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3495 A Molecular Classifier Increased the Accuracy of Lymphoma Diagnosis By Expert Pathologists in the Diffuse Large B-Cell Lymphoma Gained Trial from the Lysa

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational—Molecular and Genetic: Poster III
Hematology Disease Topics & Pathways:
Translational Research, Clinically Relevant, Technology and Procedures, Molecular Testing, Pathology
Monday, December 13, 2021, 6:00 PM-8:00 PM

Amine Moslemi1*, Victor Bobée, PharmD2,3*, Paul Blanc-Durand4*, Fanny Drieux, MD, PhD2*, Fabienne Desmots-Loyer5,6*, Josette Briere, MD7*, Olivier Casasnovas, MD8*, Danielle Canioni, MD9*, Herve Ghesquieres, MD10*, Philippe Gaulard, MD, PhD11*, Lucie Oberic, MD12*, Diane Damotte, MD, PhD13*, Franck Morschhauser14*, Antoine Martin15*, Hervé Tilly, MD16, Catherine Thieblemont, MD, PhD17, Vincent Ribrag, MD18, Olivier Hermine, MD, PhD19,20, Corinne Haioun, MD21, Thierry Lamy, PhD, MD22, Thierry Fest23,24*, Fabrice Jardin, MD, PhD25,26*, Steven Le Gouill27, Emmanuel Itti, MD, PhD4*, Philippe Ruminy28* and Thierry Jo Molina, MD PhD29*

1CHU Amiens, Amiens, France
2INSERM U1245, Centre Henri Becquerel, UNIROUEN, University of Normandie, Rouen, France
3Department of Biological Hematology, Rouen University Hospital, Rouen, France
4Nuclear Medicine, Henri Mondor Hospital, Créteil, France
5CHU Pontchaillou, Rennes, France
6INSERM U1236 /hematology laboratory/university hospital of Rennes, Rennes, France
7Pathology Department, Hopital Necker, Paris, France
8Hematology Department, University Hospital F. Mitterrand and Inserm UMR 1231, Dijon, France
9Pathology, Hopital Necker, Paris, France
10Department of Hematology, Hopital Lyon Sud, Pierre Benite, France
11Department of Pathology, Henri Mondor Hospital, APHP, Paris Est-Créteil (UPEC) University Faculty, INSERM UMR-S 955, Créteil, France
12Department of Hematology, Institut Universitaire Cancerologie Toulouse-Oncopole, Toulouse, France
13Département de Pathologie, APHP, Hôpital Cochin, Paris, France
14Centre Hospitalier Universitaire (CHU) Lille, Lille, FRA
15Pathology, Avicenne Hospital, APHP, University Paris XIII, Bobigny, France
16Department of Haematology and INSERM 1245, Henri Becquerel Center, Rouen, France
17Hemato-Oncology, Hôpital Saint-Louis, APHP, University of Paris, Paris, France
18Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy Institute of Cancer, Villejuif, France
19Department of adult hematology, Necker Children's Hospital, Université de Paris, Assistance Publique-Hôpitaux de Paris, Paris, France
20Imagine Institute, INSERM U1163, University of Paris, Paris, France
21Unité d'hémopathies lymphoïdes, Centre Hospitalier Universitaire Henri-Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Est Créteil (UPEC), Creteil, France
22INSERM CIC 1414, Hospital Pontchaillou, Rennes, France
23Inserm U1236 / University hospital of Rennes, Rennes, France
24Department of Biological Hematology, University Hospital of Rennes, Rennes, France
25Inserm U1245, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France
26Department of Hematology, Centre Henri Becquerel, Rouen, France
27Service d’hématologie clinique du CHU de Nantes, INSERM CRCINA Nantes-Angers, NeXT Université de Nantes, Nantes, France
28Centre Henri Becquerel, Rouen, FRA
29Pathology, University of Paris, APHP, Necker-Enfants Malades and Robert Debré Hospital, Paris, France

Introduction

We (Bobée et al, 2020) have recently described a new molecular classifier combining gene expression profiling of 137 genes and machine learning able to diagnose B-cell lymphomas. As this tool can be easily performed from formalin fixed paraffin embedded tissue, we proposed to evaluate how it may be useful after the process of central review by expert pathologists in a LYSA diffuse large B-cell lymphoma (DLBCL) clinical trial, the GAINED trial (Le Gouill et al, 2021).

Methods

The GAINED trial was a multicenter randomized phase 3 trial comparing obinutuzumab to rituximab followed by a PET-driven consolidation in patients with DLBCL. Histological inclusion criteria were : DLBCL, high grade B-cell lymphoma double/triple hit (DH/TH) or high grade NOS. 670 patients were included and 646 underwent a central review of the biopsy by at least two LYSA pathologists. The central review performed immunostaining of full slides by anti-CD20, CD5, CD10, BCL6, MUM1, MYC, BCL2 if sufficient material was available as well as RNA extraction for the molecular classifier, the nanostring Lymph2CX and DNA extraction for targeted NGS. The molecular classifier was able to deliver 8 different signatures: DLBCL GCB, DLBCL ABC, primary mediastinal large B-cell lymphoma (PMBL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma/lymphoplasmacytic lymphoma, CLL/lymphocytic Lymphoma, T-cell rich signature. We compared classification by the histopathology review and by the molecular classifier. Discordant cases were reviewed both by two histopathologists (JB, TJM) and the molecular biologist (PR) and a reconciliation diagnosis was proposed

Results

The central histopathological review alone identified 580 patients with DLBCL or high grade B-cell lymphoma and 40 patients with a lymphoma subtype not eligible for the trial. Among the 470 patients evaluated by the molecular classifier, the reconciliation diagnosis identified 292 DLBCL NOS with 40 associated with a small B-cell component, 13 High grade DH/TH, 9 high grade NOS, 109 PMBL, 16 T-cell rich large B-cell Lymphoma (TCRBCL), 5 DLBCL EBV+ NOS. 29 cases did not fit with inclusion criteria and were mainly FL (3A or 3B), MCL, Nodular lymphocyte Predominant Hodgkin Lymphoma (NLPHL). Among them, the classifier helped to identify one case of CD5- MCL initially diagnosed as DLBCL with CD5- marginal zone lymphoma as well as one case of CD10+ follicular T-cell lymphoma (T-cell rich signature with Rho A mutation) initally diagnosed as FL 3B. Among 235 patients with GCB/ ABC subtyping, the correlation with Nanostring was 97.4% for the molecular classifier and 86,4% for the Hans algorithm. Although the main aim of the pathology review was not dedicated to differentiate DLBCL NOS from PMBL but to validate histological inclusion criteria, after reconciliation 22 DLBCL NOS were reclassified as PMBL. Overall, among the 109 PMBL , PET-CT at baseline in 108 cases evaluable found in 93 cases (86%) a mediastinal mass unique (37) or with satellite lymph nodes(56), in 12 cases (11%) a mediastinal mass with extramediastinal localization and in only 3 cases (3%) the absence of mediastinal mass. This observation fits well with the known anatomical distribution of PMBL and with the rare non mediastinal lymphomas with a PMBL signature. However, the molecular classifier was able to identify 8 signatures and could not recognize other lymphoma subtypes such as High grade B-cell Lymphomas NOS or DH/TH. In addition, 14 follicular lymphomas in our series comprising 5 grade 3A and 6 grade 3B were diagnosed molecularly mainly as DLBCL GC or rarely ABC . Although the TCRBCL were all included in the T-cell signature lymphoma, this signature included high grade B-cell lymphoma, DLBCL NOS, PMBL, DLBCL EBV+, NLPHL.

Conclusion

Overall, the molecular classifier in addition to the expert pathologic review increased accuracy of diagnostic by the pathologists particularly for difficult or rare cases, as well as it strongly helped to identify PMBL and GC/ABC DLCBL. However, the pathologist should be aware of the limit of the tool when dealing with DLBCL differential diagnosis, particularly for the identification of FL3A, FL3B or for cases with a T-cell rich microenvironment such as TCRBCL.

Disclosures: Bobée: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. . Drieux: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties.. Casasnovas: ROCHE: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Ghesquieres: Mundipharma Research Limited: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Takeda: Other: Travel, accommodation, expenses. Oberic: Celgene: Honoraria; Janssen: Honoraria, Other: Support for attending meetings and/or travel; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; AbbVie: Other: Support for attending meetings and/or travel; Incyte: Membership on an entity's Board of Directors or advisory committees. Morschhauser: abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; jannssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Tilly: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance and travel, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Thieblemont: Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Hospira: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation, Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Ribrag: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Haioun: Takeda: Honoraria, Research Funding; Servier: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding. Jardin: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. . Ruminy: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. .

*signifies non-member of ASH