Mutational Analysis as a Prognostic and Predictive Marker of Cardiovascular (CVD) Disease in Patients With Myelodysplasia

NCT04110925 | Unknown

• 1 other identifier: MDS CVD
• Study Type: interventional
• Target: 400
• Locations: 1 country
• Sites: 1

Brief Summary

This study evaluates the relationship between myelodysplastic syndromes (MDS) and cardiovascular disease. MDS patients will be evaluated for the presence of mutations and whether they are associated with an increased risk of heart disease (CVD) and inflammation compared to healthy adults. Patients without symptoms of CVD will receive CT scans to assess for hidden disease and if that is related to their mutations.

Conditions

MDS; Cardiovascular Diseases; Inflammation

Keywords

CT imaging; next generation sequencing; myelodysplastic syndrome

Outcome Measures

Primary Outcomes (3)

• Measure the allelic frequency and type of myeloid cancer-associated mutations in MDS patients diagnostic bone marrow aspirates or slides

  Screen for Presence of myeloid-cancer associated mutations and their variant allele frequencies (VAF) at diagnosis of MDS as measured through next generation sequencing of 40 myeloid genes.

  2 years

• Screen for occult and potentially clinically significant CAD in MDS patients by means of coronary CT

  Patients at Sunnybrook hospital with no pre-existing history of CAD who receive CT of the heart and found to harbour occult CAD by means of coronary calcium scoring: 1. zero calcium (No CAD) 2. 1-400: mild-moderate calcification 3. \>400: severe calcification

  2 years

• Identify any correlation between selected myeloid mutations and/or their VAF with the presence of pre-existing incident or occult CAD

  Comparing the presence of myeloid-cancer associated mutations and their variant allele frequencies (VAF) at diagnosis of MDS as measured through next generation sequencing of 40 myeloid genes between patients with pre-existing/occult CAD and those without.

  2 years

Secondary Outcomes (2)

• Track how often newly discovered CAD from coronary CT leads to further intervention or changes in monitoring

  2 years

• Screen for serum inflammatory cytokines in the blood of patients with incident or occult CAD

  2 years

Study Arms (1)

MDS patients

OTHER

All Canadian MDS patients on the MDS-database to be included.

Genetic: Genetic Mutations; Other: Inflammatory and lipid markers; Other: Computed Tomography (CT) of the heart

Interventions

Genetic Mutations GENETIC

DNA sequencing for mutations to be obtained by bloodwork within 6 months of diagnosis, or by accessing diagnostic bone marrow aspirate slides.

MDS patients

Inflammatory and lipid markers OTHER

Bloodwork to be done for lipid profile, c-reactive protein (CRP), and multiplex chemokine/cytokine analysis.

MDS patients

Computed Tomography (CT) of the heart OTHER

Sunnybrook Patients with no history of cardiovascular disease \[ex: past/present coronary artery disease (CAD), peripheral vascular disease (PVD), angina, myocardial infarction (MI), stroke, transient ischemic attack (TIA), or stents\], not pregnant, and able to undergo CT will receive a CT of the heart to look for and quantify any occult coronary artery disease.

MDS patients

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of: myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), Chronic myelomonocytic leukemia leukemia (CMML), or low-blast acute myeloid leukemia (AML, blasts 20-29%) less than 24 months ago
• Alive and registered in the MDS-Canada (MDS-CAN) database
• Known comorbidity history and known history of cardiovascular disease
• Able to provide peripheral blood sample for cytokine analysis
• Able top provide samples for next generation sequencing (NGS) - if diagnosis 0-6 months ago: peripheral blood; if diagnosis 6-24 months ago: diagnostic bone marrow aspirate slides or peripheral blood

You may not qualify if:

• MDS/MPN patients other than CMML due to higher prevalence of Janus Kinase 2 (JAK2) mutation (a known risk factor for CVD)
• Disease progression without available diagnostic bone marrow slides for NGS

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre: lead
• Ontario Molecular Pathology Research Network: collaborator
• Queen's University: collaborator

Study Sites (1)

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Related Publications (6)

• Stahl M, Zeidan AM. Management of lower-risk myelodysplastic syndromes without del5q: current approach and future trends. Expert Rev Hematol. 2017 Apr;10(4):345-364. doi: 10.1080/17474086.2017.1297704. Epub 2017 Mar 9.

  PMID: 28277851 BACKGROUND

• Brunner AM, Blonquist TM, Hobbs GS, Amrein PC, Neuberg DS, Steensma DP, Abel GA, Fathi AT. Risk and timing of cardiovascular death among patients with myelodysplastic syndromes. Blood Adv. 2017 Oct 18;1(23):2032-2040. doi: 10.1182/bloodadvances.2017010165. eCollection 2017 Oct 24.

  PMID: 29296849 BACKGROUND

• Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P, Yoon CJ, Ellis P, Wedge DC, Pellagatti A, Shlien A, Groves MJ, Forbes SA, Raine K, Hinton J, Mudie LJ, McLaren S, Hardy C, Latimer C, Della Porta MG, O'Meara S, Ambaglio I, Galli A, Butler AP, Walldin G, Teague JW, Quek L, Sternberg A, Gambacorti-Passerini C, Cross NC, Green AR, Boultwood J, Vyas P, Hellstrom-Lindberg E, Bowen D, Cazzola M, Stratton MR, Campbell PJ; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013 Nov 21;122(22):3616-27; quiz 3699. doi: 10.1182/blood-2013-08-518886. Epub 2013 Sep 12.

  PMID: 24030381 BACKGROUND

• Elbaek MV, Sorensen AL, Hasselbalch HC. Cardiovascular disease in chronic myelomonocytic leukemia: do monocytosis and chronic inflammation predispose to accelerated atherosclerosis? Ann Hematol. 2019 Jan;98(1):101-109. doi: 10.1007/s00277-018-3489-0. Epub 2018 Sep 4.

  PMID: 30182347 BACKGROUND

• Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, McConkey M, Gupta N, Gabriel S, Ardissino D, Baber U, Mehran R, Fuster V, Danesh J, Frossard P, Saleheen D, Melander O, Sukhova GK, Neuberg D, Libby P, Kathiresan S, Ebert BL. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017 Jul 13;377(2):111-121. doi: 10.1056/NEJMoa1701719. Epub 2017 Jun 21.

  PMID: 28636844 BACKGROUND

• Okwuosa TM, Greenland P, Ning H, Liu K, Bild DE, Burke GL, Eng J, Lloyd-Jones DM. Distribution of coronary artery calcium scores by Framingham 10-year risk strata in the MESA (Multi-Ethnic Study of Atherosclerosis) potential implications for coronary risk assessment. J Am Coll Cardiol. 2011 May 3;57(18):1838-45. doi: 10.1016/j.jacc.2010.11.053.

  PMID: 21527159 BACKGROUND

MeSH Terms

Conditions

Cardiovascular Diseases; Inflammation; Myelodysplastic Syndromes

Interventions

Mutation

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Genetic Variation; Genetic Phenomena

Study Officials

• Rashmi S Goswani, MD

  Sunnybrook Health Sciences Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rena Buckstein, MD

CONTACT

416-480-5847; rena.buckstein@sunnybrook.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: SCREENING
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 23, 2019
• First Posted: October 1, 2019
• Study Start: September 1, 2019
• Primary Completion: September 1, 2021
• Study Completion: September 1, 2021
• Last Updated: October 1, 2019

Record last verified: 2019-09

Locations

CA (1)