Can Circulating Tumor DNA Improve the Predictive Value of Interim Response in Patients with Advanced Hodgkin Lymphoma and PET-2 DS3?
Authors: Mocikova Heidi , Kupcova Kristyna , Markova Jana , Gaherova Lubica , Maco Maria , Hamova Iva , Velasova Adriana , Sykorova Alice , Stepankova Pavla , Kredatusova Alexandra , Prochazka Vit , Koren Jan , Nehasil Petr , Zemankova Petra , Kozak Tomas , Havranek Ondrej 
Published: December 2024

Background: Analysis of 441 patients with classical HL in advanced stages from the Czech Hodgkin Lymphoma Registry treated with 6 or 4 cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) according to the interim PET-2 has shown that within patients that received 4 cycles of eBEACOPP, there is a trend for a higher 5-year progression-free survival (PFS) in patients with PET-2 Deauville score (DS) 1-2 in comparison to patients with PET-2 DS3 (91% [95% CI 84-99] vs. 78% [95% CI 64-95], p=0.061), accepted for ISHL13. To better stratify patients with PET-2 DS3 into 4 or 6 cycles of eBEACOPP, we analyzed circulating tumor DNA (ctDNA) within the ongoing trial NCT06263530 and correlated it with interim PET-2 results.

Methods: To analyze ctDNA levels and its dynamics, we collected peripheral blood from 67 patients with classical HL in advanced stages III/IV, including clinical stages IIB with massive mediastinal tumor and/or extranodal involvement. 60 patients received eBEACOPP (30 patients 4 cycles and 30 patients 6 cycles), 4 patients received combination of eBEACOPP (4 cycles) and ABVD (2 cycles), and only 3 patients received 6 cycles of ABVD. Blood samples were collected at diagnosis, after two cycles of chemotherapy, and at the end of treatment (EoT). Following cell free DNA extraction, levels of ctDNA were determined using a custom panel of 538 genes frequently altered in lymphomas utilizing next generation sequencing-based CAPP-Seq (CAncer Personalized Profiling by deep Sequencing) approach. Plasma ctDNA levels were consequently correlated with PET results at the same timepoints.

Results: Out of 67 patients (all white race, male gender 39 patients, median age at diagnosis 33 with range 19 - 70 years) 56 achieved PET-2 metabolic complete remission - CMR (30 patients DS1-2 and 26 patients DS3) and 11 patients achieved partial remission - PR (DS4-5). At the end of chemotherapy, the number of CMR increased to 61, 5 patients were in PR, and unknown response was achieved in 1 patient. Overall, 9 patients relapsed/progressed after the first-line treatment (with interim PET-2: DS2 in 3 patients, DS3 in 2 patients, and DS4-5 in 4 patients). Preliminary analysis suggests that ctDNA might improve PET-2 based disease status evaluation and patient stratification. Correlation of ctDNA with interim PET-2 and EoT PET will be presented.

Conclusion: ctDNA is a promising sensitive tool to better stratify treatment of patients with Hodgkin lymphoma.

This work was supported by grants AZV NU22-03-00182 from the Ministry of Health of the Czech Republic, MH CZ DRO (FNOl_00098892, VFN00064165), National Institute for Cancer Research (EXCELES - LX22NPO5102), Cooperatio Program (research areas Oncology and Haematology and Biology), and SVV 260637.