Genomic and Proteomic Study of Richter Syndrome (CGPSR) (CGPSR)

• ClinicalTrials.gov Identifier: NCT03619512
• Recruitment Status: Recruiting
• First Posted: August 8, 2018
• Last Update Posted: March 24, 2023
• Sponsor: Central Hospital, Nancy, France
• Collaborators: French Innovative Leukemia Organization (FILO); Institut National de la Santé Et de la Recherche Médicale, France
• Information provided by (Responsible Party): Central Hospital, Nancy, France

Tracking Information

• First Submitted Date: July 19, 2018
• First Posted Date: August 8, 2018
• Last Update Posted Date: March 24, 2023
• Actual Study Start Date: September 6, 2017
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 2, 2018)

• Whole exome sequencing data using next generation sequencing method [ Time Frame: 3 years ]
  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".
• RNA sequencing data using next generation sequencing method [ Time Frame: 3 years ]
  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.
• Proteomic analysis using mass spectrometry [ Time Frame: 3 years ]
  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.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Genomic and Proteomic Study of Richter Syndrome (CGPSR)
• Official Title: Genomic and Proteomic Study of Richter Syndrome

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.

Detailed Description

With the help of the French National Research Group on CLL (FILO / French Innovative Leukemia Organization), the investigators are currently gathering fresh frozen cell pellets at CLL stage, and lymph node biopsies at Richter stage. The investigators also gathered lymph node biopsies from DLBCL, as a reference group.

The investigators will perform genomic and proteomic comparative studies between CLL and Richter, as well as between Richter and primitive DLBCL, to understand the biological determinants of clonal evolution and chemorefractoriness of Richter Syndrom.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Retrospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• 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).

• Condition: Richter Syndrome

Intervention

• Genetic: Whole exome sequencing.
  Retrospective biological exploration of the samples, including tumoral DNA exploration.
• Genetic: RNA sequencing
  Characterization of tumor transcriptomic profile.
• Other: Mass spectrometry
  Characterization of tumor proteomic profiles.

Study Groups/Cohorts

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

  • 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.
  Interventions:

  • 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.
  Interventions:

  • 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.
  Interventions:

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

Publications *

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 2, 2018): 170
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 5, 2024
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• Samples that do not meet the inclusion criteria (insufficient clinical data, analysis impossible due to insufficient sample quality).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Julien Broseus, MD, PhD; + 33 (0)3 83 15 49 14; j.broseus@chru-nancy.fr

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

• Listed Location Countries: France

Administrative Information

• NCT Number: NCT03619512
• Other Study ID Numbers: 2017-A01978-45; PSS2017/CGPSR-BROSÉUS/VS ( Other Identifier: CHRU Nancy )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Central Hospital, Nancy, France
• Original Responsible Party: Same as current
• Current Study Sponsor: Central Hospital, Nancy, France
• Original Study Sponsor: Same as current

Collaborators

• French Innovative Leukemia Organization (FILO)
• Institut National de la Santé Et de la Recherche Médicale, France

Investigators

• Principal Investigator: Julien Broseus, MD, PhD; Central Hospital, Nancy, France
• Study Director: Pierre Feugier, MD, PhD; Central Hospital, Nancy, France

• PRS Account: Central Hospital, Nancy, France
• Verification Date: March 2023