Casper, Ellie

Introduction There is no prospective data to guide the utilization of peri-transplant radiation (PTRT) in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). In retrospective analyses, PTRT has been associated with local disease control, however evidence supporting improved progression free survival (PFS) is less well defined (Milgrom SA et al Cancer. 2017; 123(8):1363-1371). Furthermore, the added benefit of PTRT in the era of recent advancement in salvage strategies, including brentuximab vedotin (BV) and checkpoint inhibitors (CPI), is unclear. In a multicenter, retrospective analysis, we evaluated the impact of PTRT on PFS for patients with R/R cHL. Methods We identified consecutive pts ≥7 years old at time of diagnosis with R/R cHL treated with autologous stem cell transplant (ASCT) at 5 US academic institutions between 2010-2021. PTRT was defined as radiation administered within 3 months of ASCT. The primary objective was to compare the post-ASCT PFS, defined as the time from ASCT to subsequent relapse or death from any cause, between the two groups. Univariable and Multivariable Cox regression was performed to evaluate the impact of various relevant clinical factors on post-ASCT PFS. Results A total of 958 eligible pts were identified ( Table 1). The median age at cHL diagnosis was 31 (range, 7-72). At the time of first relapse/primary refractory disease, 406 (54%) pts had early-stage disease, 167 (24%) pts had bulky disease (≥5.0 cm), 308 (36%) pts had extra-nodal disease, 182 (22%) pts had B-symptoms (B-sx), and 338 (45%) had primary refractory disease. A total of 302 (32%) pts received >1 line of salvage before ASCT. Salvage treatment at any time point before ASCT included chemotherapy only for 457 (48%) patients, BV(+/- chemotherapy) for 308 (32%) patients, and CPI (+/- BV or +/- chemotherapy) for 193 (20%) patients. In total, 239 (24.9%) pts received PTRT, 139 (58.1%) before ASCT and 100 (41.8%) after ASCT. Among pts with available dosing information (23.3%), the median radiation dose administered was 28 Gy. The most common doses administered were 30 Gy in 77 (31.7%) pts, 36 Gy in 62 (27.8%) pts, and 18 Gy in 43 (19.2%) pts. Radiated sites included mediastinum in 172 (80.7%) pts, neck/cervical lymph nodes in 68 (31.9%) pts, and supra/infra clavicular region and axilla, each in 31 (14.6%) pts. Compared to the 719 pts that did not receive PTRT, patients treated with PTRT were more likely to have early stage disease (73% vs 47%, p<0.001), bulky disease (30% vs 22%, p = 0.048), primary refractory disease (56% vs 40%, p <0.001), >1 line of salvage treatment prior to ASCT (40% vs 29%, p<0.001), and <CR prior to ASCT (36% vs 27%, p = 0.007) (Table 1). Patients treated with PTRT were less likely to have RT at initial diagnosis (5.9% vs 22%, p<0.001), extra-nodal disease (19% vs 42%, p<0.001), B-sx (17% vs 25%, p=0.035), salvage treatment that included CPI (11% vs 23%, p<0.001), and BV maintenance (20 vs 31%, p<0.001). After a median follow up from ASCT of 4.5 years (range, 2.4-7.2), 2-year PFS was 76% (73%, 79%) and 5-year PFS was 70% (67%, 73%). In univariable analysis, receipt of PTRT showed non-significant reduced hazard for PFS (HR 0.79, 95% CI 0.59-1.05, p = 0.093) (Figure 1). In a multivariable model, PTRT showed significant association with PFS (HR 0.56, 95% CI 0.36-0.88, p=0.009) when adjusting for other clinically relevant factors at relapse such as stage, B-sx, bulk, primary refractory disease, BV(+/- chemotherapy) or CPI (+/- BV or +/- chemotherapy) in salvage, PET response prior to ASCT, and BV maintenance after ASCT. To determine if specific subgroups benefited from PTRT, we tested for interaction effects between PTRT and clinically relevant factors. Only bulk (HR 0.37, 95% CI 0.16-0.85, p=0.013) and B-sx (HR 0.45, 95% CI 0.20-1.02, p=0.041) showed significant interaction with PTRT.Among pts with bulky disease, 5-year PFS was significantly improved with receipt of PTRT (81% vs 62%, p=0.013). Conclusion In this large multi-center analysis of pts with R/R cHL undergoing ASCT, there was no significant difference in PFS regardless of receipt of PTRT. However, after adjusting for known clinically relevant factors, receipt of PTRT was significantly associated with PFS and was particularly beneficial for patients with bulky disease or B-sx at relapse. We found decreased utilization of PTRT in pts receiving CPI-based salvage; therefore the role for PTRT for pts receiving CPI-based salvage is unclear.

Background: For patients with relapsed and refractory (R/R) classical Hodgkin lymphoma (HL), the standard of care remains salvage therapy followed by autologous stem cell transplant (ASCT) for responding patients. Historical data suggest 40% of patients may relapse after ASCT, and these patients have generally a poor median overall survival (OS) of less than 2 years (Moskowitz et al., Br J Haematol. 2009;146(2):158-62). However, since these reports, the treatment landscape of R/R HL has dramatically improved, most notably with the introduction of two novel therapies, brentuximab vedotin (BV) and anti-PD1 agents. To refine our understanding of clinical outcomes in this context, we characterized patients who relapsed after ASCT in the modern era. Methods: We used a multicenter retrospective patient database at 5 transplant centers in the United States to identify patients with HL aged ≥ 12 years at diagnosis who had received ASCT on or after 1/1/2010. The primary objective was to determine the median OS for patients who relapsed after ASCT (post-ASCT-relapse OS), defining survival as the time from relapse after ASCT to subsequent death from any cause. Univariable Cox regression was performed to evaluate the impact of various factors on post-ASCT OS. Outcomes by era were evaluated using three different eras based on approval dates of novel agents: (1) pre-BV approval (pre-7/31/2011), (2) post-BV approval (8/1/2011-4/30/2016), (3) post-anti-PD1 approval (5/1/16-present). Results: A total of 215 patients were identified. The median age at ASCT was 34. Before ASCT, 128 patients (62%) had no exposure to novel agents, 76 patients (35%) had received BV and no anti-PD-1 therapy, and 11 patients (5.1%) had received anti-PD-1 therapy with or without BV. Conditioning was mostly with BEAM (59%) or CBV (32%). The median time to relapse after ASCT was 6 months (range: 1-109 months). Nearly half all relapses (47%) occurred within 6 months of ASCT. Only 14% of relapses occurred after 1 year. Among 126 patients with available treatment information, the median number of post-ASCT lines of therapy was 2 (IQR: 1, 4). Therapy for post-ASCT relapse included BV and no anti-PD-1 therapy in 41 patients (29%), anti-PD-1 therapy with or without BV for 70 patients (50%), and no novel agents for only 15 patients (11%). The median followup time from the date of ASCT among survivors was 5.0 (IQR: 2.8, 7.8) years. The median post-ASCT-relapse OS was not reached ( Figure 1). The 2- and 5-year post-ASCT-relapse OS were 75% (95% CI: 70%-81%) and 59% (95% CI: 53%-67%), respectively. On univariable Cox regression for post-ASCT-relapse OS ( Table 1), time to relapse greater than 6 (HR 0.55, 95% CI 0.35-0.85) or 12 months (HR 0.53, 95% CI 0.29-0.96) were significantly associated with improved post-ASCT-relapse OS. Increasing age at relapse was associated with worse OS (HR 1.05, 95% CI 1.04-1.07). Receipt of a novel agent (compared to chemotherapy alone) as the first salvage regimen for post-ASCT relapse was associated with improved post-ASCT OS (BV: HR 0.43, 95% CI 0.20-0.96; anti-PD-1: HR 0.44, 95% CI 0.18-1.08). Outcomes improved over time as regulatory approvals for novel agents occurred (post-BV-approval: HR 0.70, 95% CI 0.39-1.24; post-anti-PD-1 approval: HR 0.45, 95% CI 0.23-0.91). Conclusion: We show prolonged overall survival post-ASCT relapse compared to historical data likely due to the introduction of BV and anti-PD1 agents. This report represents one of the largest datasets of post-ASCT relapse in cHL, and this data should serve as an updated benchmark for future evaluations.