Circulating tumor DNA assessment in patients with early-stage classical Hodgkin lymphoma treated with combination of brentuximab vedotin and nivolumab.

7040 Background: Recent data suggest circulating tumor DNA (ctDNA) can be detected in patients with classical Hodgkin lymphoma (cHL), with molecular response potentially complementing imaging assessments. We report on the use of an ultra-sensitive assay for ctDNA detection in patients with early-stage cHL to explore its utility in this population. Methods: In SGN35-027 (NCT03646123) Part C study, patients with stage I or II cHL without bulky disease (N=154) received brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine (AN+AD) intravenously on days 1 and 15 of each 28-day cycle. Responses were assessed by PET/CT according to Lugano Classification with LYRIC at cycle (C) 2 day (D) 25-28 and end of treatment (EOT). 36 of 154 patients (23%) had plasma samples (collected at baseline, prior to C2D1 and C4D1, and EOT) analyzed for ctDNA using the PhasEDseq MRD assay. PET/CT results were compared with ctDNA dynamic changes in those with detectable baseline ctDNA. A genAI tool (12/19/24; Pfizer; GPT-4o) developed the 1st draft; authors assume content responsibility. Results: Baseline ctDNA was detectable in 34 of 36 patients (94%) and was higher in patients with greater disease burden (indicated by baseline stage/risk status [ P =0.015] and International Prognostic Score [ P =0.014]). At C2D1, ctDNA was undetectable in 27 of 33 patients (82%). ctDNA levels decreased in all patients after 1 cycle of treatment. At C2 interim PET/CT, 18 of 34 patients (53%) achieved complete metabolic response (CMR); of these, 17 patients had ctDNA samples evaluable with 16 patients having undetectable ctDNA. The remaining 16 patients achieved partial metabolic response (PMR); of these, 5 patients had detectable ctDNA and 11 had undetectable ctDNA (all 11 patients with undetectable ctDNA achieved CMR at later time points). At C4D1, only 1 patient continued to have detectable ctDNA. At EOT, PET/CT showed that 26 of 34 patients (76%) achieved CMR, 5 achieved PMR, and 3 achieved indeterminate response (IR); none had detectable ctDNA at EOT. In long-term follow up (LTFU), 4 of the 5 PMRs eventually converted to CMR; 1 patient developed a second primary malignancy (mantle cell lymphoma). Follow up assessments during LTFU confirmed that 2 IRs converted to CMR and 1 converted to PMR. Conclusions: ctDNA was detectable in majority of patients with early-stage cHL at baseline, and higher levels are associated with increased disease burden. Treatment with AN+AD reduced ctDNA levels, with ctDNA becoming undetectable by EOT in all patients. In some patients, decline in ctDNA levels was observed earlier than responses observed through imaging, suggesting that ctDNA clearance may be an early indicator of treatment response. The potential value of ctDNA as a biomarker for early detection and monitoring of treatment response in early-stage cHL should be further investigated. Clinical trial information: NCT03646123 .