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Relevance of Peripheral Cells in the Pathophysiology of Chronic Myelomonocytic Leukemia (CMML)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03280888
Recruitment Status : Unknown
Verified March 2018 by Centre Hospitalier Universitaire de Nice.
Recruitment status was:  Recruiting
First Posted : September 13, 2017
Last Update Posted : March 19, 2018
Information provided by (Responsible Party):
Centre Hospitalier Universitaire de Nice

Brief Summary:

Chronic Myelomonocytic Leukemia (CMML) is the most frequent of myelodysplastic/myeloproliferative syndromes, as defined by the WHO classification of myeloid malignancies. The median age at diagnosis is around 70 years with a strong male predominance. CMML is a clonal disease of the bone marrow hematopoietic stem cell mainly characterized by persistent monocytosis (>1x109/L) and the presence of immature dysplastic granulocytes in the peripheral blood of CMML patients. Allogeneic stem cell transplantation (ASCT) remains the only curative option in CMML. However, CMML patients are rarely eligible for this kind of therapy, mainly due to their advanced age. The gold standard treatment of CMML thus remains hydroxyurea, which is usually initiated when the disease becomes proliferative, and demethylating agents, which could be efficient in the most aggressive forms of CMML. Nevertheless, the pathogenesis of CMML remains poorly understood and new therapies are urgently needed for patients in treatment failure.

In recent years, a large numbers of gene mutations have been discovered in CMML, none of which are specific of this entity, as they can be encountered with different frequencies in other myeloid neoplasms. These mutated genes encode signaling molecules (NRAS, KRAS, CBL, JAK2, FLT3 and several members of the Notch pathway), epigenetic regulators (TET2, ASXL1, EZH2, IDH1, IDH2,.) and splicing factors (SF3B1, SRSF2, ZRSF2). Mutations in the transcription regulators RUNX1, NPM1 and TP53 have also been reported in CMML. However, the role of these mutations in leukemogenesis is still unclear. CMML is also characterized by defects in monocyte to macrophage differentiation. These defects in monocyte differentiation can be attributed to the presence of immature dysplastic granulocytes that secrete high levels of alpha-defensins HNP1-3 that antagonize the purinergic receptor P2RY6 in CMML patients. These CD14-/CD15+/CD24+ immature granulocytes that belong to the same clone than the leukemic monocytes seem to have immunosuppressive properties ressembling those of the myeloid-derived suppressor cells (MDCS) described in solid tumours. Whether these immature granulocytes contribute to autoimmune manifestations or immunoescape and progression of CMML is a conendrum and remains to be determined.

In this context, the proposed project aims at identifying news insights into the pathophysiology of CMML through a better definition of the phenotype and function of monocytes and immature granulocytes that characterize this pathology.

Condition or disease
Chronic Myelomonocytic Leukemia

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 50 participants
Observational Model: Other
Time Perspective: Prospective
Target Follow-Up Duration: 1 Day
Official Title: Relevance of Peripheral Cells in the Pathophysiology of Chronic Myelomonocytic Leukemia (CMML)
Actual Study Start Date : November 5, 2014
Estimated Primary Completion Date : November 5, 2018
Estimated Study Completion Date : November 5, 2018

Primary Outcome Measures :
  1. Characterization of molecular mechanisms [ Time Frame: at 3 years ]
    Characterization of the molecular mechanisms involved in the lack of differentiation of monocytes originating from patients with CML.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
patients with chronic myelomonocytic leukemia

Inclusion Criteria:

  • Patients newly diagnosed or undergoing treatment in the Clinical Hematology department of the participating establishments

Exclusion Criteria:

  • NA

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 identifier (NCT number): NCT03280888

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Contact: Laurence Legros, PH +33 (0)4 92 03 58 41

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CHU de Nice Recruiting
Nice, France, 06000
Contact: Laurence Legros, PH    +33 (0)04 92 03 58 41   
Sponsors and Collaborators
Centre Hospitalier Universitaire de Nice
Additional Information:

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Responsible Party: Centre Hospitalier Universitaire de Nice Identifier: NCT03280888    
Other Study ID Numbers: 13-PP-11
First Posted: September 13, 2017    Key Record Dates
Last Update Posted: March 19, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Neoplasms by Histologic Type
Leukemia, Myeloid
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases