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Sterile Inflammation and Molecular Aberrations in MDS (InflamGen)

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ClinicalTrials.gov Identifier: NCT04313231
Recruitment Status : Recruiting
First Posted : March 18, 2020
Last Update Posted : February 24, 2021
Sponsor:
Collaborators:
University Hospital, Bonn
Universitätsklinikum Leipzig
Information provided by (Responsible Party):
Medical University Innsbruck

Brief Summary:
The objective of this study is the description of the possible association between genetic mutation/aberration profiles, inflammatory tonus and clinical phenotype based on PROMs and HRQoL. Apart from gaining a better understanding of the causal correlation between genetics, sterile inflammatory processes and QoL (e.g. fatigue) in MDS, this study is supposed to identify potential novel biomarkers and, ultimately, therapeutic targets.

Condition or disease Intervention/treatment
Myelodysplastic Syndromes Diagnostic Test: Next Generation Sequencing Diagnostic Test: Tumorimmunological examinations - multiplex assays/quantitative polymerase chain reaction Diagnostic Test: flow cytometry Diagnostic Test: Metagenomics of stool samples Diagnostic Test: Clinical/demographic data Other: Elicitation of the HRQoL

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 130 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 12 Months
Official Title: Sterile Inflammation and Molecular Aberrations in Myelodysplastic Syndrome: Determinants of Quality of Life and Vulnerability
Actual Study Start Date : January 22, 2020
Estimated Primary Completion Date : January 2022
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
MDS
  • Female and male patients aged 18 years and older
  • MDS, MDS/MPN diagnosis based on current WHO classification. CCUS and CHIP defined by Valent (Valent, Oncotarget, 2018) and by Stauder (Stauder, Blood, 2018)
Diagnostic Test: Next Generation Sequencing
Sequencing of patient samples will be performed in the facilities of ZIMCL. Following DNA extraction, the sequencing of granulocytes as well as of lymphocytes (control) will be carried out. IN addition to whole exome sequencing, a panel from SOPHIA GENETICS (which is also available for routine diagnostics) will be applied including the following MDS specific genes: ASXL1, BRAF, CBL, CEBPA, CSF3R, DNMT3A, EZH2, FLT3, HRAS, IDH1, IDH2, KRAS, MPL, NPM1, NRAS, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR. Each patient sample will be "bulk sequenced", meaning that relevant mutations are detected down to an allele frequency of 2%.

Diagnostic Test: Tumorimmunological examinations - multiplex assays/quantitative polymerase chain reaction

Inflammasome activation is quantified by analyses of inflammasome-associated cytokine patterns. Multiplex assays for the quantification of the inflammasome-specific cytokines will be done from serum as well as from supernatants the stimulated blood cells. Cytokine quantification is carried out with Luminex FlexMap 3D. Serum cytokine levels will be quantitated in parallel.

Quantification of RNA expression levels of inflammasome-related gene products will be performed by qPCRs from unstimulated and stimulated (=cryotube) blood cells. The necessary RNA extraction will be performed using a RNA extraction kit.


Diagnostic Test: flow cytometry
A detailed evaluation of the individual immune status is being conducted by the analysis of two specialized panels: Panel A provides a broad overview over various immune cell populations, while Panel B identifies T-cell sup-populations.

Diagnostic Test: Metagenomics of stool samples
DNA will be extracted from frozen fecal samples applying a bead-beating method using a GNOME DNA Isolation Kit (MP Biomedicals). DNA quality will be assessed using an Agilent 4200 TapeStation (Agilent Technologies). After final precipitation, DNA samples will be re-suspended in TE buffer and stored at -80 °C for further sequencing analysis. To this end, sequencing libraries will be generated using a Nextera XT DNA Sample Prep Kit (Illumina). Library quality will be confirmed using an Agilent 4200 TapeStation. Whole-genome shotgun sequencing of fecal samples will be carried out on a HiSeq2500 platform (Illumina).

Diagnostic Test: Clinical/demographic data
Demographic and clinical data include: age, age at initial diagnosis, sex, diagnosis, actual comorbidities, medication at inclusion in study, cytogenetic and molecular profiles and standard laboratory parameters (blood count, differential leukocyte count, biochemistry, iron status, inflammatory markers like CRP, albumin, fibrinogen).

Other: Elicitation of the HRQoL
Evaluation of HRQOL, of functional activities and of performance status will be done by the patient and/or the physician using validated scores.

control
age-matched healthy persons
Diagnostic Test: Next Generation Sequencing
Sequencing of patient samples will be performed in the facilities of ZIMCL. Following DNA extraction, the sequencing of granulocytes as well as of lymphocytes (control) will be carried out. IN addition to whole exome sequencing, a panel from SOPHIA GENETICS (which is also available for routine diagnostics) will be applied including the following MDS specific genes: ASXL1, BRAF, CBL, CEBPA, CSF3R, DNMT3A, EZH2, FLT3, HRAS, IDH1, IDH2, KRAS, MPL, NPM1, NRAS, RUNX1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, ZRSR. Each patient sample will be "bulk sequenced", meaning that relevant mutations are detected down to an allele frequency of 2%.

Diagnostic Test: Tumorimmunological examinations - multiplex assays/quantitative polymerase chain reaction

Inflammasome activation is quantified by analyses of inflammasome-associated cytokine patterns. Multiplex assays for the quantification of the inflammasome-specific cytokines will be done from serum as well as from supernatants the stimulated blood cells. Cytokine quantification is carried out with Luminex FlexMap 3D. Serum cytokine levels will be quantitated in parallel.

Quantification of RNA expression levels of inflammasome-related gene products will be performed by qPCRs from unstimulated and stimulated (=cryotube) blood cells. The necessary RNA extraction will be performed using a RNA extraction kit.


Diagnostic Test: flow cytometry
A detailed evaluation of the individual immune status is being conducted by the analysis of two specialized panels: Panel A provides a broad overview over various immune cell populations, while Panel B identifies T-cell sup-populations.

Diagnostic Test: Metagenomics of stool samples
DNA will be extracted from frozen fecal samples applying a bead-beating method using a GNOME DNA Isolation Kit (MP Biomedicals). DNA quality will be assessed using an Agilent 4200 TapeStation (Agilent Technologies). After final precipitation, DNA samples will be re-suspended in TE buffer and stored at -80 °C for further sequencing analysis. To this end, sequencing libraries will be generated using a Nextera XT DNA Sample Prep Kit (Illumina). Library quality will be confirmed using an Agilent 4200 TapeStation. Whole-genome shotgun sequencing of fecal samples will be carried out on a HiSeq2500 platform (Illumina).

Diagnostic Test: Clinical/demographic data
Demographic and clinical data include: age, age at initial diagnosis, sex, diagnosis, actual comorbidities, medication at inclusion in study, cytogenetic and molecular profiles and standard laboratory parameters (blood count, differential leukocyte count, biochemistry, iron status, inflammatory markers like CRP, albumin, fibrinogen).

Other: Elicitation of the HRQoL
Evaluation of HRQOL, of functional activities and of performance status will be done by the patient and/or the physician using validated scores.




Primary Outcome Measures :
  1. Definition of correlation between molecular aberrations and the sterile inflammatory tonus [ Time Frame: baseline ]
  2. Definition how genetic aberrations and associated sterile inflammation impacts on health-related quality of life (HRQoL, e.g. fatigue) and functional activities in patients with MDS, MDS/MPN, or CHIP/CCUS [ Time Frame: baseline ]

Secondary Outcome Measures :
  1. Definition of correlation of sterile inflammatory tonus with clinical variables (e.g. progression to secondary acute myeloid leukemia (sAML), complications (e.g. infections), and survival) [ Time Frame: baseline ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Probability Sample
Study Population
MDS, MDS/MPN diagnosis based on current WHO classification. CCUS and CHIP defined by Valent (Valent, Oncotarget, 2018) and by Stauder (Stauder, Blood, 2018)
Criteria

Inclusion Criteria:

  • Female and male patients > 18 years
  • MDS, MDS/MPN diagnosis based on current WHO classification. CCUS and CHIP defined by Valent (Valent, Oncotarget, 2018) and by Stauder (Stauder, Blood, 2018)
  • Signed and dated declaration of consent by the patient according to ICH-GCP Guidelines

Exclusion Criteria:

  • Any other illness, whether physical or mental, or any laboratory abnormalities which prevent a declaration of consent by the patient
  • Patients with an acute and/or uncontrolled infection, including patients that are afebrile under treatment with antibiotic/antifungal/antiviral prophylactic medication
  • Any pre-existing autoimmune disease requiring a systemic immunosuppression
  • Steroid therapy (>10mg Prednison/day or equivalent), regardless of its necessity up to 4 weeks before inclusion in the study
  • Anamnestic and/or current therapy with hypomethylating agents (HMA) or immunomodulatory imide drugs (IMiDs)
  • Status post allogenic stem cell transplantation
  • Previous or ongoing chemotherapy
  • Pregnancy or breastfeeding period

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04313231


Contacts
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Contact: Domink Wolf, Univ.Prof. 0043512504 ext 24003 dominik.wolf@i-med.ac.at
Contact: Verena Petzer, MD 0043512504 ext 82979

Locations
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Austria
Medical University of Innsbruck Recruiting
Innsbruck, Tyrol, Austria, 6020
Contact: Dominik Wolf, Univ.Prof.    0043512504 ext 24003    dominik.wolf@i-med.ac.at   
Contact: Verena Petzer, MD    +43-512-504 ext 82979    verena.petzer@i-med.ac.at   
Sponsors and Collaborators
Medical University Innsbruck
University Hospital, Bonn
Universitätsklinikum Leipzig
Investigators
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Principal Investigator: Domink Wolf, Univ.Prof. Medical University Innsbruck
Publications:
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Responsible Party: Medical University Innsbruck
ClinicalTrials.gov Identifier: NCT04313231    
Other Study ID Numbers: 20200129-2183
First Posted: March 18, 2020    Key Record Dates
Last Update Posted: February 24, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Presentation at conferences and publication in a peer-reviewed journal

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Medical University Innsbruck:
anemia
health-related quality of life
inflammation
Additional relevant MeSH terms:
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Preleukemia
Myelodysplastic Syndromes
Syndrome
Inflammation
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms