EA4241 – Therapy Assessment in Risk-stratified Groups with Established Treatments in Hodgkin Lymphoma in first relapse (TARGET-HL)

Classical Hodgkin lymphoma (cHL) is an aggressive disease that develops in the lymphatic system, part of the immune system. It can develop at any age but occurs most frequently in two age groups: young adulthood, especially in the 20s, and older adulthood, after age 55 (American Cancer Society). Although first-line treatment cures most patients, approximately 15% experience a relapse or have lymphoma that no longer responds to treatment. EA4241/TARGET-HL aims to improve the chance of cure for these patients.

The current standard of care for relapsed/refractory cHL is additional treatment (salvage therapy). If salvage therapy leads to a complete or partial remission, it may be followed by high-dose chemotherapy and an autologous stem cell transplant (HDT-ASCT)—if the patient is physically fit enough to withstand the difficult procedure, which involves high-dose chemotherapy followed by re-infusion of their own blood stem cells.

EA4241/TARGET-HL explores a more personalized, risk-adapted approach that aims to maintain or improve disease control while limiting treatment-related side effects. The trial asks two central questions: Can some patients avoid transplant? Can immunotherapy after transplant improve outcomes for others?

In recent years, immunotherapy in the form of PD-1 checkpoint inhibitors has emerged as an important treatment option for patients with cHL. Both nivolumab and pembrolizumab have US Food and Drug Administration-approved indications for cHL, although their approved uses differ by age, disease stage, and treatment history. Neither is approved as maintenance treatment for relapsed or refractory cHL and the optimal use of these agents, particularly in relation to HDT-ASCT, remains uncertain. In addition, HDT-ASCT is associated with a risk of serious short- and long-term side effects. Emerging evidence has challenged the longstanding assumption that it is required to achieve durable progression-free survival (PFS).

TARGET-HL investigators hypothesize that:

1. For standard-risk patients, a transplant-free regimen consisting of maintenance therapy with a checkpoint inhibitor and involved-site radiation therapy will be at least as effective as (noninferior to) HDT-ASCT, and potentially superior to it.
2. For high-risk patients, maintenance therapy with a checkpoint inhibitor following HDT-ASCT will improve PFS compared with HDT-ASCT alone.

Patients will be assigned to a risk group based on clinical factors, including time to relapse, prior exposure to checkpoint inhibitor therapy, and disease extent. Both groups first receive two to four cycles of salvage treatment selected by their physician. Only patients whose lymphoma shows a complete or partial response proceed to randomization.

Standard-risk patients will be randomized to receive either HDT-ASCT or a transplant-free regimen. The transplant-free regimen consists of involved-site radiation therapy followed by maintenance treatment with brentuximab vedotin plus nivolumab for up to four cycles, followed by two additional cycles of nivolumab alone.

High-risk patients will be randomized to receive transplant-based treatment with or without immunotherapy (pembrolizumab) as maintenance. The study allows radiation and/or brentuximab vedotin maintenance in both high-risk groups.

All patients will be monitored for treatment response until disease progression or relapse and followed for survival outcomes for up to 15 years after registration.

This study allows a wide range of ages, enrolling patients from 5-75 years old with biopsy-confirmed relapsed or refractory cHL following first-line chemotherapy. Baseline imaging must confirm relapse before salvage treatment begins and within 56 days before trial registration. Patients must be medically fit to undergo a stem cell transplant.

Vaishalee P. Kenkre, MD (University of Wisconsin/UW Carbone Cancer Center) is the study chair for this trial. The co-chairs are Andrew M. Evens, DO, MBA, MSc (Rutgers Cancer Institute) and Catherine S. Diefenbach, MD (New York University/NYU Langone Perlmutter Cancer Center). The community co-chair is Tim R. Wassenaar, MD (ProHealth Care).