Sterile Inflammation and Molecular Aberrations in MDS

Myelodysplastic Syndromes Clinical Trial

— InflamGen  

Official title:

Sterile Inflammation and Molecular Aberrations in Myelodysplastic Syndrome: Determinants of Quality of Life and Vulnerability

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04313231
• Other study ID #: 20200129-2183
• Status: Recruiting
• Start date: January 22, 2020
• Est. completion date: January 2023

Study information

• Verified date: January 2022
• Source: Medical University Innsbruck
• Contact: Domink Wolf, Univ.Prof.
• Phone: 0043512504
• Email: dominik.wolf[@]i-med.ac.at
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: January 2023
• Est. primary completion date: January 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Inflammation
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

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%.
• 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.
• 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.
• 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).
• 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.

Locations

Country	Name	City	State
Austria	Medical University of Innsbruck	Innsbruck	Tyrol

Sponsors (3)

Lead Sponsor	Collaborator
Medical University Innsbruck	Universitätsklinikum Leipzig, University Hospital, Bonn

Country where clinical trial is conducted

Austria, 

References & Publications (2)

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. Review. — View Citation

Valent P, Stauder R, Theurl I, Geissler K, Sliwa T, Sperr WR, Bettelheim P, Sill H, Pfeilstöcker 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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Definition of correlation between molecular aberrations and the sterile inflammatory tonus		baseline
Primary	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		baseline
Secondary	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)		baseline