Brentuximab Vedotin-Based Regimens for Older Patients with Newly Diagnosed Classical Hodgkin Lymphoma - International, Multi-Center Real-World Experience

Introduction: Despite excellent outcomes for young patients(pts) with HL, pts age 60 have less favorable outcomes with a 5-year PFS of about 60% (Cheng et al. Blood Advances 2022). This disparity is attributed to disease biology factors such as mixed cellularity, EBV positivity, and advanced-stage disease, as well as comorbidities that make patients more vulnerable to treatment toxicity, dose reductions, and interruptions. Brentuximab vedotin (BV) is increasingly used in the front-line setting for older pts. While BV concurrent with AVD (CON) is approved based on ECHELON-1, its use in older pts is limited by toxicity. A phase 2 study (Evens et al., JCO 2018) showed promising results by administering BV sequentially with AVD (SEQ) to improve safety. This study aimed to assess real-world outcomes with BV-based regimens in newly diagnosed older pts with HL. Methods: This retrospective multicenter study was conducted at five medical centers in the US and Israel. Older pts age ≥60 consecutively diagnosed with HL between 03/2013-04/2023 were identified. Data on demographics, comorbidities (including cumulative illness rating scale-geriatrics [CIRS-G] score), AEs, treatment reductions, interruptions, PFS and OS were manually collected from electronic medical records. Results: 136 pts were treated with BV-based regimens. Pt characteristics included a median age of 71 years (range 60-91), 65% male, a median CIRS-G score of 5 (range 0-16), 34% with a history of other malignancy, 54% stage IV disease, 29% with bone marrow involvement, 67% with B symptoms, 46% EBV positive in tumor, and 32% with non-nodular sclerosis histology. Of these pts, 56 (41%) received CON BV-AVD, 54 (40%) were treated with SEQ BV-AVD; the rest (26, 19%) received BV monotherapy or BV-based palliative regimens. Patients treated with CON BV-AVD were younger compared to those treated with SEQ BV-AVD (median 69 vs. 72 years old, p=0.049); Other baseline characteristics did not differ significantly between the two groups. At a median follow up of 2.3 years (range 0.06-10.4), 2-year PFS and OS were 65% (95% CI 56-74%) and 83% (95% CI 76-90%), respectively. After excluding 26 pts treated with palliative regimens, 2-year PFS and OS were 73% (95% CI 64-83%) and 86% (95% CI 80-94%), respectively. We found no significant difference in PFS between SEQ and CON BV-AVD (76% vs. 70% 2-year PFS; p=0.5). In a multivariable Cox regression analysis including age and treatment regimen (SEQ or CON), the regimen was not statistically significant (p=0.2) with no difference in OS (p=0.7). The most common AEs were neuropathy (all 44%/CON 45%/ SEQ 48%), infections (all 29%/CON 29%/ SEQ 26%), and neutropenic fever (all 16%/CON 28%/SEQ 11%), leading to treatment interruption in 33% of pts and treatment reduction in 52%, primarily involving BV. Of 107 patients treated with curative intent with full treatment data, 78 (73%) completed six cycles of AVD. However, only 58 (54%) completed the treatment as initially planned, mainly due to toxicity. Patients on CON BV-AVD were significantly more likely to complete treatment as planned when compared to those on SEQ (74% vs 34%, p<0.001). Rate of treatment interruption between cycles, or dose reduction did not differ significantly between CON and SEQ regimens. During the study follow-up, 20 patients treated with curative intent died: 5 from infections (2 CON/3 SEQ including 3 from COVID-19), 7 from disease progression (4 CON/3 SEQ), and 8 from other comorbidities (2 CON/ 6 SEQ). Among 36 pts who relapsed or had primary refractory disease, 4 died upon progression, and 2 were missing information after progression. Thirteen underwent treatment with PD-1-based combinations, while 17 received alternative chemotherapies. Conclusions: In a multicenter study, evaluating the real-world outcomes of frontline BV in elderly HL pts, both CON and SEQ BV-AVD regimens demonstrated comparable efficacy and safety to those reported previously and to each other. More SEQ pts discontinued the treatment plan. SEQ BV-AVD had similar outcomes to CON BV-AVD, even after adjusting for age, indicating SEQ may not mitigate the adverse outcomes associated with older age. Recently, SWOG 1826 reported nivolumab-AVD over BV-AVD in advanced stage HL (Herrera et al., ASCO and ICML 2023) with similar findings in geriatric subsets (Torka et al, ICML 2023; Rutherford et al, ASH 2023). These finding support combining anti-PD-1 in frontline treatment for older patients.