Research Papers:
The prognostic value of clonal heterogeneity and quantitative assessment of plasma circulating clonal IG-VDJ sequences at diagnosis in patients with follicular lymphoma
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Abstract
Clémentine Sarkozy1,2, Sarah Huet2,3, Victoria E.H. Carlton4, Bettina Fabiani5, Alain Delmer6, Fabrice Jardin7, Marie-Helene Delfau-Larue8, Maya Hacini9, Vincent Ribrag10, Stéphanie Guidez11, Malek Faham4, Gilles Salles1,2
1Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Service d’Hématologie, 69495 Pierre Bénite Cedex, France
2NSERM1052, CNRS 5286, Université Claude Bernard, Faculté de Médecine Lyon-Sud Charles Mérieux Lyon-1, 69495 Pierre Bénite Cedex, France
3Hospices Civils De Lyon, Laboratoire d’Hématologie, Pierre Bénite, France
4Adaptive Biotechnologies Corp., South San Francisco, CA, USA
5Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Antoine, Paris, France
6Service d’Hématologie, CHU de Reims, Reims, France
7Centre Henri Becquerel, Service d’Hématologie, Rouen, France
8Department of Biological Hematology and Immunology, Assistance Publique – Hôpitaux de Paris, Groupe Hospitalier Mondor, Créteil, France
9Centre Hospitalier de Chambery, Service d’Hématologie, Chambery, France
10Institut Gustave Roussy, Service d’Hématologie, Université Paris-Sacley, Villejuif, France
11Service d’Hématologie, CHU de Poitiers, France
Correspondence to:
Gilles Salles, email: [email protected]
Keywords: follicular lymphoma, circulating tumor DNA, prognostic factor, rituximab, maintenance
Received: December 02, 2016 Accepted: December 05, 2016 Published: January 02, 2017
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.
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