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Azacytidine and Lymphocytes in Relapse of AML or MDS After Allogeneic Stem Cell Transplantation.

Primary Purpose

Acute Myelogenous Leukemia, Myelodysplastic Syndrome

Status
Completed
Phase
Phase 2
Locations
Belgium
Study Type
Interventional
Intervention
Donor lymphocyte infusion
Azacytidine
Sponsored by
Carlos Graux, MD, PhD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myelogenous Leukemia focused on measuring Hematology, Acute Myelogenous Leukemia, Myelodysplasic syndrome, Allogeneic stem cell transplantation, Donor lymphocyte infusion, DLI, Azacytidine, Vidaza, Overall response rate, Relapse

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Patients:

    • Age ≥ 18 years
    • Be able to understand and sign informed consent
    • Fertile patients must use a reliable contraception method

  2. Disease status at transplantation:

    • AML in first or subsequent complete remission (< 5% marrow blasts)
    • MDS with less than 10% marrow blasts at the time of transplantation

  3. Transplantation:

    • Allogeneic transplantation using a sibling or unrelated donor with matching in 10/10 alleles (HLA-A, B, C, DRB1, DQB1) or maximum of one allele or one antigen or 1 antigen + 1 allele or 1 antigen + 1 DQB1 antigen or 2 alleles mismatches.
    • Myeloablative or reduced-intensity conditioning
    • Second transplantation is allowed
    • Donor is willing to donate lymphocytes

  4. Clinical situation:

    • Cytological relapse after allo-SCT defined as the recurrence of more than 5% blasts on bone marrow aspiration (AML) or evidence of MDS
    • Immunophenotypic relapse defined as the recurrence of an abnormal phenotype on flow cytometry in bone marrow aspirate (only in case of a specific phenotype).
    • Cytogenetic or molecular relapse defined as the persistence or recurrence of a cytogenetic abnormality or molecular marker in bone marrow aspiration or peripheral blood. WT1 expression is not considered as reliable marker for relapse in this protocol but FLT3-ITD, NPM1, CEBPA, or translocation-specific markers (such as MLL-PTD, AML-ETO, CBFB-MYH11) are.
  5. Immunosuppressive therapy should have been stopped before inclusion.

Exclusion Criteria:

  • More than 30% marrow blasts at the time of inclusion
  • Extramedullary relapse including CNS involvement
  • ECOG Performance status > 2
  • Active acute grade II-IV GvHD at the time of inclusion
  • Active chronic GvHD requiring systemic therapy at the time of inclusion
  • Uncontrolled infection
  • HIV positive
  • Acute or chronic heart failure (NYHA class III or IV) or symptomatic ischemic heart disease or ejection fraction < 35% or uncontrolled arrhythmia
  • Severe liver failure (total bilirubin > 3 mg/dL, SGPT > 4 X upper normal limit)
  • Severe pulmonary failure (corrected DLCo < 35%)
  • Terminal renal failure requiring dialysis
  • Severe neurological or psychiatric disorders
  • Concurrent investigational drug.
  • Other treatment for relapse, except for hydroxyurea but it should be stopped before inclusion in the study.
  • Female who is pregnant or breastfeeding

Sites / Locations

  • Ziekenhuis Netwerk Antwerpen
  • AZ Sint-Jan Brugge
  • Institut Jules Bordet
  • Universitair Ziekenhuis Antwerpen
  • Universitair Ziekenhuis Gent
  • Hopital de Jolimont
  • Universitair Ziekenhuis Brussel
  • Universitair Ziekenhuis Leuven
  • CHU Liège
  • Hartziekenhuis Roeselare Menen
  • Cliniques Universitaires Saint-Luc
  • CHU Mont-Godinne

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Azacytidine + Donor lymphocyte infusion

Arm Description

Azacytidine will be administered subcutaneously for 5 days. During the first cycle, a dose of 100mg/m2/day will be used and for the following cycles a dose of 35mg/m2/day will be administered. Each cycle will consist in 28 days. All patients will receive at least 6 cycles of Azacytidine and the total number of cycles will depend on the response to treatment. Donor lymphocyte infusion will be performed on day 1 of cycle 2, 4 and 6 of Azacytidine. The amount of cells infused will depend on donor origin.

Outcomes

Primary Outcome Measures

Response rate
To assess the response rate to DLI by the combination with azacytidine in the population of patients with relapsed AML and MDS after allo-SCT.

Secondary Outcome Measures

Disease-free survival
Disease-free survival of patients
Overall survival
Overall survival of patients
Evaluation of the treatment Toxicity
Evaluate haematological and non-haematological toxicities and safety of the planned therapy.
Incidence and severity of GvHD
Incidence and severity of GvHD
Incidence and severity of infections
Incidence and severity of infections

Full Information

First Posted
December 16, 2013
Last Updated
December 6, 2019
Sponsor
Carlos Graux, MD, PhD
Collaborators
Celgene Corporation, Belgian Hematological Society
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1. Study Identification

Unique Protocol Identification Number
NCT02017457
Brief Title
Azacytidine and Lymphocytes in Relapse of AML or MDS After Allogeneic Stem Cell Transplantation.
Official Title
Sequential Administration of 5-azacytidine (AZA) and Donor Lymphocyte Infusion (DLI) for Patients With Acute Myelogenous Leukemia (AML) and Myelodysplastic Syndrome (MDS) in Relapse After Allogeneic Stem Cell Transplantation.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2019
Overall Recruitment Status
Completed
Study Start Date
December 2013 (undefined)
Primary Completion Date
November 2019 (Actual)
Study Completion Date
November 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Carlos Graux, MD, PhD
Collaborators
Celgene Corporation, Belgian Hematological Society

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The present project is a multicenter, phase II trial which aims at evaluating if the administration of azacytidine (Vidaza®) combined to donor lymphocyte infusion (DLI) could improve the response rate to DLI in the population of patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation.
Detailed Description
This is a prospective, multicenter, non-randomized phase II study. The aims at evaluating if the administration of azacytidine (Vidaza®) combined to donor lymphocyte infusion (DLI) could improve the response rate to DLI in the population of patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation. Because the investigators focus our interest on relapsed MDS and low marrow blast count relapsed AML, the investigators postulate that one cycle at higher doses of azacytidine given at 100 mg/m² during 5 days is enough to induce temporary disease control, as suggested by the predictive value of the immediate response rate after the first cycle described in the study of Czibere et al. Starting with cycle 2, the investigators propose to administer DLI along with azacytidine to optimise the immunomodulatory effect. Because these immunomodulatory effects have been described at low dose, the investigators postulate that 35 mg/m² given during 5 days is enough to harness a graft-versus-leukemia effect and induce durable remissions without exacerbating GvHD. DLI will be given every other cycle following an escalated-dose regimen. The investigators have estimated a sample size of 50 patients to be recruited during 4 years with a 2-year follow-up and a 3-year long-term follow-up. The whole study will be completed within 9 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Keywords
Hematology, Acute Myelogenous Leukemia, Myelodysplasic syndrome, Allogeneic stem cell transplantation, Donor lymphocyte infusion, DLI, Azacytidine, Vidaza, Overall response rate, Relapse

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Azacytidine + Donor lymphocyte infusion
Arm Type
Experimental
Arm Description
Azacytidine will be administered subcutaneously for 5 days. During the first cycle, a dose of 100mg/m2/day will be used and for the following cycles a dose of 35mg/m2/day will be administered. Each cycle will consist in 28 days. All patients will receive at least 6 cycles of Azacytidine and the total number of cycles will depend on the response to treatment. Donor lymphocyte infusion will be performed on day 1 of cycle 2, 4 and 6 of Azacytidine. The amount of cells infused will depend on donor origin.
Intervention Type
Biological
Intervention Name(s)
Donor lymphocyte infusion
Other Intervention Name(s)
DLI
Intervention Description
On day 1 of cycle 2, 4 and 6 of Azacytidine, patients will be infused with donor lymphocytes (ideally on day 1 but in case of organizational problems, DLI can be administered until day 5) . Patients with a sibling donor will receive: 5x10exp7 CD3+/kg on day 1 of cycle 2 5x10exp7 CD3+/kg on day 1 of cycle 4 10x10exp7 CD3+/kg on day 1 of cycle 6 Patients with an unrelated donor will receive: 1x10exp7 CD3+/kg on day 1 of cycle 2 5x10exp7 CD3+/kg on day 1 of cycle 4 10x10exp7 CD3+/kg on day 1 of cycle 6
Intervention Type
Drug
Intervention Name(s)
Azacytidine
Other Intervention Name(s)
Vidaza
Intervention Description
Cycle 1: Subcutaneous administration of 100mg/m2/day for 5 days. Cycle 2: Subcutaneous administration of 35mg/m2/day for 5 days. Cycles will be administered every 28 days. All patients will receive at least 6 cycles of Azacytidine except if progression requests additional disease-related treatment such as hydroxyurea or other chemotherapeutic agents. In such cases, the patient will be excluded from the study and only disease status and survival status will be reported during the 3-year follow-up period. In case of complete remission after cycle 5, 2 additional cycles will be administered after achievement of complete remission. In case of stable disease or partial response, Azacytidine will be continued until progression. In case of disease progression after cycle 6, Azacytidine will be stopped.
Primary Outcome Measure Information:
Title
Response rate
Description
To assess the response rate to DLI by the combination with azacytidine in the population of patients with relapsed AML and MDS after allo-SCT.
Time Frame
Will be evaluated at day 24 of cycle 1, 3 and 5. Then every 3 months for a year after cycle 6 thereafter at 1.5 and 2 years after cycle 6
Secondary Outcome Measure Information:
Title
Disease-free survival
Description
Disease-free survival of patients
Time Frame
2 years after cycle 6
Title
Overall survival
Description
Overall survival of patients
Time Frame
2 years after cycle 6
Title
Evaluation of the treatment Toxicity
Description
Evaluate haematological and non-haematological toxicities and safety of the planned therapy.
Time Frame
At the beginning of each cycle and at the discretion of the investigator until cycle 6, then monthly for 6 months, thereafter every 3 months for 1.5 years
Title
Incidence and severity of GvHD
Description
Incidence and severity of GvHD
Time Frame
At the beginning of each cycle and at the discretion of the investigator until cycle 6, then monthly for 6 months, thereafter every 3 months for 1.5 years
Title
Incidence and severity of infections
Description
Incidence and severity of infections
Time Frame
At the beginning of each cycle and at the discretion of the investigator until cycle 6, then monthly for 6 months, thereafter every 3 months for 1.5 years
Other Pre-specified Outcome Measures:
Title
Immune reconstitution
Description
Immune reconstitution (hemoglobuline in g/dL)
Time Frame
On day 1 of each cycle until cycle 6, then every 3 months for a year and at 1.5 and 2 years after cycle 6
Title
Immune reconstitution
Description
Immune reconstitution (ANC, ALC, platelet in cells/µL)
Time Frame
On day 1 of each cycle until cycle 6, then every 3 months for a year and at 1.5 and 2 years after cycle 6
Title
Treg expansion
Description
Treg expansion
Time Frame
On day 1 of each cycle until cycle 6, then every 3 months for a year and at 1.5 and 2 years after cycle 6

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients: Age ≥ 18 years Be able to understand and sign informed consent Fertile patients must use a reliable contraception method Disease status at transplantation: AML in first or subsequent complete remission (< 5% marrow blasts) MDS with less than 10% marrow blasts at the time of transplantation Transplantation: Allogeneic transplantation using a sibling or unrelated donor with matching in 10/10 alleles (HLA-A, B, C, DRB1, DQB1) or maximum of one allele or one antigen or 1 antigen + 1 allele or 1 antigen + 1 DQB1 antigen or 2 alleles mismatches. Myeloablative or reduced-intensity conditioning Second transplantation is allowed Donor is willing to donate lymphocytes Clinical situation: Cytological relapse after allo-SCT defined as the recurrence of more than 5% blasts on bone marrow aspiration (AML) or evidence of MDS Immunophenotypic relapse defined as the recurrence of an abnormal phenotype on flow cytometry in bone marrow aspirate (only in case of a specific phenotype). Cytogenetic or molecular relapse defined as the persistence or recurrence of a cytogenetic abnormality or molecular marker in bone marrow aspiration or peripheral blood. WT1 expression is not considered as reliable marker for relapse in this protocol but FLT3-ITD, NPM1, CEBPA, or translocation-specific markers (such as MLL-PTD, AML-ETO, CBFB-MYH11) are. Immunosuppressive therapy should have been stopped before inclusion. Exclusion Criteria: More than 30% marrow blasts at the time of inclusion Extramedullary relapse including CNS involvement ECOG Performance status > 2 Active acute grade II-IV GvHD at the time of inclusion Active chronic GvHD requiring systemic therapy at the time of inclusion Uncontrolled infection HIV positive Acute or chronic heart failure (NYHA class III or IV) or symptomatic ischemic heart disease or ejection fraction < 35% or uncontrolled arrhythmia Severe liver failure (total bilirubin > 3 mg/dL, SGPT > 4 X upper normal limit) Severe pulmonary failure (corrected DLCo < 35%) Terminal renal failure requiring dialysis Severe neurological or psychiatric disorders Concurrent investigational drug. Other treatment for relapse, except for hydroxyurea but it should be stopped before inclusion in the study. Female who is pregnant or breastfeeding
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Xavier Poiré, MD
Organizational Affiliation
Cliniques universitaires Saint-Luc
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Carlos Graux, MD, PhD
Organizational Affiliation
Cliniques Universitaires Mont-Godinne
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ziekenhuis Netwerk Antwerpen
City
Antwerpen
ZIP/Postal Code
2060
Country
Belgium
Facility Name
AZ Sint-Jan Brugge
City
Brugge
ZIP/Postal Code
8000
Country
Belgium
Facility Name
Institut Jules Bordet
City
Brussels
ZIP/Postal Code
1000
Country
Belgium
Facility Name
Universitair Ziekenhuis Antwerpen
City
Edegem
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Universitair Ziekenhuis Gent
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Hopital de Jolimont
City
Haine-St-Paul
ZIP/Postal Code
7100
Country
Belgium
Facility Name
Universitair Ziekenhuis Brussel
City
Jette
ZIP/Postal Code
1090
Country
Belgium
Facility Name
Universitair Ziekenhuis Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
CHU Liège
City
Liège
ZIP/Postal Code
4000
Country
Belgium
Facility Name
Hartziekenhuis Roeselare Menen
City
Roeselare
ZIP/Postal Code
8800
Country
Belgium
Facility Name
Cliniques Universitaires Saint-Luc
City
Woluwe-Saint-Lambert
ZIP/Postal Code
1200
Country
Belgium
Facility Name
CHU Mont-Godinne
City
Yvoir
ZIP/Postal Code
5530
Country
Belgium

12. IPD Sharing Statement

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Azacytidine and Lymphocytes in Relapse of AML or MDS After Allogeneic Stem Cell Transplantation.

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