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Flow Cytometric Analysis of Peripheral Blood Neutrophil Myeloperoxidase Expression and Myelodysplastic Syndromes (MPO-MDS-PILOT)

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ClinicalTrials.gov Identifier: NCT03363399
Recruitment Status : Completed
First Posted : December 6, 2017
Last Update Posted : September 25, 2018
Sponsor:
Information provided by (Responsible Party):
University Hospital, Grenoble

Brief Summary:

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal bone marrow neoplasms that predominate in the elderly, with a median age at diagnosis of 70 years. MDS are characterized by peripheral blood cytopenia and morphologic dysplasia for one or more hematopoietic cell lineage, reflecting ineffective hematopoiesis.

The diagnostic work-up of MDS includes a bone marrow aspirate and biopsy, which is an invasive procedure, for cytomorphologic and cytogenetic evaluations. Because the prevalence of disease is lower than 20% in subjects referred for suspected MDS, many patients are exposed to unnecessary bone marrow aspiration-related discomfort and harms.

An objective assay is highly desirable for accurately ruling out MDS based on peripheral blood samples, which may obviate the need for invasive bone marrow aspiration and biopsy in patients with negative results.

Few studies have investigated the value of peripheral blood flow cytometric analysis for the diagnosis of MDS and/or chronic myelomonocytic leukemia (CMML). Although promising, these studies lacked replication of their results, used a case-control design, which was prone to spectrum bias, or yielded imprecise diagnostic accuracy estimates due to relatively limited sample sizes.

Anecdotal evidence supports the potential of flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression for the diagnosis of MDS and CMML. Myeloperoxidase is an enzyme synthetized during myeloid differentiation that constitutes the major component of neutrophil azurophilic granules. Myeloperoxidase expression may reflect neutrophil hypogranulation, which is a classical although subjective dysplastic feature of MDS. Flow cytometric analysis of myeloperoxidase expression in bone marrow neutrophil granulocytes has been used for discriminating low versus high grade MDS. Yet a study reporting on the accuracy of flow cytometric analysis of peripheral blood neutrophil myeloperoxidase expression for the diagnosis of MDS is still lacking, to our knowledge.

In this study, the investigators hypothesize that flow cytometric analysis of neutrophil myeloperoxidase expression in peripheral blood may accurately rule out MDS and obviate the need for bone marrow aspiration and biopsy, with sensitivity approaching 100%, in routine practice.

In this observational diagnostic accuracy study, burden will be null for recruited patients. No specific intervention is assigned to participants. All diagnostic testing, procedures, and medication ordering are performed at the discretion of attending physicians. Flow cytometry analysis of peripheral blood neutrophil myeloperoxidase expression will not require additional blood sample. A test result will have no impact on patient management. No follow-up visits are planned in this cross-sectional study.


Condition or disease Intervention/treatment
Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia Diagnostic Test: Flow cytometry analysis of neutrophil myeloperoxidase expression

  Show Detailed Description

Study Type : Observational
Actual Enrollment : 60 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Flow Cytometric Analysis of Peripheral Blood Neutrophil Myeloperoxidase Expression for Ruling Out Myelodysplastic Syndromes: A Pilot Diagnostic Accuracy Study
Actual Study Start Date : February 22, 2018
Actual Primary Completion Date : September 6, 2018
Actual Study Completion Date : September 6, 2018



Intervention Details:
  • Diagnostic Test: Flow cytometry analysis of neutrophil myeloperoxidase expression

    Flow cytometry analysis of neutrophil myeloperoxidase expression in peripheral blood samples will be performed within 24 h of MDS diagnostic evaluation and blinded to the reference standard. Peripheral blood samples will be collected in 5 ml (EDTA) anticoagulant plastic tubes and processed within 24 h maximum of collection. The samples will be stored at 4°C overnight.

    Blood samples containing at least 105 neutrophils will be incubated with a panel of antibodies conjugated to fluorochromes, according to the manufacturers' recommendations.

    At least 10,000 cell events will be acquired on a 3-laser, 8-color flow cytometer and analyzed using Becton Dickinson (BD) Fluorescence-activated cell sorting (FACS) Diva Software version 6. Each marker will be expressed as median, geometric and arithmetic mean, regular and robust coefficient of variation.



Primary Outcome Measures :
  1. Area under the Receiver Operating Characteristic (ROC) curve of neutrophil myeloperoxidase expression in peripheral blood [ Time Frame: Baseline ]
    The primary outcome is the discrimination of the index test (i.e., flow cytometry analysis of neutrophil myeloperoxidase expression in peripheral blood) for the diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMLL) quantified by the area under the ROC curve point estimate along with its 95% confidence interval.


Secondary Outcome Measures :
  1. Sensitivity point estimates (along with 95% confidence interval) of neutrophil myeloperoxidase expression in peripheral blood for the diagnosis of MDS or CMML [ Time Frame: Baseline ]
  2. Specificity point estimates (along with 95% confidence interval) of neutrophil myeloperoxidase expression in peripheral blood for the diagnosis of MDS or CMML [ Time Frame: Baseline ]
  3. Negative predictive value point estimates (along with 95% confidence interval) of neutrophil myeloperoxidase expression in peripheral blood for the diagnosis of MDS or CMML [ Time Frame: Baseline ]
  4. Positive predictive value point estimates (along with 95% confidence interval) of neutrophil myeloperoxidase expression in peripheral blood for the diagnosis of MDS or CMML [ Time Frame: Baseline ]
  5. Prevalence point estimate (along with 95% confidence interval) for alternate diagnosis established by bone marrow cytomorphology. [ Time Frame: Baseline ]


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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Eligible participants are consecutive unselected adults of 50 years of age or more and who are referred for suspected MDS or CMML. Suspicion of MDS or CMML is based on medical history and peripheral blood cytopenia.

To be eligible, patients will be required to meet all three inclusion criteria and none of the exclusion criteria. Yet, patients with milder levels of cytopenia might by eligible based on medical history.

Criteria

Inclusion Criteria:

  • Age ≥50 years;
  • Clinical suspicion of myelodysplastic syndromes (MDS) and / or chronic myelomonocytic leukemia (CMML);
  • Peripheral blood cytopenia defined by hemoglobin concentration <10 g/dL, platelet count <100 x109/L, and/or absolute neutrophil count <1.8 x109/L.

Exclusion Criteria:

  • History of or active documented MDS or CMML;
  • Admission to the intensive care unit;
  • Suspicion of hematological disease other than MDS requiring bone marrow aspirate and/or biopsy (i.e., acute leukemia,…);
  • Absolute neutrophil count <0.5 x109/L;
  • Not affiliated with a social security system;
  • Homelessness;
  • Incarcerated;
  • Inability to understand research information and/or to provide non-opposition, because of language restriction, dementia, or altered mental status;
  • Refusal to participate;
  • Previous enrollment in the study.

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): NCT03363399


Locations
France
Centre Hospitalier Universitaire Estaing
Clermont-Ferrand, France, 63003
Centre Hospitalier Universitaire Grenoble Alpes
Grenoble, France, 38043
Sponsors and Collaborators
University Hospital, Grenoble
Investigators
Study Chair: Tatiana Raskovalova, MD Centre Hospitalier Universitaire Grenoble Alpes, France
Principal Investigator: Richard Veyrat-Masson, MD Centre Hospitalier Universitaire Clermont-Ferrand, France
Principal Investigator: Sophie Park, MD Centre Hospitalier Universitaire Grenoble Alpes, France
Principal Investigator: Marc Berger, MD Centre Hospitalier Universitaire Clermont-Ferrand, France
Principal Investigator: Jean-Yves Cesbron, MD Centre Hospitalier Universitaire Grenoble Alpes, France
Principal Investigator: Marie-Christine Jacob, MD Centre Hospitalier Universitaire Grenoble Alpes, France

Responsible Party: University Hospital, Grenoble
ClinicalTrials.gov Identifier: NCT03363399     History of Changes
Other Study ID Numbers: 38RC17.249
2017-A02361-52 ( Other Identifier: ID RCB )
First Posted: December 6, 2017    Key Record Dates
Last Update Posted: September 25, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: The principal investigators will respond directly to data requests by providing a de-identified data set. Individual participant data that underlie the results reported in the published articles (i.e., main text, tables, figures, and appendices) will be supplied.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame:

Beginning 12 months after publication of the main findings of the final dataset.

No end date.

Access Criteria:

De-identified data will be available for individual participant data meta-analysis purpose.

Researchers should submit a methodologically sound proposal that complies with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement. Proposals should be directed to TRaskovalova@chu-grenoble.fr. Data requestors will need to sign a data access agreement.


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

Keywords provided by University Hospital, Grenoble:
Diagnostic accuracy study
Flow cytometry analysis
Myeloperoxidase
Peripheral blood sample

Additional relevant MeSH terms:
Syndrome
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Disease
Pathologic Processes
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Myelodysplastic-Myeloproliferative Diseases