Proof of Concept for Real-time Multicentric Monitoring of MRD by PET and ctDNA in Aggressive B-Cell Lymphomas (RT4)

Proof of Concept for Real-time Multicentric Monitoring of Minimal Residual Disease (MRD) by PET and Circulating Tumor DNA (ctDNA) in Aggressive B-Cell Lymphomas

RT4 (REAL TIME TAILORED THERAPY) study was designed as a national, multicenter proof of concept aiming to demonstrate the technical and operational capacity of the French Connect network and the Positron Emission Tomography (PET) review network to ensure, within a coordinated framework, real time MINIMAL RESIDUAL DISEASE (MRD) monitoring through ctDNA analysis and centralized review of PET imaging.

Study Overview

• Status: Not yet recruiting
• Conditions: Aggressive B-cell Lymphomas
• Intervention / Treatment: Other: blood test

Detailed Description

Monitoring measurable residual disease (MRD) through the analysis of circulating tumor DNA (ctDNA) in plasma is rapidly emerging as one of the major recent advances in the management of lymphomas. Over the past years, several studies have shown that ctDNA enables a dynamic and highly sensitive assessment of treatment response, surpassing the limitations of conventional approaches based on imaging only.

Importantly, these advances do not replace or diminish the role of PET imaging. On the contrary, metabolic imaging and molecular monitoring are increasingly seen as complementary tools. When used together, PET imaging and ctDNA kinetic analysis may dynamically refine risk stratification and enable truly individualized adaptive treatment strategies. However, this synergy between MRD and PET can only influence clinical practice or trial design if results are available throughout patient management within a timeframe compatible with therapeutic decision making.

• Study Type: Observational
• Enrollment (Estimated): 129

Contacts and Locations

• Study Contact: Name: Project Management Project Management; Phone Number: +33 (0) 4 27 01 27 22; Email: RT4@lysarc.org

Study Locations

• France
  • Amiens, France, 80054
    • CHU D'AMIENS - HOPITAL SUD - Service Hématologie Clinique et Thérapie Cellulaire
    • Contact: Dr. Caroline SKRZYPCZAK; Phone Number: +33 (0)3 22 45 59 14; Email: skrzypczak.caroline@chu-amiens.fr
  • Angers, France, 49033
    • CHU D'ANGERS - Service des Maladies du Sang
    • Contact: Dr. Jérôme PAILLASSA; Phone Number: +33 (0)6 21 82 31 85; Email: jerome.paillassa@chu-angers.fr
  • Avignon, France, 84000
    • CH D'AVIGNON - HOPITAL HENRI DUFFAUT - Service d'Onco-Hématologie
    • Contact: Dr. Thierry TAKAM; Phone Number: +33 (0)4 32 75 93 78; Email: takam.thierry@ch-avignon.fr
  • Besançon, France, 25030
    • CHU JEAN MINJOZ - Service Hématologie
    • Contact: Dr. Adrien CHAUCHET; Phone Number: +33 (0)3 81 66 82 32; Email: achauchet@chu-besancon.fr
  • Clermont-Ferrand, France, 63003
    • CHU ESTAING - Service Thérapie Cellulaire et Hématologie Clinique
    • Contact: Dr. Sébastien BAILLY; Phone Number: +33 (0)4 73 75 00 65; Email: s-bailly@chu-clermontferrand.fr
  • Créteil, France, 94010
    • HOPITAL HENRI MONDOR - Unité Hémopathies Lymphoïdes
    • Contact: Dr. François LEMONNIER; Phone Number: +33 (0)1 49 81 20 51; Email: francois.lemonnier@aphp.fr
  • Dijon, France, 21000
    • CHU DIJON BOURGOGNE - Service Hématologie Clinique
    • Contact: Pr. Cédric ROSSI; Phone Number: +33 (0)6 80 29 50 41; Email: cedric.rossi@chu-dijon.fr
  • La Roche-sur-Yon, France, 85925
    • CHD DE VENDEE - Service Hématologie
    • Contact: Dr. Antoine LEVEQUE; Phone Number: +33 (0)2 51 44 61 73; Email: antoine.leveque@ght85.fr
  • La Tronche, France, 38700
    • CHU DE GRENOBLE - Service Hématologie
    • Contact: Dr. Sylvain CARRAS; Phone Number: +33 (0)4 76 76 57 55; Email: scarras@chu-grenoble.fr
  • Le Chesnay, France, 78157
    • CH DE VERSAILLES - HOPITAL ANDRE MIGNOT - Service Hématologie Adolescents et Jeunes Adultes
    • Contact: Dr. Aurélie CABANNES-HAMY; Phone Number: +33 (0)1 39 63 90 33; Email: acabannes@ght78sud.fr
  • Lille, France, 59020
    • HOPITAL SAINT VINCENT-DE-PAUL - Service Hématologie Clinique
    • Contact: Dr. Sandy AMORIM; Phone Number: +33 03 20 87 45 32; Email: amorim.sandy@ghicl.net
  • Lille, France, 59037
    • CHU DE LILLE - HOPITAL CLAUDE HURIEZ - Service des Maladies du Sang
    • Contact: Pr. Franck MORSCHHAUSER; Phone Number: +33 (0)3 20 44 57 13; Email: franck.morschhauser@chu-lille.fr
  • Lyon, France, 69373
    • CENTRE LEON BERARD - Service Hématologie
    • Contact: Dr. Sylvain LAMURE; Phone Number: +33 (0)4 69 85 61 93; Email: sylvain.lamure@lyon.unicancer.fr
  • Montpellier, France, 34295
    • CHU DE MONTPELLIER - Département d'Hématologie Clinique
    • Contact: Dr. Charles HERBAUX; Phone Number: +33 (0)4 67 33 83 64; Email: c-herbaux@chu-montpellier.fr
  • Nantes, France, 44093
    • CHU DE NANTES - Service Hématologie
    • Contact: Dr. Benoit TESSOULIN; Phone Number: +33 (0)2 40 08 32 71; Email: benoit.tessoulin@chu-nantes.fr
  • Orléans, France, 45067
    • CHU ORLEANS - Service Oncologie Médicale
    • Contact: Dr. Marlène OCHMANN; Phone Number: +33 (0)2 38 57 52 54; Email: marlene.ochmann@chu-orleans.fr
  • Paris, France, 75014
    • HOPITAL COCHIN - Hématologie clinique
    • Contact: Dr. Loïc RENAUD; Phone Number: +33 (0)1 42 11 45 07; Email: loic.renaud@aphp.fr
  • Paris, France, 75475
    • HOPITAL SAINT-LOUIS - Service Hématologie Adolescents et Jeunes Adultes
    • Contact: Dr. Florian CHEVILLON; Phone Number: + 33 01 42 38 51 27; Email: florian.chevillon@aphp.fr
  • Paris, France, 75651
    • HOPITAL DE LA PITIE SALPETRIERE - Service Hématologie Clinique
    • Contact: Dr. Daphné KRZISCH; Phone Number: +33 (0)1 84 82 84 94; Email: daphne.krzisch@aphp.fr
  • Paris, France, 75743
    • HOPITAL NECKER - Service Hématologie Adultes
    • Contact: Dr. Morgane CHEMINANT; Phone Number: +33 (0)1 44 49 52 83; Email: morgane.cheminant@aphp.fr
  • Pessac, France, 33604
    • CHU DE BORDEAUX - HOPITAL HAUT-LEVEQUE - CENTRE FRANCOIS MAGENDIE - Service d'Hématologie et Thérapie Cellulaire
    • Contact: Dr. François-Xavier GROS; Phone Number: +33 (0)5 57 65 65 11; Email: francois-xavier.gros@chu-bordeaux.fr
  • Pierre-Bénite, France, 69495
    • CHU LYON-SUD - Hématologie Clinique
    • Contact: Dr. Pierre SESQUES; Phone Number: +33 (0)4 78 86 43 46; Email: pierre.sesques@chu-lyon.fr
  • Poitiers, France, 86021
    • CHU DE POITIERS - HOPITAL DE LA MILETRIE - Service d'Oncologie Hématologique et Thérapie Cellulaire
    • Contact: Dr. Stéphanie GUIDEZ; Phone Number: fr +33 (0)5 49 44 43 07; Email: stephanie.guidez@chu-poitiers.fr
  • Reims, France, 51092
    • CHU DE REIMS - HOPITAL ROBERT DEBRE - Service Hématologie
    • Contact: Dr. Eric DUROT; Phone Number: +33 (0)6 64 77 25 61; Email: edurot@chu-reims.fr
  • Rennes, France, 35033
    • CHU PONTCHAILLOU - Hématologie Clinique
    • Contact: Pr. Roch HOUOT; Phone Number: +33 (0)2 99 28 98 73; Email: roch.houot@chu-rennes.fr
  • Rouen, France, 76038
    • CENTRE HENRI BECQUEREL - Service Hématologie
    • Contact: Dr. Vincent CAMUS; Phone Number: +33 (0)2 32 08 29 47; Email: vincent.camus@chb.unicancer.fr
  • Saint-Cloud, France, 92210
    • INSTITUT CURIE - SITE SAINT-CLOUD - Service Hématologie
    • Contact: Dr. Adrien GILBERT; Phone Number: +33 (0)1 47 11 15 15; Email: adrien.gilbert@curie.fr
  • Toulouse, France, 31059
    • IUCT ONCOPOLE - Service Hématologie
    • Contact: Dr. Lucie OBERIC; Phone Number: +33 (0)5 61 77 20 78; Email: oberic.lucie@iuct-oncopole.fr
  • Vandœuvre-lès-Nancy, France, 54511
    • CHRU NANCY - HÔPITAL BRABOIS - Service Hématologie
    • Contact: Pr. Pierre FEUGIER; Phone Number: +33 (0)3 83 15 32 57; Email: p.feugier@chru-nancy.fr
  • Villejuif, France, 94085
    • GUSTAVE ROUSSY CANCER CAMPUS GRAND PARIS - Département Médecine Oncologique
    • Contact: Dr. Vincent RIBRAG; Phone Number: +33 (0)1 42 11 45 07; Email: vincent.ribrag@gustaveroussy.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Participants with aggressive B cell lymphoma

Description

Inclusion criteria

Participants must meet all of the following criteria to be included in the study:

1. Participant who understands and voluntarily signs an informed consent form prior to any study-specific assessment or procedure.
2. Age 18 or older at the time of signing the Informed Consent Form (ICF)

3. Histologically confirmed diagnosis, according to the WHO 2022 classification, of any of the following lymphomas:

   Aggressive B-cell lymphoma, including:

   • Diffuse large B-cell lymphoma, unspecified (DLBCL not specified)

   • High-grade B-cell lymphoma (LBHG), including:

     1. With rearrangements of the MYC and BCL2 and/or BCL6 genes (double/triple hit)
     2. Unspecified (i.e., no double/triple rearrangement)
   • Primary B-cell lymphoma of the mediastinum (PMBL)

   • Transformed indolent B-cell lymphoma, including:

     1. Transformed follicular lymphoma (LFt)
     2. Transformed marginal zone lymphoma (t-MZL)
     3. Transformed, unspecified nodal or splenic B-cell lymphomas (NOS)
4. Presence of a measurable disease on pre-therapeutic PET imaging, defined as at least one two-dimensional measurable nodal lesion, defined as > 1.5 cm in its largest dimension (and FDG-greedy lesion), or at least one two-dimensional measurable extranodal lesion, defined as > 1.0 cm in its largest dimension (and FDG-hungry lesion).
5. Requiring standard first-line systemic treatment with curative intent
6. Person covered by a social security scheme
7. Person able to understand and speak French. Exclusion criteria

Participants who meet any of the criteria below will not be eligible for inclusion / should be excluded from the study:

1. Systemic anticancer treatment of current lymphoma prior to inclusion in the study. All participants must be previously untreated for current lymphoma.

   Note: Short-term corticosteroid therapy (e.g., for symptom control or as part of diagnostic workup) is allowed prior to inclusion and is not an exclusion criterion.

2. Lymphomas associated with an immuno-privileged site (e.g., primary central nervous system lymphoma, primary testicular lymphoma, primary vitreoretinal lymphoma).
3. Absence of mandatory blood sampling for the analysis of circulating tumor DNA (ctDNA) during screening (pre-therapeutic sampling).
4. Absence of 18F-FDG PET examination performed within 2 months ≤ the date of signing the consent (mandatory pre-therapeutic PET imaging).
5. Pregnant, intending to be pregnant, or breastfeeding woman of childbearing potential
6. Any significant medical condition, laboratory abnormality, or psychiatric illness that may interfere with participation in this clinical study (in the opinion of the investigator)
7. Person deprived of liberty by judicial or administrative decision
8. Person hospitalized without their consent
9. Adult under legal protection

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
All participants will receive standard of care treatment only, according to local practice.	Other: blood test; Three blood tests will be performed (one before treatment, one at mid treatment, and one at the end of treatment) for ctDNA analysis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary endpoint is the proportion of participants for whom MRD results are delivered within these timelines at the predefined interim treatment response assessment.	The primary objective of the study is to assess the feasibility of providing investigators with MRD results for participants with previously untreated aggressive B cell lymphomas at the time of the predefined interim response assessment, within strict timelines: no more than 14 calendar days from blood collection for ctDNA results, and; no more than 7 calendar days after the imaging examination for the centralized PET review results.	at interim timepoint, after Cycle 4 (each cycle is 14 or 21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Event Free Survival (EFS) by histology subtype	at 1 year
Progression/relapse	Duration of response (DoR) as defined by Lugano 2014 criteria	at 1 year
Survival	Progression-free survival (PFS) by histology subtype	1year
Survival	Overall Survival (OS) by histology subtype	1year
Evaluate the prognostic value of ctDNA/radiomics PET at mid-treatment and end-of-treatment	EFS according to ctDNA MRD status at the interim assessment and at the end of treatment assessment (positive vs negative), according to the interim PET response (response per Lugano 2014 and other radiomic parameters), and according to their combination (ctDNA + PET).	at 1 year
Evaluate the prognostic value of ctDNA/radiomics PET at mid-treatment and end-of-treatment	OS according to ctDNA MRD status at the interim assessment and at the end of treatment assessment (positive vs negative), according to the interim PET response (response per Lugano 2014 and other radiomic parameters), and according to their combination (ctDNA + PET).	at 1 year
Number of participants with concordant results (positive PET and ctDNA or negative PET and ctDNA) and number of participants with discordant results (positive PET and negative ctDNA or negative PET and positive ctDNA).	Concordance rate between metabolic PET response and ctDNA result	Each timepoint (pre-treatment, interim timepoint, end of treatment)
To document and classify the reasons for unsuccessful PET acquisition, analysis or reporting	Number of participants with delayed results, and reasons associated.	at interim timepoint, after Cycle 4 (each cycle is 14 or 21 days)
To document and classify the reasons for unsuccessful ctDNA sampling, processing or result reporting.	Number of participants with delayed results, and reasons associated.	at interim timepoint, after Cycle 4 (each cycle is 14 or 21 days)
Evaluate the prognostic value of ctDNA/radiomics PET at mid-treatment and end-of-treatment	PFS according to ctDNA MRD status at the interim assessment and at the end of treatment assessment (positive vs negative), according to the interim PET response (response per Lugano 2014 and other radiomic parameters), and according to their combination (ctDNA + PET).	at 1 year
To assess the proportion of informative cfDNA samples for phased variant monitoring	Proportion of samples with at least twenty phased variants detectable at baseline	Baseline
Describe the timelines for the delivery of the results of the centralized PET review.	Proportions of participants for whom results are delivered within the predefined time frame in the protocol (time between the date of image acquisition or collection and the date of transmission to the investigator ≤ target time), at baseline (before interim evaluation) and at the end of treatment (≤ 5 weeks) with a 95% confidence interval. The observed delays (in calendar days) will also be described by their distribution (median, interquartile range, minimum-maximum)	Two timepoints (Baseline, end of treatment)
Describe the timelines for the delivery of the results of ctDNA results.	Proportions of participants for whom results are delivered within the predefined time frame in the protocol (time between the date of blood collection and the date of transmission to the investigator ≤ target time), at baseline (before interim evaluation) and at the end of treatment (≤ 5 weeks), estimated globally and by RT4 platform with a 95% confidence interval. The observed delays (in calendar days) will also be described by their distribution (median, interquartile range, minimum-maximum), overall and by platform	Two timepoints (Baseline, end of treatment)

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Investigators: Principal Investigator: Vincent CAMUS, Dr, CENTRE HENRI BECQUEREL - Service Hématologie; Principal Investigator: Cédric ROSSI, Pr, CHU DIJON BOURGOGNE - Service Hématologie Clinique

Publications and helpful links

General Publications

• Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.
• Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the First International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009 Aug;50(8):1257-60. doi: 10.1080/10428190903040048.
• Wang S, Nijland M, Strobbe L, Oosterveld M, Boersma R, Koene H, Klerk C, de Jongh E, Koster A, Pruijt H, van der Poel M, van Werkhoven E, Zanders H, Dinmohamed A, Pegtel M, Meek S, Stowell SL, Warinske H, Alizadeh AA, Kurtz DM, Chamuleau MED. Prospective Validation of Circulating Tumor DNA Measurable Residual Disease After First-Line Therapy in Large B-Cell Lymphoma. J Clin Oncol. 2026 Feb 10;44(5):400-409. doi: 10.1200/JCO-25-01712. Epub 2025 Dec 12.
• Krupka JA, Moutsopoulos I, Cutmore NH, Trethewey CS, Dayimu A, Goodhew R, Kaji F, Raso-Barnett L, Cheow H, Elzubeir L, Smith J, Kamil A, Barbara RR, Price J, Elston K, Kolodziejczyk A, Tarantino S, Mariscotti F, Barry P, Frost S, Demiris N, Thomas MG, Hassane D, Munugalavadla V, Nagumantry SK, Karanth MJ, Ahearne M, Shah N, Fox CP, Anand S, Hodson DJ. Phased Variant-Supported Circulating Tumor DNA as a Prognostic Biomarker After First-Line Treatment in Large B-Cell Lymphoma: Findings From the DIRECT Study. J Clin Oncol. 2026 Feb 10;44(5):410-420. doi: 10.1200/JCO-25-01587. Epub 2025 Dec 22.
• Kurtz DM, Soo J, Co Ting Keh L, Alig S, Chabon JJ, Sworder BJ, Schultz A, Jin MC, Scherer F, Garofalo A, Macaulay CW, Hamilton EG, Chen B, Olsen M, Schroers-Martin JG, Craig AFM, Moding EJ, Esfahani MS, Liu CL, Duhrsen U, Huttmann A, Casasnovas RO, Westin JR, Roschewski M, Wilson WH, Gaidano G, Rossi D, Diehn M, Alizadeh AA. Enhanced detection of minimal residual disease by targeted sequencing of phased variants in circulating tumor DNA. Nat Biotechnol. 2021 Dec;39(12):1537-1547. doi: 10.1038/s41587-021-00981-w. Epub 2021 Jul 22.
• Kurtz DM, Scherer F, Jin MC, Soo J, Craig AFM, Esfahani MS, Chabon JJ, Stehr H, Liu CL, Tibshirani R, Maeda LS, Gupta NK, Khodadoust MS, Advani RH, Levy R, Newman AM, Duhrsen U, Huttmann A, Meignan M, Casasnovas RO, Westin JR, Roschewski M, Wilson WH, Gaidano G, Rossi D, Diehn M, Alizadeh AA. Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2018 Oct 1;36(28):2845-2853. doi: 10.1200/JCO.2018.78.5246. Epub 2018 Aug 20.

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: March 13, 2026
• First Submitted That Met QC Criteria: April 1, 2026
• First Posted (Actual): April 7, 2026

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Circulating Tumor DNA; Large B-Cell Lymphoma; Measurable Residual Disease; PhasED-Seq; PET-Scan in Lymphoma
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm, Residual; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Hematologic Tests
• Other Study ID Numbers: RT4

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No