8% and 15% of patients. Severe nonhematologic AEs were reported in 17% of patients in BrECAPP and 4% of patients in BrECADD arm. Peripheral neuropathy occurred in 30% and 35% of patients and was reversible grade 1/2, except in one patient who received BrECAPP. Two patients in the BrECAPP arm discontinued treatment due to AEs and dose reductions were required in 16% of patients receiving BrECAPP and 8% of patients receiving BrECADD.

The investigators concluded that both BV-based chemotherapy combinations achieved the desired endpoint of complete response after chemotherapy and that outcomes appears to be similar to those reported with eBEACOPP. Both regimens were well tolerated, but the toxicity profile of the BrECADD regimen was more favorable. This regimen is now being examined further in the ongoing phase III HD21 study, which compares BrECADD to standard eBEACOPP in previously untreated patients.

In an accompanying commentary, the author agreed that these regimens were effective and associated with acceptable tolerability profile, indicating that first-line BV will be an inevitable development in Hodgkin lymphoma. The precise first-line regimen is yet to be determined. The phase III ECHELON-1 trial recently demonstrated that combination of BV with AVD (doxorubicin, vinblastine, dacarbazine) significantly improved modified PFS (primary endpoint of the study) compared to ABVD and survival data are expected to be reported at the upcoming American Society of Hematology (ASH) annual meeting.

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