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B-cell Lymphoma

Monitoring of circulating tumor DNA after 2 and 4 cycles of chemotherapy

Circulating tumor DNA monitoring

VINCENT CAMUS, MD

RICHARD DORIANE, PhD

PIERRE SESQUES, MD

The purpose of this study is to compare the predictive value in terms of specificity of circulating tumor DNA (ctDNA) and positron emission computed tomography (PET-CT) after 2 cycles of chemotherapy (C2), on the probability of obtaining a metabolic complete response after 4 cycles of induction chemotherapy (C4) in patients with primary mediastinal large B cell lymphoma (PMBL) receiving standard R-CHOP14 or R-ACVBP.

The majority of studies with PMBL patients pinpoint the importance of being able to identify primary chemo refractory patients at an early stage, in order to be able to improve their prognosis. Indeed, a biomarker such as circulating tumor DNA (ctDNA) monitoring would be of great help to better assess the therapeutic response and offer an individualized care given the frequent positive residual uptake of the mediastinum at end of treatment. Indeed, ctDNA can be detected with Next-Generation Sequencing (NGS).

The hypothesis of this study is that it would be helpful to prospectively compare the predictive value of ctDNA versus PET on the capacity to detect primary refractory patients after 2 or 4 cycles of first line chemotherapy.

To date, there are no prospective studies reporting the evolution of the tumor clone under treatment or after obtaining complete remission in PMBL. The establishment of this prospective, multicenter, ambitious and original pilot project will make it possible to structure the analysis of tumor DNA circulating within these centers caring for patients with lymphomas within LYSA group.

The notion of minimal residual disease (MRD) has shown its interest in follicular lymphomas and mantle cell lymphomas. The level of sensitivity of NGS-type approaches on the one hand and the informativeness of the recurrent mutations recently described on the other hand constitute two elements for reconsidering the problem of MRD in PMBLs. Molecular MRD by analysis of circulating tumor DNA could constitute a new marker for monitoring response to treatment in addition to PET-CT and be useful as a tool for non-invasive tumor sequencing at diagnosis and at relapse, in order to to determine the eligibility for possible targeted therapies (based on the inactivation of mutated genes) or immunotherapies.

This study will evaluate the prognostic value of obtaining a quantified complete molecular response (RMC) by analysis of free circulating DNA (ctDNA) after 2 and 4 cycles of first-line chemotherapy (C2 and C4) for the treatment of PMBL, and that of positron emission computed tomography (PET) performed at the same time, on overall survival and progression-free survival.

The investigators will describe 3 different populations of patients included in the study:

1. Patients with "negative" plasma DNA at diagnosis (defined by the absence of somatic mutation detectable at diagnosis by ctDNA analysis)
2. Patients with "positive" plasma DNA at diagnosis (defined by the presence of at least one somatic mutation detectable at diagnosis by ctDNA analysis) and whose plasma DNA becomes "negative" after 2 cycles of chemotherapy
3. Patients with "positive" plasma DNA and whose plasma DNA remains "positive" after 2 cycles of chemotherapy For these 3 patient profiles, we will perform comparisons, search for correlations with different variables and perform univariate and multivariate statistical analyzes.

Circulating Tumor DNA in Primary Mediastinal Large B-cell Lymphoma (PMBL)

specificity of ctDNA at Cycle 2 of chemotherapy on the prediction of achieving a complete metabolic response (determined by PET-CT scan) at cycle 4 of chemotherapy

Proportion of patient in complete metabolic response at the end of first line treatment

Percentage of patients in complete metabolic response, partial metabolic response, stable disease or pregression after 4 cycles of chemotherapy

Percentage of patients in complete metabolic response, partial metabolic response, stable disease or pregression at the end of treatment

Lenght of time after the end of tratment and events like progression, lake of response, relapse of death whatever the cause

Next-Generation-sequencing on diagnostic biopsy

Determination of molecular profile and evaluation of pronostic impact

Comparison between the result of Next generation Sequencing and the molocular profile obtained on circulation tumor DNA of each patient

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Circulating Tumor DNA in Primary Mediastinal Large B-cell Lymphoma (PMBL)	NCT04824950	Primary Mediast...	Circulating tum...	18 Years -	Centre Henri Becquerel
Circulating Tumor DNA in Primary Mediastinal Large B-cell Lymphoma (PMBL)	NCT04824950	Primary Mediast...	Circulating tum...	18 Years -	Centre Henri Becquerel

Spots Global Cancer Trial Database for circulating tumor dna monitoring