Sterile Inflammation and Molecular Aberrations in MDS

NCT ID: NCT04313231

Last Updated: 2022-04-07

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Total Enrollment

130 participants

Study Classification

OBSERVATIONAL

Study Start Date

2020-01-22

Study Completion Date

2023-01-31

Brief Summary

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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.

Detailed Description

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Conditions

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Myelodysplastic Syndromes

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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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)

Next Generation Sequencing

Intervention Type DIAGNOSTIC_TEST

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%.

Tumorimmunological examinations - multiplex assays/quantitative polymerase chain reaction

Intervention Type DIAGNOSTIC_TEST

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.

flow cytometry

Intervention Type DIAGNOSTIC_TEST

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.

Metagenomics of stool samples

Intervention Type DIAGNOSTIC_TEST

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).

Clinical/demographic data

Intervention Type DIAGNOSTIC_TEST

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).

Elicitation of the HRQoL

Intervention Type OTHER

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

Next Generation Sequencing

Intervention Type DIAGNOSTIC_TEST

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%.

Tumorimmunological examinations - multiplex assays/quantitative polymerase chain reaction

Intervention Type DIAGNOSTIC_TEST

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.

flow cytometry

Intervention Type DIAGNOSTIC_TEST

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.

Metagenomics of stool samples

Intervention Type DIAGNOSTIC_TEST

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).

Clinical/demographic data

Intervention Type DIAGNOSTIC_TEST

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).

Elicitation of the HRQoL

Intervention Type OTHER

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

Interventions

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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%.

Intervention Type 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.

Intervention Type 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.

Intervention Type 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).

Intervention Type 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).

Intervention Type DIAGNOSTIC_TEST

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.

Intervention Type OTHER

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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University Hospital, Bonn

OTHER

Sponsor Role collaborator

Universitätsklinikum Leipzig

OTHER

Sponsor Role collaborator

Medical University Innsbruck

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Domink Wolf, Univ.Prof.

Role: PRINCIPAL_INVESTIGATOR

Medical University Innsbruck

Locations

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Medical University of Innsbruck

Innsbruck, Tyrol, Austria

Site Status RECRUITING

Countries

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Austria

Central Contacts

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Domink Wolf, Univ.Prof.

Role: CONTACT

0043512504 ext. 24003

Verena Petzer, MD

Role: CONTACT

0043512504 ext. 82979

Facility Contacts

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Dominik Wolf, Univ.Prof.

Role: primary

0043512504 ext. 24003

Verena Petzer, MD

Role: backup

+43-512-504 ext. 82979

References

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Valent P, Stauder R, Theurl I, Geissler K, Sliwa T, Sperr WR, Bettelheim P, Sill H, Pfeilstocker M. Diagnosis, management and response criteria of iron overload in myelodysplastic syndromes (MDS): updated recommendations of the Austrian MDS platform. Expert Rev Hematol. 2018 Feb;11(2):109-116. doi: 10.1080/17474086.2018.1420473. Epub 2018 Jan 2.

Reference Type BACKGROUND
PMID: 29292655 (View on PubMed)

Stauder R, Valent P, Theurl I. Anemia at older age: etiologies, clinical implications, and management. Blood. 2018 Feb 1;131(5):505-514. doi: 10.1182/blood-2017-07-746446. Epub 2017 Nov 15.

Reference Type BACKGROUND
PMID: 29141943 (View on PubMed)

Loacker L, Petzer V, Bachmann S, Griesmacher A, Wolf D, Stauder R. High concordance of clone detection between peripheral blood and bone marrow by targeted next-generation sequencing-A pilot study in patients with MDS. Br J Haematol. 2023 Aug;202(3):e16-e19. doi: 10.1111/bjh.18889. Epub 2023 Jun 1. No abstract available.

Reference Type DERIVED
PMID: 37263977 (View on PubMed)

Other Identifiers

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20200129-2183

Identifier Type: -

Identifier Source: org_study_id

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