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MIF Involvement in AML (MIFAML)

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ClinicalTrials.gov Identifier: NCT03918655
Recruitment Status : Not yet recruiting
First Posted : April 17, 2019
Last Update Posted : April 17, 2019
Sponsor:
Collaborators:
Institut National de la Santé Et de la Recherche Médicale, France
CHRU Tours: centre Hospitalier Universitaire de Tours
Gustave Roussy, Cancer Campus, Grand Paris
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:

This study is an observational study of MIF involvement in retrospectively and prospectively included adult acute myeloid leukemia (AML). Standard care samples collected at diagnosis, after one course of treatment, at time of remission controls, and at time of relapse will be used.

The first objective is to determine which AMLs have pre-leukemic stem cells that overexpress MIF. Cytogenetic and molecular (NGS) profiling will be performed at diagnosis. Blood and bone marrow plasma, as well as bone marrow mononuclear cells will be collected and stored. The expression of MIF and its receptor (CD74 and CXCR4) will be analysed. Their prognostic value will be also tested.

The second objective is to test whether patients in complete remission have persistent pre-leukemic stem cells that overexpress MIF. Blood and bone marrow plasma, bone marrow mononuclear cells from patients in complete remission will be collected. MIF, CD74, and CXCR4 expression by hematopoietic cells at time of diagnosis and remission will be compared to determine which patients have a persistent overexpression/secretion of MIF. In the meantime, the persistence of initiating lesions in complete remission samples will be tested by NGS, digital PCR, FISH, or RT-PCR methods.

The third objective is to develop a pre-clinical model to target MIF in immuno-compromised mice (NSG mice) transplanted with primary AML cells and cells with pre-leukemic lesions. TET2 depletion leads to MIF over-expression/secretion by hematopoietic cells and improved multi-lineage NSG-repopulation capacity. MIF inhibitors and anti-MIF antibodies will be tested in these pre-clinical TET2-depleted models. Xenotransplantation of selected primary AML samples and xenotransplantation of TET2 depleted hematopoietic stem cells into NSG mice will be used.

The fourth objective is to understand how MIF is deregulated in pre-leukemic stem cells and how the MIF-dependent crosstalk between mesenchymal stromal cells (MSCs) and pre-leukemic stem cells or normal hematopoietic cells works.

The molecular mechanisms of MIF overexpression will be analyzed in hematopoietic stem and progenitor cells from normal and leukemic bone marrow, with a focus on cells depleted in TET2 or DNMT3A. To study the cross-talk between hematopoietic stem and progenitor cells, pre-leukemic stem cells, and bone marrow MSCs, co-culture experiments will be performed using available MSC cell lines and primary MSCs from healthy donors.


Condition or disease
Acute Myeloid Leukemia

  Show Detailed Description

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Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: MIF : a New Target to Eradicate the Pre-leukemic Clone in Acute Myeloid Leukemia
Estimated Study Start Date : April 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : June 2030


Group/Cohort
Patient newly diagnosed with AML (prospectively)
Patient newly diagnosed with AML in Saint Antoine hospital or Tours University hospital in 2018 to 2020.
Patient diagnosed with AML (retrospectively)
Patient diagnosed with AML in Saint Antoine hospital in 2015 to 2018



Primary Outcome Measures :
  1. MIF concentration in the blood and the bone marrow and MIF RNA expression [ Time Frame: At Day 0 ]
    MIF concentration in the blood and the bone marrow (measured by ELISA), and MIF RNA expression assessed by quantitative RT-PCR in unsorted and sorted cell populations in order to determine which AMLs have pre-leukemic stem cells that overexpress MIF


Secondary Outcome Measures :
  1. Overall and leukemia free survivals [ Time Frame: patient complete remission until the last patient visit, for 36 months period ]
    Overall and leukemia free survivals according to MIF concentrations and MIF, CD74, and CXCR4 expression measured by cytometry and quantitative RT-PCR to assess the prognostic value of MIF

  2. The number of patients in complete remission with persistent pre-leukemic stem cells that over express MIF [ Time Frame: at Day 0 and at time of complete remission or relapse until the last patient visit for a 36 months period. ]
    The persistence of initiating lesions in complete remission samples will be tested by NGS, digital PCR, FISH, or RT-PCR methods to correlate the remission genotype to the parameters assessed in 1) to test whether patients in complete remission have persistent pre-leukemic stem cells that overexpress MIF.

  3. Rate of MIF inhibitors and anti-MIF antibodies will be tested in preclinical models [ Time Frame: at Day 0 and at time of complete remission or relapse until the last patient visit for a 36 months period. ]
    MIF inhibitors and anti-MIF antibodies will be tested in pre-clinical models after xenotransplantation of selected primary AML samples and xenotransplantation of TET2 depleted HPSCs into NSG mice to develop pre-clinical models allowing to target MIF pathway in NSG mice transplanted with primary AML cells and cells with pre-leukemic lesions

  4. The molecular mechanisms of MIF overexpression [ Time Frame: at Day 0 and at time of complete remission or relapse until the last patient visit for a 36 months period. ]
    The molecular mechanisms of MIF overexpression will be analyzed in HSPCs from normal and leukemic bone marrow, with a focus on cells depleted in TET2 or DNMT3A. To study the cross-talk between HSPCs, pre-leukemic stem cells, and BM-MSCs, co-culture experiments will be performed using available MSC cell lines and primary MSCs from healthy donors to understand how MIF is deregulated in pre-leukemic stem cells and how the MIF-dependent bidirectional communication between MSCs and pre-leukemic stem cells or normal HSPCs works


Biospecimen Retention:   Samples With DNA

Only standard care blood and bone marrow samples will be used in the study :

  • Blood samples for biochemistry, blood cell counts, immunophenotyping, cytogenetics, molecular biology analyses, and tumor bank cryopreservation
  • Bone marrow samples for immunophenotyping, cytogenetics, molecular biology analyses, and tumor bank cryopreservation


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
Sampling Method:   Probability Sample
Study Population
the participants will be adult patients (over 18) newly diagnosed with AML at Saint-Antoine Hospital or Tours University Hospital.
Criteria

Inclusion Criteria:

  • Patient newly diagnosed with AML in Saint Antoine hospital or Tours University hospital
  • Age > or equal 18 years old,
  • Written informed consent signed

Exclusion Criteria:

-Patient without social insurance


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): NCT03918655


Contacts
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Contact: François DELHOMMEAU, PharmaD, PhD +33 1 49 28 22 72 francoisdelhommeau@aphp.fr
Contact: Pierre HIRSCH, MD, PhD +33 1 49 28 22 72 pierre.hirsch@aphp.fr

Locations
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France
Laboratoire d'hématologie Hôpital Saint Antoine Not yet recruiting
Paris, France, 75012
Contact: François DELHOMMEAU, PharmaD, PhD    +33 1 49 28 22 72    francoisdelhommeau@aphp.fr   
Contact: Pierre HIRSCH, MD, PhD    +33 1 49 28 22 72    pierre.hirsch@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Institut National de la Santé Et de la Recherche Médicale, France
CHRU Tours: centre Hospitalier Universitaire de Tours
Gustave Roussy, Cancer Campus, Grand Paris
Investigators
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Principal Investigator: François DELHOMMEAU, PharmaD, PhD Assistance Publique- Hôpitaux de Paris, Sorbonne université, Inserm

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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT03918655     History of Changes
Other Study ID Numbers: PRT-K16055
First Posted: April 17, 2019    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: April 2019

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

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Acute Myeloid Leukemia.
Macrophage migration inhibitory factor
Hematopoietic stem cell

Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms