Outcomes of Patients Treated with Consolidative Brentuximab Vedotin after Transplant for Hodgkin Lymphoma at High Risk of Progression or Relapse: An Innovative Comparative Analysis Based on Propensity Score Weighting from Patients Included in 4 Lysa-Cohorts

Introduction: The landmark AETHERA study showed the safety and efficacy of Brentuximab Vedotin (BV) use as maintenance in high-risk relapsed or refractory (R/R) classical Hodgkin Lymphoma (cHL). Several studies, including AMAHRELIS, confirmed its effectiveness in a real-life setting. However, the field of HL management is evolving, including practice changes in the second-line treatment that might impact patient outcomes after autologous stem cell transplant outcomes (ASCT). In that setting, it is unclear whether the indication for consolidative BV can still rely on the current criteria defining patients at high risk of progression or relapse. In this study, we compared the outcomes of patients included in 4 LYSA cohorts who received or did not receive BV maintenance according to the current indications.

Methods: Adult patients with R/R HL who received ASCT after second-line therapy from 2 clinical trials conducted by the LYSA group (AHL2011 and BV-ICE) or 2 real-life cohorts (REALYSA and AMAHRELIS) were eligible. Missing data were retrospectively collected, and a comparative analysis of their maintenance therapy was performed using the propensity score-based method. The propensity score was calculated using a logistic regression that included six patient characteristics: age, gender, Ann Arbor stage at relapse, primary refractory, early relapse, and disseminated late relapse status. Patients with missing values for variables included in the propensity score were excluded. Three age-dependent models (a cut-off approach with the median age as a cut-point, age in linear, and age modeled as spline function) were tested to improve propensity scores. All three models produced standardized mean differenced (SMD) values below 0.1. The Inverse Probability of treatment weighting (IPTW and stabilized IPTW) was then calculated to create the pseudo-population in which patient characteristics are similar. The weighted Kaplan-Meier method has been used to compare both treatment groups in the pseudo-population, in which follow-up time was previously censored at 36 months. In sensitivity analysis, the landmark method was used to investigate the immortal time bias induced by the time spent between transplantation and the start of treatment. OS and PFS were defined as the time from ASCT to progression or death, and group comparisons were analyzed using the adjusted log-rank test.

Results: 168 patients without missing values for propensity score variables were included in this analysis among the 309 patients enrolled in four French cohorts from the LYSA group: AHL2011, BV-ICE, REALYSA, and AMAHRELIS. Clinical characteristics at diagnosis included a median age of 32.4 years [18-60], and 57.1% were male. At relapse, 65.5% had disseminated disease, 50.3% had extranodal involvement and risk factors were represented as follows: primary refractory (40.5%), early relapse (26.8%), or late disseminated disease (28.6%). All received ASCT as part of salvage therapy followed by consolidative BV in 126 patients or surveillance without additional treatment for 52 patients. With a median follow-up of 39 months, while the 3years-PFS and OS were respectively at 75.2% [65.7% - 82.5%] and 95.7% [88.9% - 98.3%] in patients treated with consolidative BV, the 3years-PFS and OS were at 76.8% [61.1% - 86.8%] and 87.3% [73.2% - 94.2%] respectively in the group observed without additional therapy after ASCT. After propensity score weighting on previously mentioned risk factors, PFS and OS were not significantly different between the 2 groups (HR 1.25 [0.753-2.085, p=0.38] and 0.431 [0.162-1.144, p=0.09], respectively), and the landmark sensitivity analysis did not impact the results. These data suggest that the current risk factors failed to discriminate patients who benefit from consolidative therapy in a real-life setting.

Conclusion: Using a propensity score weighting approach, this study demonstrated that high-risk R/R cHL patients who received maintenance therapy with BV after ASCT achieved similar outcomes as patients observed without additional consolidation therapy. Our work suggests refining high-risk criteria for R/R HL, considering the recent progress achieved in cHL management. Other prognosis markers, including complete remission pre-ASCT and new biomarkers, might be needed to better identify patients with a low risk of relapse or progression from those who benefit from consolidative BV after ASCT.