Introduction: Classic Hodgkin lymphomas (cHL) have genetic bases for enhanced PD-1 signaling and the highest reported response rates to PD-1 blockade. In the S1826 phase III trial, patients (pts) with newly diagnosed advanced stage cHL who were treated with nivolumab (N)-AVD, vs brentuximab-vedotin (BV)-AVD, had improved progression-free survivals (PFS), establishing a new standard of care. We used our recently developed ctDNA assay to evaluate changes in molecular tumor burden (MTB) and compared ctDNA- and PET-assessed responses in S1826.

Methods: The first 388 trial pts with baseline, cycle 3 day 1 (C3D1) and end-of-therapy (EOT) plasma samples (and germline DNAs) were analyzed with the targeted sequencing assay that captured recurrent single nucleotide variants, indels, somatic copy number alterations (SCNAs), structural variants, sites of physiologic and aberrant somatic hypermutation and EBV status. Low-pass whole genome sequencing provided an orthogonal assessment of SCNAs. A newly developed algorithm, MTB-Tracker, identified clustered variants and measured treatment (Tx)-related changes in MTB (log-fold changes in hGE/ml) that were compared to centrally reviewed PET scans (Deauville scores 1-3 [-] vs 4-5 [+]) at C3D1 (interim [i] PET) and EOT.

Results: 375/388 (97%) pts with detectable clustered variants at baseline were included in the analysis. Clinical characteristics of these pts – median age 25y (range, 12-83y), 28% <18y, 10% >60y, 37% with IPS 4-7 – were comparable to the entire trial cohort; 3y PFS rates for the 191 N-AVD & 184 BV-AVD pts were 89% & 79%.

Pts with detectable ctDNA at C3D1 had significantly inferior outcomes in the full 375 pt cohort (FC) and both Tx arms (3y PFS ctDNA+ vs ctDNA-: FC 61% vs 89%; N-AVD 71% vs 93%; BV-AVD 50% vs 84%; p<.0001 all comparisons). In the ctDNA cohort, iPET status was not significantly associated with PFS in univariate analysis (HR 1.75, p=.075) or a multivariable model (HR 1.7, p=.091) in all pts, or in the individual Tx arms. In contrast, ctDNA positivity at C3D1 remained independently prognostic (FC, HR 4.5, p<.0001; N-AVD, HR 6.0, p<.001; BV-AVD, HR 4.3, p<.0001).

Among pts with detectable ctDNA at C3D1, the magnitude of decline in MTB from baseline further delineated risk groups. Pts with a major (≥ median log-fold) drop in MTB had 3y PFS rates in the FC, N-AVD and BV-AVD Tx arms of 83%, 88% and 77%. In contrast, those with only a minor (< median log-fold) drop in MTB had significantly poorer outcomes: 3y PFS in FC, N-AVD and BV-AVD pts of 38%, 52% and 25%.

To assess the added value of ctDNA dynamics at C3D1, we compared a 2-group model (ctDNA+ vs ctDNA-) to a 3-group model that separated ctDNA+ pts into those with major vs minor drops in MTB. While the binary model was associated with outcome (HR 4.3; p<.0001), the 3-group model identified pts with only a minor drop in MTB as driving adverse prognosis (HR 8.9; p<.0001). In contrast, those with a major drop in MTB had outcomes similar to ctDNA- pts (HR 1.5, p=.424, relative to ctDNA- group). Model fit significantly improved with the 3-group approach (p<.0001), highlighting the value of capturing ctDNA dynamics at C3D1. Incorporating iPET into the 3-group ctDNA model did not improve outcome assessment.

At EOT, pts with detectable ctDNA had significantly inferior 3y PFS in the FC and both Tx arms (ctDNA+vsctDNA-: FC 32% vs 89%; N-AVD 39% vs 91%; BV-AVD 27% vs 87%; p<.0001 all comparisons). PET positivity at EOT also correlated with worse outcomes in the FC and both Tx arms (PET+ vs PET-: FC 55% vs 90%; N-AVD 61% vs 90%; BV-AVD 50% vs 89%; p<.0001 all comparisons). Combining ctDNA and PET assessments further refined EOT risk stratification: ctDNA−&PET− pts had the most favorable 3y PFS (92% for FC, N-AVD and BV-AVD), whereas ctDNA+&PET+ pts had the poorest 3y PFS (FC 6%; N-AVD 14%; BV-AVD 0%), p<.0001 all comparisons. In EOT multivariable analysis, both ctDNA positivity (FC, HR 11.1; N-AVD, HR 11.8; BV-AVD, HR 11.4; p<.0001 all comparisons) and PET positivity (FC, HR 4.8, p<.0001; N-AVD, HR 3.5, p=.009; BV-AVD, HR 6.1, p<.0001) were independently associated with inferior outcomes, with ctDNA status having a stronger prognostic impact across the FC and both Tx arms.

Conclusions: In S1826, ctDNA-guided analyses of MTB enabled early risk stratification at C3D1 and strongly outperformed PET assessments at EOT. Future prospective studies should incorporate ctDNA analyses of MTB to improve precision therapy in cHL.

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2025
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