Results from a Systematic Review of Advanced-Stage Hodgkin Lymphoma Treatments and a Matching-Adjusted Indirect Treatment Comparison of A+AVD vs PET-Guided ABVD
Authors: Kristo Fjoralba , Molinari Alexa , Lan Zhiyi , Paly Victoria Federico , Khan Ramsha , Poirier Abbey , Kwon Christina Soeun , Moradian Hoora , Savani Bipin N. , Zomas Athanasios , Ashaye Ajibade 
Published: December 2024

Introduction: According to National Comprehensive Care Network® guidelines, positron-emission tomography (PET)-guided adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), and brentuximab vedotin in combination with doxorubicin, vinblastine, and dacarbazine (A+AVD) are currently the preferred front-line regimens for the management of advanced Hodgkin Lymphoma (aHL). The ECHELON-1 (E1) trial demonstrated improved outcomes with A+AVD over ABVD for both overall survival (OS) and progression-free survival (PFS). However, PET adaptation was not used to guide the choice of regimens in the E1 trial. The objective of this exercise was to review the existing evidence and subsequently investigate the comparative efficacy of A+AVD vs PET-guided ABVD in adult patients with aHL.
Methods: A systematic literature review (SLR) of relevant published evidence through December 2023 on the clinical efficacy of front-line treatments for aHL was conducted, followed by an indirect treatment comparison (ITC) feasibility assessment of the relevant studies identified. Of 48 randomized controlled trials (RCTs) and 143 non-RCTs identified in the SLR, the Risk-Adapted Therapy for aHL (RATHL; randomized for PET-negative patients) and SWOG S0816 (non-RCT) were selected as relevant trials for comparison of PET-guided ABVD with A+AVD (E1). In both RATHL and SWOG S0816 trials, patients received 2 cycles of ABVD, followed by adapted therapy based on PET results. Long-term OS and PFS data were available for all 3 trials, with median follow-up of 89.3 (E1), 70.8 (SWOG S0816), and 87.6 (RATHL) months.
Based on Cox regression analyses using individual patient-level data from E1 and expert opinion, age, international prognostic score (IPS), Eastern Cooperative Oncology Group performance status (ECOG), and extranodal site at baseline were considered to be both effect modifiers and prognostic variables. However, extranodal site data were not available in RATHL and SWOG S0816, and ECOG was not reported in SWOG S0816.
Using an unanchored matching-adjusted indirect comparison (MAIC) approach, A+AVD (E1, restricted to patients aged ≤60 years to match the selection criteria in SWOG S0816) was compared with PET-guided ABVD (overall trial population) in SWOG S0816, adjusting for age and IPS. A+AVD (E1) was also compared with PET-guided ABVD (stage III and IV overall trial population) in RATHL, adjusting for age, IPS, and ECOG. Hazard ratios (HR) with 95% confidence intervals (CI) were generated using weighted Cox regression. For situations in which the proportional hazards assumption was violated, restricted mean survival time (RMST) at 8 years and piecewise Cox regression (split time into different intervals based on delayed separation of Kaplan-Meier curves) were performed.
Results: MAIC reweighting resulted in an effective sample size of 521 and 526 of the A+AVD arm of E1 after matching to patient characteristics in SWOG S0816 and RATHL, respectively; 336 patients from SWOG S0816, and 702 patients from RATHL were included in the analyses.Using weighted Cox-regression, A+AVD (E1) demonstrated significantly improved PFS (HR=0.55 [95% CI: 0.40-0.75], p&lt;0.001) and OS (HR=0.49 [95% CI: 0.26-0.92], p&lt;0.05) compared to PET-guided ABVD in SWOG S0816. Similarly, A+AVD (E1) was associated with significant improvement in PFS (HR=0.56 [95% CI: 0.43-0.73), p&lt;0.001) and OS (HR=0.37 [95% CI: 0.24-0.57], p&lt;0.001) compared to PET-guided ABVD in RATHL.
RMST and piecewise Cox regression were performed given the violation of the proportional hazard assumption in the PFS analyses. Compared with PET-guided ABVD in SWOG S0816 and RATHL, A+AVD (E1) was associated with significantly longer RMST of PFS (difference=8.46 months [95% CI: 3.77-13.15] and 6.67 months [95% CI: 2.98-10.37], respectively), and significantly improved PFS during the &gt;6 months period (vs SWOG S0816, HR=0.47 [95% CI: 0.34-0.66]) and during the &gt;16 months period (vs RATHL, HR=0.20 [95% CI: 0.12-0.34]).
Conclusions: In patients with aHL, sustained PFS and OS benefit was shown for A+AVD (E1) vs PET-guided ABVD (SWOG S0816 and RATHL), providing insight into the durability of benefits associated with A+AVD. These results were consistent with the findings of E1 study based on long term survival data, supporting the use of A+AVD over PET-guided ABVD in treating patients with aHL.