Myelodysplastic Syndromes Clinical Trial
Official title:
Flow Cytometric Analysis of Peripheral Blood Neutrophil Myeloperoxidase Expression for Ruling Out Myelodysplastic Syndromes: A Pilot Diagnostic Accuracy Study
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.
The primary objective of MPO-MDS-pilot study is to estimate the accuracy of flow cytometric
analysis of neutrophil myeloperoxidase expression in peripheral blood for the diagnosis of
myelodysplastic syndromes (MDS) and/or chronic myelomonocytic leukemia (CMML).
The secondary objectives are:
1. to provide accuracy estimates for prespecified thresholds of neutrophil myeloperoxidase
expression in peripheral blood in ruling out MDS and/or CMML.
2. to estimate the prevalence of alternate diagnosis established by bone marrow
cytomorphology.
The MPO-MDS-pilot project is a multicenter, phase II, cross-sectional, diagnostic accuracy
study of consecutive unselected patients referred for suspected MDS or CMML.
Screening: All consecutive patients referred to the immuno-hematology lab at the study sites
for suspicion of MDS will be screened for eligibility. A lab physician will review inclusion
and exclusion criteria, using computerized medical and laboratory records.
Recruitment: Participants will be included in the study once all the screening activities
have been conducted and only if the patient meets all inclusion and none exclusion criteria.
The consent for flow cytometry analysis of peripheral blood sample and data collection
through chart review will be sought under a regime of "non-opposition" (opt-out): after
appropriate written information is delivered, cross-sectional data will be collected except
in case of opposition from the patient. All patients included in the study will be assigned a
unique patient identification number. This number will be used to identify the patient
throughout the study.
Index test: Flow cytometry analysis of neutrophil myeloperoxidase expression in peripheral
blood will be performed within 24 h of MDS diagnostic evaluation and blinded to the reference
standard.
Reference standard: The diagnosis of MDS will be established according to the World Health
Organization (WHO) classification, based on clinical data, peripheral blood cytopenia,
cytomorphology of peripheral blood and bone marrow aspirate, and cytogenetic analysis. The
criteria for MDS diagnosis are 1) the presence of ≥10% dysplastic cells in any hematopoietic
lineage, 2) the exclusion of acute myeloid leukemia (defined by the presence of ≥20%
peripheral blood or bone marrow blasts), and 3) the exclusion of reactive etiologies of
dysplasia. Cytopenia is defined by hemoglobin concentration <10 g/dL, platelet count
<100x109/L, and/or absolute neutrophil count <1.8 x109/L. Yet a diagnosis of MDS could be
made with milder levels of cytopenia. Idiopathic cytopenia of uncertain significance (ICUS)
is defined by unexplained mild persistent cytopenia for at least 6 months and the failure to
establish the diagnosis to MDS according to published guidelines. Consistent with WHO
classification, MDS subcategorization will rely on the degree of dysplasia (unilineage versus
multilineage), blast percentages, presence of ring sideroblasts, and cytogenetic analysis
(del(5q)). The criteria for CMML diagnosis are 1) the presence of persistent peripheral blood
monocytosis ≥1 x109/L, and 2) monocyte accounting for more than 10% of the white blood cell
differential count. Evaluation of bone marrow cytomorphology will be performed prospectively
by experienced hematopathologists who are blinded to the index test results.
Patients with confirmed suspicion of MDS: Participants for whom the diagnosis of MDS (or
CMML) is confirmed by the reference standard will be categorized as patients with confirmed
suspicion of MDS.
Patients with unconfirmed suspicion of MDS: Participants for whom the diagnosis of MDS (or
CMML) is ruled out by the reference standard will be categorized as patients with unconfirmed
suspicion of MDS. This latter subgroup will include patients with ICUS, as defined in
accordance with published guidelines
Follow-up: No follow-up visit is planned in this cross-sectional diagnostic accuracy study.
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