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

Official title

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

Overview

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.

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.

Interventions

• 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.

Primary outcome measures

• The primary endpoint is the proportion of participants for whom MRD results are delivered within these timelines at the predefined interim treatment response assessment. [Time frame: at interim timepoint, after Cycle 4 (each cycle is 14 or 21 days)]

Secondary outcome measures (12)

• Survival [Time frame: at 1 year]
• Progression/relapse [Time frame: at 1 year]
• Evaluate the prognostic value of ctDNA/radiomics PET at mid-treatment and end-of-treatment [Time frame: at 1 year]
• To document and classify the reasons for unsuccessful PET acquisition, analysis or reporting [Time frame: at interim timepoint, after Cycle 4 (each cycle is 14 or 21 days)]
• Survival [Time frame: 1year]
• Survival [Time frame: 1year]
• Evaluate the prognostic value of ctDNA/radiomics PET at mid-treatment and end-of-treatment [Time frame: at 1 year]
• Evaluate the prognostic value of ctDNA/radiomics PET at mid-treatment and end-of-treatment [Time frame: 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). [Time frame: Each timepoint (pre-treatment, interim timepoint, end of treatment)]
• To document and classify the reasons for unsuccessful ctDNA sampling, processing or result reporting. [Time frame: at interim timepoint, after Cycle 4 (each cycle is 14 or 21 days)]
• To assess the proportion of informative cfDNA samples for phased variant monitoring [Time frame: Baseline]
• Describe the timelines for the delivery of the results of the centralized PET review. [Time frame: Two timepoints (Baseline, end of treatment)]

Eligibility criteria

Inclusion criteria

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

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

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

• Transformed follicular lymphoma (LFt)
• Transformed marginal zone lymphoma (t-MZL)
• Transformed, unspecified nodal or splenic B-cell lymphomas (NOS)
• 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).
• Requiring standard first-line systemic treatment with curative intent
• Person covered by a social security scheme
• 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:

• 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.

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Other

Study locations

France · 30 centers

• CHU D'AMIENS - HOPITAL SUD - Service Hématologie Clinique et Thérapie Cellulaire — Amiens
• CHU D'ANGERS - Service des Maladies du Sang — Angers
• CH D'AVIGNON - HOPITAL HENRI DUFFAUT - Service d'Onco-Hématologie — Avignon
• CHU JEAN MINJOZ - Service Hématologie — Besançon
• CHU ESTAING - Service Thérapie Cellulaire et Hématologie Clinique — Clermont-Ferrand
• HOPITAL HENRI MONDOR - Unité Hémopathies Lymphoïdes — Créteil
• CHU DIJON BOURGOGNE - Service Hématologie Clinique — Dijon
• CHD DE VENDEE - Service Hématologie — La Roche-sur-Yon
• … and 22 more centers

Publications

• 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. PMID 19544140
• 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; Germ PMID 25113753
• 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 PMID 41385760
• 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 PMID 41428995
• 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 PMID 34294911
• 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 On PMID 30125215

Identifiers

NCT: NCT07514715 · RT4

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗