<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03280888</url>
  </required_header>
  <id_info>
    <org_study_id>13-PP-11</org_study_id>
    <nct_id>NCT03280888</nct_id>
  </id_info>
  <brief_title>Relevance of Peripheral Cells in the Pathophysiology of Chronic Myelomonocytic Leukemia (CMML)</brief_title>
  <official_title>Relevance of Peripheral Cells in the Pathophysiology of Chronic Myelomonocytic Leukemia (CMML)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Hospitalier Universitaire de Nice</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre Hospitalier Universitaire de Nice</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Chronic Myelomonocytic Leukemia (CMML) is the most frequent of&#xD;
      myelodysplastic/myeloproliferative syndromes, as defined by the WHO classification of myeloid&#xD;
      malignancies. The median age at diagnosis is around 70 years with a strong male predominance.&#xD;
      CMML is a clonal disease of the bone marrow hematopoietic stem cell mainly characterized by&#xD;
      persistent monocytosis (&gt;1x109/L) and the presence of immature dysplastic granulocytes in the&#xD;
      peripheral blood of CMML patients. Allogeneic stem cell transplantation (ASCT) remains the&#xD;
      only curative option in CMML. However, CMML patients are rarely eligible for this kind of&#xD;
      therapy, mainly due to their advanced age. The gold standard treatment of CMML thus remains&#xD;
      hydroxyurea, which is usually initiated when the disease becomes proliferative, and&#xD;
      demethylating agents, which could be efficient in the most aggressive forms of CMML.&#xD;
      Nevertheless, the pathogenesis of CMML remains poorly understood and new therapies are&#xD;
      urgently needed for patients in treatment failure.&#xD;
&#xD;
      In recent years, a large numbers of gene mutations have been discovered in CMML, none of&#xD;
      which are specific of this entity, as they can be encountered with different frequencies in&#xD;
      other myeloid neoplasms. These mutated genes encode signaling molecules (NRAS, KRAS, CBL,&#xD;
      JAK2, FLT3 and several members of the Notch pathway), epigenetic regulators (TET2, ASXL1,&#xD;
      EZH2, IDH1, IDH2,.) and splicing factors (SF3B1, SRSF2, ZRSF2). Mutations in the&#xD;
      transcription regulators RUNX1, NPM1 and TP53 have also been reported in CMML. However, the&#xD;
      role of these mutations in leukemogenesis is still unclear. CMML is also characterized by&#xD;
      defects in monocyte to macrophage differentiation. These defects in monocyte differentiation&#xD;
      can be attributed to the presence of immature dysplastic granulocytes that secrete high&#xD;
      levels of alpha-defensins HNP1-3 that antagonize the purinergic receptor P2RY6 in CMML&#xD;
      patients. These CD14-/CD15+/CD24+ immature granulocytes that belong to the same clone than&#xD;
      the leukemic monocytes seem to have immunosuppressive properties ressembling those of the&#xD;
      myeloid-derived suppressor cells (MDCS) described in solid tumours. Whether these immature&#xD;
      granulocytes contribute to autoimmune manifestations or immunoescape and progression of CMML&#xD;
      is a conendrum and remains to be determined.&#xD;
&#xD;
      In this context, the proposed project aims at identifying news insights into the&#xD;
      pathophysiology of CMML through a better definition of the phenotype and function of&#xD;
      monocytes and immature granulocytes that characterize this pathology.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">November 5, 2014</start_date>
  <completion_date type="Anticipated">November 5, 2018</completion_date>
  <primary_completion_date type="Anticipated">November 5, 2018</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>1 Day</target_duration>
  <primary_outcome>
    <measure>Characterization of molecular mechanisms</measure>
    <time_frame>at 3 years</time_frame>
    <description>Characterization of the molecular mechanisms involved in the lack of differentiation of monocytes originating from patients with CML.</description>
  </primary_outcome>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Chronic Myelomonocytic Leukemia</condition>
  <eligibility>
    <study_pop>
      <textblock>
        patients with chronic myelomonocytic leukemia&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients newly diagnosed or undergoing treatment in the Clinical Hematology department&#xD;
             of the participating establishments&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  NA&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Laurence Legros, PH</last_name>
    <phone>+33 (0)4 92 03 58 41</phone>
    <email>legros.l@chu-nice.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>CHU de Nice</name>
      <address>
        <city>Nice</city>
        <zip>06000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Laurence Legros, PH</last_name>
      <phone>+33 (0)04 92 03 58 41</phone>
      <email>legros.l@chu-nice.fr</email>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2018</verification_date>
  <study_first_submitted>January 31, 2017</study_first_submitted>
  <study_first_submitted_qc>September 12, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <last_update_submitted>March 16, 2018</last_update_submitted>
  <last_update_submitted_qc>March 16, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Acute</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Chronic</mesh_term>
    <mesh_term>Leukemia, Myelomonocytic, Juvenile</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03280888
org study id: 13-PP-11
nct id: NCT03280888
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
observational model: Other
time perspective: Prospective
measure: Characterization of molecular mechanisms
time frame: at 3 years
description: Characterization of the molecular mechanisms involved in the lack of differentiation of monocytes originating from patients with CML.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Laurence Legros, PH
phone: +33 (0)4 92 03 58 41
email: legros.l@chu-nice.fr
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myelomonocytic, Acute
mesh term: Leukemia, Myelomonocytic, Chronic
mesh term: Leukemia, Myelomonocytic, Juvenile
sharing ipd: No