# CIRCULATING TUMOR DNA FOR MONITORING PRIMARY MEDIASTINAL B-CELL LYMPHOMA IN COMPLEMENT TO PET: A PROSPECTIVE MULTICENTER LYSA STUDY

V. Camus, D. Krzisch, A. Bruscaggin, E. Lévêque, M. Viennot, L. Fornecker, M. Cheminant, S. Bailly, F. Morschhauser, P. Feugier, et al.

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## To cite this version:

V. Camus, D. Krzisch, A. Bruscaggin, E. Lévêque, M. Viennot, et al. CIRCULATING TUMOR DNA FOR MONITORING PRIMARY MEDIASTINAL B-CELL LYMPHOMA IN COMPLEMENT TO PET: A PROSPECTIVE MULTICENTER LYSA STUDY. 18th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 17 - 21 June, 2025, Jun 2025, Lugano, Switzerland. pp.e42_70093, 10.1002/hon.70093_42. hal-05163068

HAL Id: hal-05163068

https://univ-rennes.hal.science/hal-05163068v1

Submitted on 23 Jan 2026

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**Methods:** ctDNA-MRD was assessed using Foresight CLARITY in LBCL patients enrolled on HOVON-902. Patients were treated with curative-intent 1L therapy (R-CHOP/DA-EPOCH-R). We evaluated the prognostic significance of MRD status on PFS and OS. PVs were identified from pretreatment biopsies or plasma with matched normal DNA. EOT plasma samples were used for MRD detection. Genetic classification by LymphGen from pretreatment samples was also performed.

**Results:** A total of 150 of 156 (96%) eligible patients had successful PV identification. IPI distribution was 22% low, 29% low-intermediate, 27% high-intermediate, and 22% high risk; median age was 67.5. The 24-month PFS and OS in this cohort were 74% and 86%, respectively (median follow-up: 31 months). Higher levels of ctDNA were associated with both higher Ann Arbor Stage (p = 0.015) and higher IPI (p < 0.0001). In cases where LymphGen classification was available from both tumor and pre-treatment plasma, we observed a high concordance (87%, 34/39) between tissue and non-invasive subtyping.

At the EOT, 76% of patients were MRD- and 24% were MRD+. MRD+ status significantly predicted inferior PFS (2 yr PFS 88 versus 28%; HR 9.7, 95% CI 4.2-22.3, *p* < 0.0001) and OS (2 yr OS 97 versus 50%; HR 10.6, 95% CI 4.1-27.7, *p* < 0.0001). Moreover, in patients without complete response, MRD+ was significantly prognostic for PFS, suggesting an ability to adjudicate imaging results (HR PFS 7.6, 95% CI 3.6-16.3, *p* < 0.0001). Among patients who were MRD- and achieved CMR at EOT, 2-year PFS and OS were 91% and 99%, respectively. All patients who failed to achieve CMR and remained MRD+ experienced relapse.

ctDNA-MRD was prognostic for outcomes in all subgroups considered, including source of baseline sample (tumor versus plasma), best clinical response, IPI, sex, lactate dehydrogenase, stage, or extranodal disease. In multivariate analysis including ctDNA-MRD, IPI, and best overall response, ctDNA-MRD was significantly and independently prognostic for both PFS [HR ctDNA: 7.1, 95% CI 3.5-14.3, *p* < 0.0001] and OS [HR ctDNA: 5.1, 95% CI 2.2-11.9, *p* = 0.00018].

**Conclusions:** We validated the prognostic value of PhasED-Seq-based ctDNA-MRD in a real-world 1L DLBCL cohort. This highlights the utility of ctDNA-MRD to confirm residual disease in patients without complete response by imaging, as well as the potential to identify patients who may benefit from consolidation therapy. These results support the integration of MRD as a standard component of response evaluation in 1L DLBCL treatment.

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**Encore Abstract:** ASCO 2025; EHA 2025

**Keywords:** genomics, epigenomics, and other -omics; aggressive B-cell non-Hodgkin lymphoma; diagnostic and prognostic biomarkers

**Potential sources of conflict of interest:**

B. J. Sworder

Consultant or advisory role: Foresight Diagnostics, Inc

S. Close

Employment or leadership position: Foresight Diagnostics, Inc

K. Brown

Employment or leadership position: Foresight Diagnostics, Inc

S. Meek

Employment or leadership position: Foresight Diagnostics, Inc

A. A. Alizadeh

Consultant or advisory role: Foresight Diagnostics, Inc

D. M. Kurtz

Employment or leadership position: Foresight Diagnostics, Inc

Stock ownership: Foresight Diagnostics, Inc

D. M. Kurtz

Employment or leadership position: Foresight Diagnostics, Inc

Stock ownership: Foresight Diagnostics, Inc

42 | CIRCULATING TUMOR DNA FOR MONITORING PRIMARY MEDIASTINAL B-CELL LYMPHOMA IN COMPLEMENT TO PET: A PROSPECTIVE MULTICENTER LYSA STUDY

V. Camus<sup>1,2,3</sup>, D. Krzisch<sup>4</sup>, A. Bruscaggin<sup>2</sup>, E. Lévêque<sup>5</sup>, M. Viennot<sup>3</sup>, L. Fornecker<sup>6</sup>, M. Cheminant<sup>7</sup>, S. Bailly<sup>8</sup>, F. Morschhauser<sup>9</sup>, P. Feugier<sup>10</sup>, S. Choquet<sup>11</sup>, E. Durot<sup>12</sup>, S. Carras<sup>13</sup>, C. Delette<sup>14</sup>, G. Damaj<sup>15</sup>, A. Waultier-Rascalou<sup>16</sup>, P. Lebreton<sup>1,17</sup>, K. Le Du<sup>18</sup>, K. Bouabdallah<sup>19</sup>, R. Houot<sup>20</sup>, N. Morineau<sup>21</sup>, K. Laribi<sup>22</sup>, L. Lebras<sup>23</sup>, L. Oberic<sup>24</sup>, S. Amorim<sup>25</sup>, S. Bocchetta<sup>2</sup>, P. Viailly<sup>3</sup>, V. Rainville<sup>3</sup>, P. Ruminy<sup>3</sup>, M. Caillot<sup>3</sup>, L. Terzi Di Bergamo<sup>2</sup>, M. Pirosa<sup>2</sup>, M. Salehi<sup>2</sup>, G. Forestieri<sup>2</sup>, D. Piffaretti<sup>2</sup>, F. Drieux<sup>3,26</sup>, E. Veresezan<sup>3,26</sup>, A. Traverse-Glehen<sup>27</sup>, M. Donzel<sup>27</sup>, L. Burel<sup>5</sup>, E. Bohers<sup>3</sup>, M. Lanic<sup>3</sup>, D. Penther<sup>28</sup>, S. Becker<sup>29</sup>, P. Decazes<sup>29</sup>,
D. Tonnelet²⁹, S. Draye-Carbonnier²⁹, H. Tilly¹, F. Jardin¹,³,
D. Rossi², P. Pesques³⁰

¹Department of Hematology, Centre Henri Becquerel, Rouen, France,
²Laboratory of Experimental Hematology, Institute of Oncology Research, Bellinzona, Switzerland, ³Centre Henri Becquerel, INSERM U1245, Cancer & Brain Genomics, Rouen, France, ⁴Department of Hemato-Oncology, Hôpital Saint-Louis, Université de Paris, Assistance Publique-Hôpitaux de Paris, Paris, France, ⁵Clinical Research Unit, Centre Henri Becquerel, Rouen, France, ⁶Department of Hematology, Strasbourg University Hospital, Strasbourg, France, ⁷Department of Hematology, Université de Paris Cité, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France, ⁸Department of Hematology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France, ⁹Department of Hematology, Claude Huriez Hospital, Lille University Hospital, Lille, France, ¹⁰Department of Hematology, Hôpital de Brabois, Nancy University Hospital, Nancy, France, ¹¹Pitié-Salpêtrière University Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France, ¹²Department of Hematology, Reims University Hospital, Reims, France, ¹³Molecular Biology and Hematology Departments, Univ. Grenoble Alpes. Institute For Advanced Biosciences (INSERM U1209, CNRS UMR 5309), University Hospital, Grenoble, France, ¹⁴Department of Clinical Hematology, Amiens University Hospital, Amiens, France, ¹⁵Department of Hematology, Caen University Hospital, Caen, France, ¹⁶Department of Hematology, Nimes University Hospital, Rouen, France, ¹⁷Jacques Monod Hospital, Groupe Hospitalier du Havre, Montivilliers, France, ¹⁸Hôpital Privé du Confluent, Nantes, France, ¹⁹Hematology and Cellular Therapy Department, University Hospital of Bordeaux, Bordeaux, France, ²⁰Department of Hematology, CHU Rennes, University of Rennes, INSERM U1236, EFS, Rennes, France, ²¹Centre Hospitalier Départemental de Vendée, La Roche sur Yon, France, ²²Centre Hospitalier du Mans, Le Mans, France, ²³Department of Hematology, Leon Berard Cancer Center, Lyon, France, ²⁴Department of Hematology, Institut Universitaire du Cancer, Toulouse-Oncopole, Toulouse, France, ²⁵Department of Hematology, Hopital Saint Vincent de Paul, Lille, France, ²⁶Department of Pathology, Centre Henri Becquerel, Rouen, France, ²⁷Department of Pathology, Hospices Civils de Lyon, CHU Lyon-Sud, Pierre-Bénite, France, ²⁸Laboratory of Genetic Oncology, Centre Henri Becquerel, Rouen, France, ²⁹Department of Nuclear Medicine and QuantIF-LITIS/AIMS, Centre Henri Becquerel, Rouen, France, ³⁰Department of Hematology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, Pierre-Bénite, France

**Introduction:** Positron Emission Tomography (PET), is routinely used for Primary Mediastinal B-cell Lymphoma (PMBL) therapy guidance, but has limited sensitivity (Se) and specificity (Sp) for minimal residual disease (MRD) assessment in this disease.

**Methods:** In the prospective CAMIL study (NCT04824950), we evaluated ctDNA and PET in newly diagnosed PMBL patients (pts) treated with immunochemotherapy (ICT) at 31 LYSA centers (2021–2023). PET4 response was centrally reviewed, with a ΔSUVmax threshold of > 70% to define negativity. Blood samples were collected before ICT and on PET4 day. ctDNA was analyzed using a CAPP-seq protocol (~380 kb selector, 155 genes, > 2000× coverage, detection limit: 10⁻³).

**Results:** Of 84 pts with centrally confirmed PMBL, the median age was 32 years (Q1: 26; Q3: 40), with 64% female. Key features: elevated LDH (85%), PS 0–1 (91%), stage I-II (67%), IPI 0–2 (89%), renal/adrenal involvement (3.6%), bulky disease

≥ 10 cm (70%), mediastinal (100%) and extra-nodal involvement (50%). Median metabolic tumor volume (MTV, fixed SUV4 method) and total lesion glycolysis (TLG) were 453 cm³ (231; 664) and 4022 (2019; 7918). Induction regimens were R-CHOP14 (61%) and R-ACVBP (39%). For consolidation, three pts underwent autologous transplantation, four received radiotherapy, and the others continued ICT. Baseline ctDNA was detected in 82/84 (98%) pts, with a median level of 755 hGE/mL, 8.9% variant allele frequency, 7 variants per gene, and 101 variants per sample. Among 131 mutated genes, the most frequent were BCL6 (98%, mainly non-coding), SOCS1 (89%), IGLL5 (85%), B2M (73%), and CD83 (72%). PET4 was performed in 98% of pts and was negative in 90.2%, regardless of induction regimen. ctDNA4 negativity (> 3 log clearance) was achieved in 88% (64/73) with no regimen differences. ctDNA4 outperformed PET4 in predicting progressions (9 events), with higher Se (1 versus 0.44), Sp (0.99 versus 0.94), positive predictive value (0.89 versus 0.5), and negative predictive value (1 versus 0.93). After a median follow-up of 21.5 months, 1-year (yr) PFS and OS were 90.5% and 99% (1 non-lymphoma related death). 1-year PFS was 93.2% for PET4- versus 62.5% for PET4+ pts (*p* < 10⁻⁴) and 98.4% for ctDNA4- versus 33.3% for ctDNA4+ pts (*p* < 10⁻⁴). ctDNA4+ pts had higher median baseline TLG (8448 versus 3622, *p* = 0.033) and MTV (836 versus 417 cm³, *p* = 0.03). In univariate analysis, CRP (HR = 1.19 [1.07; 1.33]), LDH (HR = 1.21 [1.08;1.37]), MTV (HR = 1.26 [0.98;1.61]), PET4+ (12.4 [3.3; 46.9]) and ctDNA4+ (78.1 [9.5;641.7]) were associated with inferior PFS, whereas ctDNA4-/PET4- was associated with a better outcome (HR = 0.01 [0;0.08]). In a multivariate model for PFS including CRP, LDH, MTV, and ctDNA4-/PET4-, ctDNA4-/PET4- was associated with longer PFS (HR 0.07 [0.01; 0.69], *p* = 0.023).

**Conclusion:** ctDNA analysis by CAPP-seq in PMBL is informative for 98% of pts. Each somatic variant served as an MRD biomarker. PET4 response and ctDNA4 clearance were strong and complementary predictors of outcome.

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**Research funding declaration:** This work was supported by grants from Centre Henri Becquerel (AO_2020), CALYM (ANR-2022), GEFLUC (AO_2021), Ligue Contre le Cancer (Seine-Maritime committee, AO_2021), Prix Bertrand Coiffier (LYSA/ELI), and ABBVIE.

**Keywords:** PET-CT; liquid biopsy; aggressive B-cell non-Hodgkin lymphoma

No potential sources of conflict of interest.