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170 Combining PET/CT and Ctdna Assessments at 6 Months from Induction Treatment Better Predicts Outcome in Previously Untreated Patients with Follicular Lymphoma: A Relevance Ancillary Lysa Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 621. Lymphomas: Translational – Molecular and Genetic: Microenvironment and Methylome in Lymphoma and Misc.
Hematology Disease Topics & Pathways:
adult, Research, Lymphomas, bioinformatics, Clinical Research, indolent lymphoma, Diseases, Lymphoid Malignancies, survivorship, Technology and Procedures, Human, Study Population, Minimal Residual Disease , molecular testing, omics technologies
Saturday, December 9, 2023: 2:15 PM

Alexis Claudel1*, Anne Ségolène Cottereau, MD2*, Emmanuel Bachy, MD, PhD3*, Pierre Feugier4*, Rene-Olivier Casasnovas, MD5*, Corinne Haioun, MD, PhD6, Herve Tilly, MD7, Nicolas Daguindau8*, Guillaume Cartron, MD, Ph-D9*, Emmanuelle Nicolas Virelizier, MD10*, Pauline Brice11*, Benoit Tessoulin12*, Christophe Fruchart13*, Sylvie Glaisner14*, Alain Jacques Delmer, MD15*, Emmanuel Fleck16*, Gian Matteo Pica, MD17*, Hacene Zerazhi, MD18*, Stephanie Guidez19*, Morgane Cheminant20*, Luc Xerri, MD, PhD21*, Laetitia Vercellino, MD, PhD22*, Loïc Chartier23*, Lucie Gomes24*, Pierre-Julien Viailly24*, Marie-Helene Delfau, MD PhD25* and Franck Morschhauser, MD PhD26

1Hemato-biology, Henri Mondor University Hospital, CRETEIL, France
2Nuclear Medicine Department, Hopital Cochin, Paris, France
3Lyon-Sud Hospital Center, Pierre-Bénite, France
4Henri Poincaré University, Vandoeuvre Les Nancy, FRA
6Lymphoid Malignancies Department, Henri Mondor University Hospital, AP-HP, Créteil, France
7Centre Henri-Becquerel, Rouen, France
8Hematologie, Centre Hospitalier Annecy Genevois, Metz-Tessy, FRA
9Centre Hospitalier Universitaire de Montpellier, Montpellier, France
10Hematology Department, Centre Léon Bérard, Lyon, FRA
11Hematology Department, Hopital Saint Louis, Paris, FRA
12Hematology Department, CHU Nantes, Nantes, France
13Hématologie, Centre hospitalier de Dunkerque, Dunkerque, FRA
14Hématologie - Centre René Huguenin, Institut Curie, ST CLOUD, FRA
15Hôpital Robert Debré CHU de Reims, Reims Cedex, -, FRA
16Centre Hospitalier de La Rochelle, LA ROCHELLE, FRA
17Hematology department, CH Chambery, Chambery, France
18Oncologie Médicale et Hématologie clinique, CH d'Avignon - Hôpital Henri Duffaut, Avignon, France
19Hematolgy department, University Hospital of Poitiers, Poitiers, France
20Department of Hematology, Necker Hospital, APHP, Paris, France
21Pathology Department, Institut Paoli Calmettes, Marseille, FRA
22Nuclear Medicine Department, Hopital Saint Louis, Paris, France
23LYSARC, Pierre Bénite, France
24INSERM U918, Centre Henri Becquerel, Rouen, France
25Hemato-biology, Henri Mondor University Hospital, Créteil, France
26Hematology Department, Centre Hospitalier Régional Universitaire de Lille, Lille, AL, France


Most patients with follicular lymphoma (FL) have long-term disease control resulting in a prolonged overall survival (OS), beyond 20 years. However, approximately 20% of patients experience disease progression within two years after treatment initiation (POD24) which is associated with a shorter OS but early prediction of POD24 remains challenging. Positron emission tomography computed tomography (PET/CT) positivity after induction therapy has been associated with shortened progression-free survival (PFS). Also, minimal residual disease (MRD) positivity in peripheral blood using BCL2-JH translocation predicts outcome but barely 50% of patients are informative with this tumor marker. Circulating tumor DNA (ctDNA) may increase the proportion of MRD informative patients up to 80%. Our objective was to evaluate the predictive value of ctDNA for PFS and POD24, either alone or coupled with PET/CT response in first-line patients enrolled in the RELEVANCE trial.


This ancillary study was carried out on patients included by French LYSA centers in RELEVANCE, a randomized phase III trial comparing the chemotherapy-free regimen R2 versus standard R-chemo followed by Rituximab maintenance in previously untreated patients with FL. All patients who had a PET/CT at diagnosis and at week 24 (W24, end of induction treatment) and for whom serum was stored at these 2 time points were eligible. Cell-free DNA (cfDNA) was extracted from a median of 2.8 mL of serum (range 0.35 to 4.1). Libraries were generated from 129kb captured-DNA custom panel (Agilent, XTHS2). Variant calling and phased variant annotation were performed using Unique Molecular Identifiers (UMI). Libraries were sequenced with a median coverage of 3257 UMI. Concentrations of ctDNA were calculated from TapeStation migration system (Agilent) using 50 bp to 600 bp limits and expressed as log hGE/mL. To ensure maximum specificity in a context of non-optimal serum samples, only patients with phased variants in ctDNA at diagnosis were studied for MRD at W24. Total metabolic tumor volume (TMTV) was computed using the 41% SUVmax method and PET/CT response assessed with Lugano criteria.


As PET/CT at W24 was optional in RELEVANCE, only 141 out of 581 patients enrolled were eligible. Compared to the overall RELEVANCE population, baseline characteristics were similar except for FLIPI (7.1% FLIPI 0-1 versus 15.9% respectively, p=0.013) and PFS event (29.3% versus 39.5% respectively, p=0.035).

At time of diagnosis, with a median of 81 variants per patient (range 1 to 659), a mutational profile could be identified from cfDNA in 99% (140/141) of patients. A significant correlation was found between ctDNA load (median 2.39 log hGE/mL (range 1.01 to 4.20) and TMTV (median 298 mL, range 5 to 3100) (p=0.023). Phased variants were detected in 124 patients (87.9%) at diagnosis and were used for MRD analyses. At W24, ctDNA remained detectable (ctDNA+) in 15 patients, 9/69 (13%) in the R2 arm and 6/55 (11%) in the R-chemo arm (p=0.787). PET/CT remained positive (Deauville 4 and 5) in 20 patients, 11/72 (15.2%) in the R2 arm and 9/56 (16.1%) in the R-chemo arm. With a median follow-up of 6.4 years, ctDNA+ patients exhibited a median PFS of 37 months versus not reached for ctDNA- patients, p=0.0096. Similarly, PET/CT+ patients had a median PFS of 34 months versus not reached for PET/CT- patients (p<0.001). When adjusting on FLIPI in a multivariate Cox model, ctDNA remains statistically significant (HR=2.63 [1.20; 5.77], p=0.0163). Among PET/CT+ patients, 13/20 (65%) patients showed discrepant PET/CT and ctDNA responses and double positive patients (7/20, 35%) presented a shorter median PFS of 8.6 months (versus not reached, p=0.0147; Figure 1). Regarding POD24, negative predictive value (NPV) and positive predictive value (PPV) were respectively 91.7% and 46.7% for ctDNA MRD and 93.3% and 45.0% for PET/CT. When combined, PET+/MRD+ identified POD24 patients with a NPV and PPV of 91.5% and 85.7% respectively.


Combining the results of ctDNA and PET/CT at W24 post induction improves early prediction of POD24 in previously untreated patients with follicular lymphoma.

Disclosures: Bachy: Novartis: Honoraria, Other: Personal Fees; Incyte: Honoraria; Takeda: Honoraria; Pfizer: Honoraria, Other: Personal Fees; Hospices Civils de Lyon Claude Bernard Lyon 1 University: Current Employment; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Honoraria, Other: Personal Fees; Roche: Consultancy, Honoraria. Casasnovas: ROCHE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BEIGENE: Consultancy, Honoraria; GILEAD/KITE: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TAKEDA: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly: F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; BMS, F. Hoffmann-La Roche Ltd, ADC therapeutics: Membership on an entity's Board of Directors or advisory committees. Cartron: Gilead: Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; MedxCell: Consultancy; Novartis: Honoraria; Ownards Therapeutics: Consultancy; MabQi: Consultancy; Janssen: Honoraria; Emercell: Consultancy; BMS: Consultancy, Honoraria; Jansen, Gilead, Novartis, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Honoraria; MedxCell, Ownards Therapeutics, MabQi, Emercell, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Consultancy; MabQi, Ownards Therapeutics, Abbvie, Roche, Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Tessoulin: Gilead: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Kite: Honoraria. Guidez: Gilead/Kite: Honoraria; Astra-Zeneca: Honoraria; Incyte: Honoraria; Takeda: Honoraria. Cheminant: AstraZeneca: Other: Travel accomodations and Meeting inscription; Innate Pharma: Research Funding; Abbvie: Research Funding; Amgen: Honoraria. Morschhauser: F. Hoffmann-La Roche Ltd, Gilead, AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd, AbbVie, BMS, Genmab, Gilead, Novartis: Consultancy.

*signifies non-member of ASH