Predictors of discordant end-of-treatment PET positivity in advanced-stage classical Hodgkin lymphoma patients with negative interim PET response

Abstract Background In advanced-stage classical Hodgkin lymphoma (cHL), achieving a negative interim PET (iPET) after two cycles of ABVD is generally considered a favorable prognostic marker. Most patients with early metabolic response proceed to complete therapy without residual disease. However, a subset of patients experience discordant end-of-treatment (EOT) findings, with evidence of the disease despite an initial complete response. This study aimed to identify baseline clinical features that might help predict this unexpected outcome.Methods A retrospective review was conducted of 122 patients with stage III or IV cHL treated at our institution between 2016 and 2024. All patients achieved complete metabolic response (Deauville score ≤3) on iPET following two cycles of ABVD. Clinical and laboratory data, including IPS score, bone marrow, and extranodal involvement, were collected. The primary outcome was residual disease identified at EOT-PET. Logistic regression was used to identify predictive factors. Disease-free survival (DFS) was estimated using Kaplan-Meier analysis.Results Of the 122 patients with negative iPET scans, 21 (17.2%) were found to have residual uptake on EOT-PET. The median age was 28 years; 63% were male, and 70.5% had nodular sclerosis subtype. Most patients (69.7%) had stage IV disease. In univariate analysis, no baseline variable- including IPS score, bone marrow involvement, extranodal disease, or B symptoms- was significantly associated with residual PET positivity. However, in multivariate analysis, stage IV disease emerged as an independent predictor, with a statistically significant association with residual disease at EOT (OR 3.32; 95% CI, 0.97–11.37; p = 0.041). The median follow-up was 28.8 months. The median DFS was not reached, and the estimated two-year DFS was 83%.Conclusions While early metabolic remission on interim PET is reassuring, a notable proportion of patients still demonstrate residual disease by the end of therapy. Stage IV disease was independently associated with this outcome when adjusted for other variables. No significant associations were identified with IPS score, bone marrow, or extranodal involvement. These findings suggest that relying solely on interim PET may overlook residual risk in a subset of patients, particularly those with extensive disease burden at baseline.