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.

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.

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

Participants with aggressive B cell lymphoma