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Clinical Trial
. 2017 Jan 31;8(5):8765-8774.
doi: 10.18632/oncotarget.14448.

The prognostic value of clonal heterogeneity and quantitative assessment of plasma circulating clonal IG-VDJ sequences at diagnosis in patients with follicular lymphoma

Clémentine Sarkozy  1   2 , Sarah Huet  2   3 , Victoria E H Carlton  4 , Bettina Fabiani  5 , Alain Delmer  6 , Fabrice Jardin  7 , Marie-Helene Delfau-Larue  8 , Maya Hacini  9 , Vincent Ribrag  10 , Stéphanie Guidez  11 , Malek Faham  4 , Gilles Salles  1   2
Affiliations
Clinical Trial

The prognostic value of clonal heterogeneity and quantitative assessment of plasma circulating clonal IG-VDJ sequences at diagnosis in patients with follicular lymphoma

Clémentine Sarkozy et al. Oncotarget. .

Abstract

Recent advances in next-generation sequencing (NGS) have enabled the quantitation of circulating tumour DNA (ctDNA) encoding the clonal rearranged V(D)J immunoglobulin locus. We aimed to evaluate the clonal heterogeneity of follicular lymphoma (FL) in the tumour and the plasma at diagnosis and to assess the prognostic value of the ctDNA level. Plasma samples at diagnosis were available for 34 patients registered in the PRIMA trial (NCT00140582). One tumour clonotype or more could be detected for 29 (85%) and 25 (74%) patients, respectively, in the tumour or plasma samples. In 18 patients, several subclones were detected in the tumour (2 to 71 subclones/cases) and/or in the plasma (2 to 20 subclones/cases). In more than half of the cases, the distribution of subclones differed between the tumour and plasma samples, reflecting high clonal heterogeneity and diversity in lymphoma subclone dissemination. In multivariate analysis, a high level of ctDNA was the only independent factor associated with patients' progression-free survival (HR 4, IC 95 (1.1-37), p=.039). In conclusion, an NGS-based immunosequencing method reveals the marked clonal heterogeneity of follicular lymphoma in patients with FL, and quantification of ctDNA at diagnosis represents a potential powerful prognostic biomarker that needs to be investigated in larger cohorts.

Keywords: circulating tumor DNA; follicular lymphoma; maintenance; prognostic factor; rituximab.

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Conflict of interest statement

CONFLICTS OF INTEREST

Gilles Salles has received research support and honoraria for advisory board meetings and symposia from Roche/Genentech.

Victoria E.H. Carlton is employee and stock holder of Adaptive.

Malek Faham is stock holder of Adaptive.

Figures

Figure 1
Figure 1. Identification of the calibrating clone and repartition of the different subclones in the tumour and in the plasma with the IGH-V, IGH-D and IGK assays
Figure 2
Figure 2
A and B. Two examples illustrating the clonal heterogeneity of FL and the heterogeneous distribution of clonal and subclonal populations between the tumour biopsy and the plasma.
Figure 3
Figure 3
A. PFS according to the level of ctDNA in 29 patients with detectable calibrating clone presence in the tumour. B. PFS according to the level of ctDNA in the PRIMA observation subgroup. C. PFS according to the level of ctDNA in the PRIMA rituximab-maintenance subgroup.
Figure 4
Figure 4. PFS according to the number of subclones identified in the tumour biopsy
See this image and copyright information in PMC

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