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出境医 / 临床实验 / Immunoevasive Tactics Employed by Myeloid Malignancy After Allogeneic Stem Cell Transplantation (EVADE)

Immunoevasive Tactics Employed by Myeloid Malignancy After Allogeneic Stem Cell Transplantation (EVADE)

Study Description
Brief Summary:
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only treatment available to cure acute myeloid leukemia and high risk myelodysplasia. Allo-HSCT has an anti-tumor effect (called the graft versus leukemia effect= GVL) mediated by donor lymphocytes. This GVL effect is often associated with graft-versus-host disease (GVHD). Several studies have shown that the relapse incidence is lower in patients developing chronic GVHD. These studies confirm the impact of donor immune system on leukemic residual cells. In fact, the relapse incidence increased in patients with no sign of GVHD. The investigators assume that leukemic cells probably use mechanisms to inhibit the allogeneic response. These escape mechanisms to immunosurveillance have been described in other malignancies. Out of context of the allo-HSCT, in acute myeloid leukemias and myelodysplasia, correlations between the severity of the disease and the presence of regulatory T cells (Tregs) or exhausted T cells (PD1 positive) in the bone marrow and in the blood of patients were described at the time of diagnosis or relapse. Myeloid Derived Suppressive Cells (MDSCs) have been described as capable of inducing Tregs and exhausted T cells in the tumor microenvironment.The investigators want to evaluate the role of myeloid suppressive cells in bone marrow after allo HSCT. They hypothesize that their presence in bone marrow and / or blood recipient is correlated to the relapse incidence.

Condition or disease Intervention/treatment Phase
Relapse Leukemia Allogeneic Stem Cell Transplantation Immune Evasion, Tumor Biological: blood sample Biological: bone marrow sample Not Applicable

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 104 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Study of the Immunoevasive Mecanisms and Especially Myeloid Suppressive Cells in the Medullar Microenvironment Employed by Myeloid Malignancy (AML and High Risk MDS) When Relapsing After Allogeneic Stem Cell Transplantation
Estimated Study Start Date : September 1, 2019
Estimated Primary Completion Date : June 30, 2022
Estimated Study Completion Date : November 1, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: immune escape mecanims
Cohort study with a representative sample of patients
 Biological: blood sample
20 ml at inclusion, and 20ml at 1, 3, 6 and 12 months after allo HSCT

Biological: bone marrow sample
3 ml at inclusion, and 3 ml at 1, 3, 6 and 12 months after allo HSCT
Outcome Measures
Primary Outcome Measures :
  1. Myeloid suppressive cells and relapse incidence [ Time Frame: 2 years ]

    To investigate the relationship between the percentage of myeloid derived suppressive cells (MDSCs) in total leukocytes in peripheral blood and the relapse incidence after allogeneic stem cell transplantation.

    The patients will be grouped according to median MDSC frequency values. Relapse incidence will be compared across the two groups (low and high frequency of MDSC).



Secondary Outcome Measures :
  1. Myeloid suppressive cells and the medullar microenvironment (regulatory T cells and mesenchymal stem cells) [ Time Frame: 2 years ]
    To correlate levels of bone marrow MDSC and regulatory T cells (Tregs) and exhausted T cells and the quality of mesenchymal cells in bone marrow.

  2. percentage of myeloid suppressive cells [ Time Frame: 2 years ]
  3. incidence of acute GVHD [ Time Frame: 2 years ]
  4. incidence of chronic GVHD [ Time Frame: 2 years ]

Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 71 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with acute myeloid leukemia in complete cytological remission with intermediate or high risk prognosis according to ELN 2017
  • Patients with myelodysplasia according to the WHO 2016 definition, with IPSS ≥1.5 and disease status is : stable or in partial response or complete response according to IWG 2006.
  • Patients with indication of first allo-HSCT with a matched related or unrelated donor
  • Patients receiving non-myeloablative or reduced toxicity conditioning
  • Patients affiliated to a social security scheme
  • Patients who have received a complete information on the organization of the research and signed his informed consent

Exclusion Criteria:

  • Patients with an alternative donor (HLA 5/10 or unit cord blood)
  • Patients with another active cancer or a history of cancer diagnosed in the previous 5 years
  • Patients with uncontrolled infection at the time of inclusion, or with positive HIV (1 + 2) or HTLV (1 + 2), Hepatitis C or active hepatitis B
  • Patients referred to in Articles L. 1121-5, L. 1121-7 and L1121-8 of the Public Health Code.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Maud D'AVENI, MD +33383153289 m.daveni-piney@chru-nancy.fr
Contact: Marie-Therese RUBIO, MD +33383153282 m.rubio@chru-nancy.fr

Sponsors and Collaborators
Central Hospital, Nancy, France
Tracking Information
First Submitted Date  ICMJE May 3, 2019
First Posted Date  ICMJE May 28, 2019
Last Update Posted Date May 28, 2019
Estimated Study Start Date  ICMJE September 1, 2019
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 24, 2019) 		Myeloid suppressive cells and relapse incidence [ Time Frame: 2 years ]
To investigate the relationship between the percentage of myeloid derived suppressive cells (MDSCs) in total leukocytes in peripheral blood and the relapse incidence after allogeneic stem cell transplantation. The patients will be grouped according to median MDSC frequency values. Relapse incidence will be compared across the two groups (low and high frequency of MDSC).
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: May 24, 2019)
  • Myeloid suppressive cells and the medullar microenvironment (regulatory T cells and mesenchymal stem cells) [ Time Frame: 2 years ]
    To correlate levels of bone marrow MDSC and regulatory T cells (Tregs) and exhausted T cells and the quality of mesenchymal cells in bone marrow.
  • percentage of myeloid suppressive cells [ Time Frame: 2 years ]
  • incidence of acute GVHD [ Time Frame: 2 years ]
  • incidence of chronic GVHD [ Time Frame: 2 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunoevasive Tactics Employed by Myeloid Malignancy After Allogeneic Stem Cell Transplantation
Official Title  ICMJE Study of the Immunoevasive Mecanisms and Especially Myeloid Suppressive Cells in the Medullar Microenvironment Employed by Myeloid Malignancy (AML and High Risk MDS) When Relapsing After Allogeneic Stem Cell Transplantation
Brief Summary Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still the only treatment available to cure acute myeloid leukemia and high risk myelodysplasia. Allo-HSCT has an anti-tumor effect (called the graft versus leukemia effect= GVL) mediated by donor lymphocytes. This GVL effect is often associated with graft-versus-host disease (GVHD). Several studies have shown that the relapse incidence is lower in patients developing chronic GVHD. These studies confirm the impact of donor immune system on leukemic residual cells. In fact, the relapse incidence increased in patients with no sign of GVHD. The investigators assume that leukemic cells probably use mechanisms to inhibit the allogeneic response. These escape mechanisms to immunosurveillance have been described in other malignancies. Out of context of the allo-HSCT, in acute myeloid leukemias and myelodysplasia, correlations between the severity of the disease and the presence of regulatory T cells (Tregs) or exhausted T cells (PD1 positive) in the bone marrow and in the blood of patients were described at the time of diagnosis or relapse. Myeloid Derived Suppressive Cells (MDSCs) have been described as capable of inducing Tregs and exhausted T cells in the tumor microenvironment.The investigators want to evaluate the role of myeloid suppressive cells in bone marrow after allo HSCT. They hypothesize that their presence in bone marrow and / or blood recipient is correlated to the relapse incidence.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Relapse Leukemia
  • Allogeneic Stem Cell Transplantation
  • Immune Evasion, Tumor
Intervention  ICMJE
  • Biological: blood sample
    20 ml at inclusion, and 20ml at 1, 3, 6 and 12 months after allo HSCT
  • Biological: bone marrow sample
    3 ml at inclusion, and 3 ml at 1, 3, 6 and 12 months after allo HSCT
Study Arms  ICMJE Experimental: immune escape mecanims
Cohort study with a representative sample of patients
Interventions:
  • Biological: blood sample
  • Biological: bone marrow sample
Publications *
  • D'Aveni M, Rossignol J, Coman T, Sivakumaran S, Henderson S, Manzo T, Santos e Sousa P, Bruneau J, Fouquet G, Zavala F, Alegria-Prévot O, Garfa-Traoré M, Suarez F, Trebeden-Nègre H, Mohty M, Bennett CL, Chakraverty R, Hermine O, Rubio MT. G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease. Sci Transl Med. 2015 Apr 1;7(281):281ra42. doi: 10.1126/scitranslmed.3010435.
  • Kumar B, Garcia M, Weng L, Jung X, Murakami JL, Hu X, McDonald T, Lin A, Kumar AR, DiGiusto DL, Stein AS, Pullarkat VA, Hui SK, Carlesso N, Kuo YH, Bhatia R, Marcucci G, Chen CC. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia. 2018 Mar;32(3):575-587. doi: 10.1038/leu.2017.259. Epub 2017 Aug 17.
  • Nadal E, Garin M, Kaeda J, Apperley J, Lechler R, Dazzi F. Increased frequencies of CD4(+)CD25(high) T(regs) correlate with disease relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Leukemia. 2007 Mar;21(3):472-9. Epub 2007 Jan 11.
  • Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, Zeng H, Schell TD, Zheng H. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer J. 2015 Jul 31;5:e330. doi: 10.1038/bcj.2015.58.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 24, 2019) 		104
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 1, 2022
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with acute myeloid leukemia in complete cytological remission with intermediate or high risk prognosis according to ELN 2017
  • Patients with myelodysplasia according to the WHO 2016 definition, with IPSS ≥1.5 and disease status is : stable or in partial response or complete response according to IWG 2006.
  • Patients with indication of first allo-HSCT with a matched related or unrelated donor
  • Patients receiving non-myeloablative or reduced toxicity conditioning
  • Patients affiliated to a social security scheme
  • Patients who have received a complete information on the organization of the research and signed his informed consent

Exclusion Criteria:

  • Patients with an alternative donor (HLA 5/10 or unit cord blood)
  • Patients with another active cancer or a history of cancer diagnosed in the previous 5 years
  • Patients with uncontrolled infection at the time of inclusion, or with positive HIV (1 + 2) or HTLV (1 + 2), Hepatitis C or active hepatitis B
  • Patients referred to in Articles L. 1121-5, L. 1121-7 and L1121-8 of the Public Health Code.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 71 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Maud D'AVENI, MD +33383153289 m.daveni-piney@chru-nancy.fr
Contact: Marie-Therese RUBIO, MD +33383153282 m.rubio@chru-nancy.fr
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03964922
Other Study ID Numbers  ICMJE 2019-A00842-55
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Central Hospital, Nancy, France
Study Sponsor  ICMJE Central Hospital, Nancy, France
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Central Hospital, Nancy, France
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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