Genomic and Proteomic Study of Richter Syndrome (CGPSR)

NCT03619512 | Unknown

• 2 other identifiers: 2017-A01978-45PSS2017/CGPSR-BROSÉUS/VS
• Study Type: observational
• Target: 170
• Locations: 1 country
• Sites: 1

Brief Summary

Biological study on Richter Syndrome (RS), an agressive lymphoma that arises from Chronic Lymphocytice Leukemia (CLL). RS presents with the same histological aspect as primitive Diffuse Large B-Cell Lymphoma (DLBCL), but is associated with a poor prognosis, due to chemorefractoriness. This study aims at understanding the biological determinants of chemotherapy resistance in Richter Syndrome.

Conditions

Richter Syndrome

Keywords

Richter Syndrome; Genomics; Proteomics; Chemotherapy resistance

Outcome Measures

Primary Outcomes (3)

• Whole exome sequencing data using next generation sequencing method

  Comparison between the DNA sequences from Richter syndrome samples and DNA sequences from primitive DLBCL samples to identify a set of mutations that are specific to Richter syndrome. For each position, the result is "mutated" or "unmutated".

  3 years

• RNA sequencing data using next generation sequencing method

  Measurment of gene expression for all genes. Comparison of these expression levels between Richter samples, primitive DLBCL samples and normal lymph nodes to identifiy a set of genes which expression levels are different in Richter samples compared primitive DLBCL and normal lymph nodes. Gene expression is a quatitative value. This set of genes forms a specific "transcriptomic signature" of Richter syndrome.

  3 years

• Proteomic analysis using mass spectrometry

  Mass spectrometry allows identification and measurment of the expression level of the 5,000 most expressed proteins in a sample. The investigators want to compare the protein expression levels between Richter samples, primitive DLBCL samples and normal lymph nodes to identifiy a set of proteins that are highly expressed in Richter samples (but not in primitive DLBCL or normal lymph nodes). This set of proteins forms a specific "proteomic signature" of Richter. Protein expression is a quatitative value expressed as an absolute number of copies in a cell.

  3 years

Study Arms (4)

Richter Syndrom at diagnosis

patients diagnosed with Richter Syndrom, for whom a suitable lymph node biopsy at diagnosis is available.

Genetic: Whole exome sequencing.; Genetic: RNA sequencing; Other: Mass spectrometry

Primitive Diffuse Large B-Cell Lymphoma

patients diagnosed with a primitive Large B-Cell Lymphoma, for whom a suitable lymph node biopsy at diagnosis is available.

Genetic: Whole exome sequencing.; Genetic: RNA sequencing; Other: Mass spectrometry

Other secundary Diffuse Large B-Cell Lymphoma

patients diagnosed with a secundary Large B-Cell Lymphoma (different from Richter Syndrom), for whom a suitable lymph node biopsy at diagnosis is available.

Genetic: Whole exome sequencing.; Genetic: RNA sequencing; Other: Mass spectrometry

Control group with no tumor involvment of lymph nodes

patients for whom a diagnostic lymph node biopsy has been performed, which did not conclude to any tumoral lymph node involvment.

Genetic: Whole exome sequencing.; Genetic: RNA sequencing; Other: Mass spectrometry

Interventions

Whole exome sequencing. GENETIC

Retrospective biological exploration of the samples, including tumoral DNA exploration.

Control group with no tumor involvment of lymph nodes; Other secundary Diffuse Large B-Cell Lymphoma; Primitive Diffuse Large B-Cell Lymphoma; Richter Syndrom at diagnosis

RNA sequencing GENETIC

Characterization of tumor transcriptomic profile.

Control group with no tumor involvment of lymph nodes; Other secundary Diffuse Large B-Cell Lymphoma; Primitive Diffuse Large B-Cell Lymphoma; Richter Syndrom at diagnosis

Mass spectrometry OTHER

Characterization of tumor proteomic profiles.

Control group with no tumor involvment of lymph nodes; Other secundary Diffuse Large B-Cell Lymphoma; Primitive Diffuse Large B-Cell Lymphoma; Richter Syndrom at diagnosis

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

* Diagnosis of Diffuse Large B-Cell Lymphoma arising in the context of a Chronic Lymphocytic Leukemia (group 1). * Diagnosis of Diffuse Large B-Cell Lymphoma de novo (group 2). * Diagnosis of Diffuse Large B-Cell Lymphoma arising in a context of small cells lymphoma, excluding CLL (group 3). * Patients who benefited from a diagnostic lymph node biopsy that did not reveal any tumor involvment (primitive or metastatic) (group 4).

You may qualify if:

• Diagnosis of a Diffuse Large B-Cell Lymphoma arising in the context of a Chronic Lymphocytic Leukemia (group 1) or diagnosis of a primitive Diffuse Large B-Cell Lymphoma (group 2), or diagnosis of a Diffuse Large B-Cell Lymphoma arising in a context of small cells lymphoma, excluding CLL (group 3), or benefit from a diagnostic lymph node biopsy that did not reveal any tumor involvment (primitive or metastatic) (group 4).
• Patients must benefit from a lymph node biopsy at diagnosis.
• Patients must be followed by a FILO (French Innovative Leukemia Organization) member
• Histology of Diffuse Large B-Cell Lymphoma or Hodgkin histology.
• Suitable clinical data available.
• Samples must meet the following requirement :RIN (RNA Integrity Number) \> 5 et DIN (DNA Integrity Number) \> 6.5.

Sponsors & Collaborators

• Institut National de la Santé Et de la Recherche Médicale, France: collaborator
• Central Hospital, Nancy, France: lead
• French Innovative Leukemia Organization (FILO): collaborator

Study Sites (1)

CHRU de Nancy

Nancy, 54035, France

RECRUITING

Related Publications (13)

• Rossi D, Spina V, Forconi F, Capello D, Fangazio M, Rasi S, Martini M, Gattei V, Ramponi A, Larocca LM, Bertoni F, Gaidano G. Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis. Int J Cancer. 2012 Jun 15;130(12):3006-10. doi: 10.1002/ijc.26322. Epub 2011 Aug 25.

  PMID: 21796624 BACKGROUND

• Ferreira PG, Jares P, Rico D, Gomez-Lopez G, Martinez-Trillos A, Villamor N, Ecker S, Gonzalez-Perez A, Knowles DG, Monlong J, Johnson R, Quesada V, Djebali S, Papasaikas P, Lopez-Guerra M, Colomer D, Royo C, Cazorla M, Pinyol M, Clot G, Aymerich M, Rozman M, Kulis M, Tamborero D, Gouin A, Blanc J, Gut M, Gut I, Puente XS, Pisano DG, Martin-Subero JI, Lopez-Bigas N, Lopez-Guillermo A, Valencia A, Lopez-Otin C, Campo E, Guigo R. Transcriptome characterization by RNA sequencing identifies a major molecular and clinical subdivision in chronic lymphocytic leukemia. Genome Res. 2014 Feb;24(2):212-26. doi: 10.1101/gr.152132.112. Epub 2013 Nov 21.

  PMID: 24265505 BACKGROUND

• Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A, De Paoli L, Cresta S, Rasi S, Spina V, Franceschetti S, Lunghi M, Vendramin C, Bomben R, Ramponi A, Monga G, Conconi A, Magnani C, Gattei V, Gaidano G. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol. 2008 Jun;142(2):202-15. doi: 10.1111/j.1365-2141.2008.07166.x. Epub 2008 May 19.

  PMID: 18492108 RESULT

• Parikh SA, Rabe KG, Call TG, Zent CS, Habermann TM, Ding W, Leis JF, Schwager SM, Hanson CA, Macon WR, Kay NE, Slager SL, Shanafelt TD. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013 Sep;162(6):774-82. doi: 10.1111/bjh.12458. Epub 2013 Jul 11.

  PMID: 23841899 RESULT

• Rossi D, Spina V, Deambrogi C, Rasi S, Laurenti L, Stamatopoulos K, Arcaini L, Lucioni M, Rocque GB, Xu-Monette ZY, Visco C, Chang J, Chigrinova E, Forconi F, Marasca R, Besson C, Papadaki T, Paulli M, Larocca LM, Pileri SA, Gattei V, Bertoni F, Foa R, Young KH, Gaidano G. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011 Mar 24;117(12):3391-401. doi: 10.1182/blood-2010-09-302174. Epub 2011 Jan 25.

  PMID: 21266718 RESULT

• Fangazio M, De Paoli L, Rossi D, Gaidano G. Predictive markers and driving factors behind Richter syndrome development. Expert Rev Anticancer Ther. 2011 Mar;11(3):433-42. doi: 10.1586/era.10.237.

  PMID: 21417856 RESULT

• Rossi D, Rasi S, Spina V, Fangazio M, Monti S, Greco M, Ciardullo C, Fama R, Cresta S, Bruscaggin A, Laurenti L, Martini M, Musto P, Forconi F, Marasca R, Larocca LM, Foa R, Gaidano G. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. Br J Haematol. 2012 Aug;158(3):426-9. doi: 10.1111/j.1365-2141.2012.09155.x. Epub 2012 May 10. No abstract available.

  PMID: 22571487 RESULT

• Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, Grunn A, Fangazio M, Capello D, Monti S, Cresta S, Gargiulo E, Forconi F, Guarini A, Arcaini L, Paulli M, Laurenti L, Larocca LM, Marasca R, Gattei V, Oscier D, Bertoni F, Mullighan CG, Foa R, Pasqualucci L, Rabadan R, Dalla-Favera R, Gaidano G. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011 Jul 4;208(7):1389-401. doi: 10.1084/jem.20110921. Epub 2011 Jun 13.

  PMID: 21670202 RESULT

• Chigrinova E, Rinaldi A, Kwee I, Rossi D, Rancoita PM, Strefford JC, Oscier D, Stamatopoulos K, Papadaki T, Berger F, Young KH, Murray F, Rosenquist R, Greiner TC, Chan WC, Orlandi EM, Lucioni M, Marasca R, Inghirami G, Ladetto M, Forconi F, Cogliatti S, Votavova H, Swerdlow SH, Stilgenbauer S, Piris MA, Matolcsy A, Spagnolo D, Nikitin E, Zamo A, Gattei V, Bhagat G, Ott G, Zucca E, Gaidano G, Bertoni F. Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome. Blood. 2013 Oct 10;122(15):2673-82. doi: 10.1182/blood-2013-03-489518. Epub 2013 Sep 4.

  PMID: 24004666 RESULT

• Scandurra M, Rossi D, Deambrogi C, Rancoita PM, Chigrinova E, Mian M, Cerri M, Rasi S, Sozzi E, Forconi F, Ponzoni M, Moreno SM, Piris MA, Inghirami G, Zucca E, Gattei V, Rinaldi A, Kwee I, Gaidano G, Bertoni F. Genomic profiling of Richter's syndrome: recurrent lesions and differences with de novo diffuse large B-cell lymphomas. Hematol Oncol. 2010 Jun;28(2):62-7. doi: 10.1002/hon.932.

  PMID: 20014148 RESULT

• Fabbri G, Khiabanian H, Holmes AB, Wang J, Messina M, Mullighan CG, Pasqualucci L, Rabadan R, Dalla-Favera R. Genetic lesions associated with chronic lymphocytic leukemia transformation to Richter syndrome. J Exp Med. 2013 Oct 21;210(11):2273-88. doi: 10.1084/jem.20131448. Epub 2013 Oct 14.

  PMID: 24127483 RESULT

• Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000 Feb 3;403(6769):503-11. doi: 10.1038/35000501.

  PMID: 10676951 RESULT

• Moulin C, Guillemin F, Remen T, Bouclet F, Hergalant S, Quinquenel A, Dartigeas C, Tausch E, Lazarian G, Blanchet O, Lomazzi S, Chapiro E, Schneider C, Nguyen-Khac F, Davi F, Hunault M, Tomowiak C, Roos-Weil D, Siebert R, Thieblemont C, Cymbalista F, Laribi K, Bene MC, Stilgenbauer S, Guieze R, Feugier P, Broseus J. Clinical, biological, and molecular genetic features of Richter syndrome and prognostic significance: A study of the French Innovative Leukemia Organization. Am J Hematol. 2021 Sep 1;96(9):E311-E314. doi: 10.1002/ajh.26239. Epub 2021 Jun 2. No abstract available.

  PMID: 34000073 DERIVED

MeSH Terms

Interventions

Exome Sequencing; Sequence Analysis, RNA; Mass Spectrometry

Intervention Hierarchy (Ancestors)

Whole Genome Sequencing; Sequence Analysis, DNA; Sequence Analysis; Genetic Techniques; Investigative Techniques; Chemistry Techniques, Analytical

Study Officials

• Julien Broseus, MD, PhD

  Central Hospital, Nancy, France

  PRINCIPAL INVESTIGATOR

• Pierre Feugier, MD, PhD

  Central Hospital, Nancy, France

  STUDY DIRECTOR

Central Study Contacts

Julien Broseus, MD, PhD

CONTACT

+ 33 (0)3 83 15 49 14; j.broseus@chru-nancy.fr

Véronique Saunier

CONTACT

+ 33 (0)3 83 15 54 58; v.saunier@chru-nancy.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2018
• First Posted: August 8, 2018
• Study Start: September 6, 2017
• Primary Completion: December 31, 2023
• Study Completion: September 5, 2024
• Last Updated: March 24, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)