Introduction Patients (pts) with newly diagnosed, advanced-stage cHL are at risk for poor health-related quality of life (HRQoL) due to their underlying disease and its treatment. We assessed PROs in S1826, a trial showing that nivolumab plus doxorubicin, vinblastine, and dacarbazine (N+AVD) resulted in longer progression-free survival compared to brentuximab vedotin plus AVD (BV+AVD).

Methods S1826 was a phase 3 multicenter, cross-network trial for pts >12 years old with stage III or IV newly diagnosed cHL. PROs assessment was required for pts able to complete questionnaires in English, Spanish, or French, and was obtained before registration (“baseline”) and at cycle 3, at 4-8 weeks after the end of treatment (EOT), and at 1 and 3 years (yrs) after randomization. The PROMIS-Fatigue 7a (or Ped PROMIS-Fatigue 10a), the FACT-GOG-Ntx, and the PROMIS-Global Health (Adult and Pediatric) scales were collected at each assessment. Two primary endpoints for fatigue (at EOT and 1 year) and two for neuropathy (at 1 and 3 yrs) were pre-specified, each tested using a two-sided alpha=.0125 test. Linear regression was used, adjusting for the baseline PRO score, age at randomization (12-17 vs 18-60 vs >60 yrs), the International Prognostic Score (IPS; 0-3 vs 4-7), and intent to use radiation (yes vs no). An effect size of 0.3 for both fatigue and neuropathy endpoints was targeted, corresponding to minimal clinically meaningful differences (MCID) of 3.6 points and 3.0 points, respectively. MCID, established separately for each questionnaire, characterizes the level at which a treatment tangibly affects a patient's daily life in terms of their well-being and HRQoL. We previously reported worse fatigue at cycle 3 and EOT for pts on the N+AVD arm, and worse neuropathy in the BV-AVD arm at the EOT and Year 1. In this update, we examine whether fatigue and neuropathy results differed by age group, using interaction tests, for mature data through 1 year (yr). We also report on the PROMIS-Global Health findings by arm and age group.

Results The N=970 eligible pts included 236 (24.3%) aged 12-17 yrs, 639 (65.9%) aged 18-60 yrs, and 95 (9.8%) aged >60 yrs. Pts were predominantly male (56.1%); 11.8% identified as Black, and 32.0% had an IPS score of 4-7. PRO completion rates ranged from 98% at baseline to 70% at 1 yr post registration. For pre-specified primary endpoints, the adjusted PROMIS-Fatigue score was 1.7 (95% CI, -3.1 to -0.4, p=.01) points lower (i.e., more fatigue) for the N+AVD arm at EOT, although the difference did not exceed the MCID. At 1 year, there was no significant difference in fatigue from baseline (p=.83). While fatigue scores did not meaningfully differ by study arm (interaction p>.70 for all assessments), they did vary by participant age, with younger pts (12-17 yrs) and older pts (>60 yrs) reporting worse fatigue on treatment. In contrast, neuropathy scores at 1 yr were better for pts on the N+AVD arm, exceeding the MCID (3.0 points, 95% CI, 2.0-3.9, p<.001), and, secondarily, at EOT (5.6 points, 95% CI, 4.4-6.3, p<.001). However, the MCID in neuropathy at EOT and Yr 1 were only observed for pts aged 18-60 and >60 but not for pts 12-17 yrs (age interaction p<.05). Global health (HRQoL) scores were better for patients on the N+AVD arm among adults in both age groups (18-60 and >60 yrs through EOT; this pattern of improvement was not seen among adolescents, aged 12-17 yrs in the between-arm comparison.

Conclusions Worse fatigue was found at the EOT, and less neuropathy was reported by yr 1, for pts on the N+AVD arm, results that were consistent across age groups. Worse neuropathy was found in the BV-AVD arm over time, specifically among pts aged 18 yrs and over. Global HRQoL was better for adult pts on the N+AVD arm through EOT, but did not differ by arm for adolescents. Trial results support the feasibility of serial collection of PROs, as indicated by high response rates, despite participants' advanced stage disease and broad institutional participation. Future analyses will address the planned 3-year outcomes as well as formal evaluation of missing data.

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2025
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