Paper Details

ABSTRACT

Background and Significance: Despite excellent progression-free survival rates (PFS) in stage IIB-IV Hodgkin lymphoma (HL), patients have continued to receive full course chemoimmunotherapy (CIT), increasing the risk of toxicity and long-term sequelae. One explanation is the fear of de-escalating therapy in a highly curable disease, highlighting the need for improved biomarkers and prognostic tools. Recently, the HD21 trial showed that a subset of patients (65%) who achieve a negative PET2, defined as a Deauville score (DS) of 1–3, can undergo four cycles of BrECADD (brentuximab vedotin (BV), etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone) with 5-year PFS of 94%, comparable to 6 cycles of BV-AVD and Nivolumab-AVD (Ferdinandus, 2025). However, the positive predictive value (PPV) of interim PET-CTs is less clear in the era of novel therapeutics, often picking up the metabolic activity of non-lymphoma, inflammatory tissues. Metabolic tumor volume (MTV) has emerged as sensitive biomarker which may further aid in patient stratification.

Similarly, circulating tumor deoxyribonucleic acid (ctDNA) is emerging as an additional tool in HL to define disease burden and aid in prognostication. Pre-treatment ctDNA levels reflect overall tumor volume and are highly correlated with MTV, acting as a complementary marker for disease burden and have been associated with PFS regardless of disease stage. Recent data has shown that patients with a DS4 at PET2 and negative MTV had similar outcomes to patients with a negative PET2 and that patients with positive MRD after 2 cycles of treatment, had increased risk of relapse, progression or death (Heger, 2026). Thus, integration of ctDNA into treatment algorithms may enhance the ability to prognosticate before and throughout treatment.

This study presents a novel treatment algorithm integrating PET2 and MTV2, with the goal of further reducing the number of patients who need to complete 6 cycles of CIT. Additionally, this study explores the concordance of ctDNA with both the DS and MTV at baseline, interim, and end of treatment (EOT). This trial is being conducted at The University of Miami/Sylvester Comprehensive Cancer Center (ClinicalTrials.gov identifier NCT07002216).

Study Design and Methods: This is an open-label, single-center, single-arm phase 2 investigator-initiated trial evaluating the safety and tolerability of an abbreviated course of BrECADD in stage IIB/Unfavorable (U) - IV HL. This study is being conducted using a group-sequential design with 2 stages: one interim analysis with 23 evaluable patients and a final analysis with a total of 43 evaluable patients. Key inclusion criteria include patients aged 18-60 with histological confirmation of HL, Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 and adequate organ function. Patients with well controlled HIV and hepatitis are included however pregnant females and patients with concurrent uncontrolled medical illnesses, including ≥ grade 2 peripheral neuropathy are excluded.

Patients receive 2 cycles (C) of BrECADD and then undergo an interim PET-CT. Patients with a negative PET2 (DS1–3) complete C3-4 of BrECADD while patients with a positive PET2 (DS4–5) are further stratified by MTV. Patients with a negative MTV-2 proceed with C3–4 of BrECADD while patients with a positive MTV undergo a biopsy. Patients with a negative biopsy can proceed with C3–4 of BrECADD while patients with a positive biopsy are removed from the study. All patients will complete an end of treatment (EOT) PET-CT. Investigators have the option of giving 30 Gy of radiotherapy at the EOT to patients with bulky disease. ctDNA using the Foresight CLAIRTY^TM assay is collected at baseline, PET2 and EOT to examine concordance with PET-CT.

 The primary endpoint is 1 yr PFS, with 2 yr PFS as the secondary endpoint. Additional secondary endpoints will examine subjective and objective measures of toxicity as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), patient reported outcomes (PRO)-CTCTAE and the Fatigue, Resistance, Aerobic Capacity, Illnesses and Loss of Weight (FRAIL) questionnaire. Predictors of treatment-related toxicity including diet and activity levels, and the presence of sarcopenia as assessed by radiomic body composition analysis, will also be assessed.

This study is actively enrolling since June 2025, with 14 patients currently on study.