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

Sponsor

Carlos Graux, MD, PhD (Other)

Overall Status

Completed

CT.gov ID

NCT02017457

Collaborator

Celgene Corporation (Industry), Belgian Hematological Society (Other)

Enrollment

Locations

Arm

Duration (Months)

4.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia Myelodysplastic Syndrome	Biological: Donor lymphocyte infusion Drug: Azacytidine	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2013

Actual Primary Completion Date :

Nov 1, 2019

Actual Study Completion Date :

Nov 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azacytidine + Donor lymphocyte infusion 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.	Biological: Donor lymphocyte infusion 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 Other Names: DLI Drug: Azacytidine 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. Other Names: Vidaza

Arm

Intervention/Treatment

Experimental: Azacytidine + Donor lymphocyte infusion

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.

Biological: Donor lymphocyte infusion

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

Other Names:

DLI

Drug: Azacytidine

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.

Other Names:

Vidaza

Outcome Measures

Primary Outcome Measures

Response rate [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]
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 [2 years after cycle 6]
Disease-free survival of patients
Overall survival [2 years after cycle 6]
Overall survival of patients
Evaluation of the treatment Toxicity [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]
Evaluate haematological and non-haematological toxicities and safety of the planned therapy.
Incidence and severity of GvHD [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]
Incidence and severity of GvHD
Incidence and severity of infections [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]
Incidence and severity of infections

Other Outcome Measures

Immune reconstitution [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]
Immune reconstitution (hemoglobuline in g/dL)
Immune reconstitution [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]
Immune reconstitution (ANC, ALC, platelet in cells/µL)
Treg expansion [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]
Treg expansion

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Ziekenhuis Netwerk Antwerpen	Antwerpen	Belgium	2060
2	AZ Sint-Jan Brugge	Brugge	Belgium	8000
3	Institut Jules Bordet	Brussels	Belgium	1000
4	Universitair Ziekenhuis Antwerpen	Edegem	Belgium	2650
5	Universitair Ziekenhuis Gent	Gent	Belgium	9000
6	Hopital de Jolimont	Haine-St-Paul	Belgium	7100
7	Universitair Ziekenhuis Brussel	Jette	Belgium	1090
8	Universitair Ziekenhuis Leuven	Leuven	Belgium	3000
9	CHU Liège	Liège	Belgium	4000
10	Hartziekenhuis Roeselare Menen	Roeselare	Belgium	8800
11	Cliniques Universitaires Saint-Luc	Woluwe-Saint-Lambert	Belgium	1200
12	CHU Mont-Godinne	Yvoir	Belgium	5530

Sponsors and Collaborators

Carlos Graux, MD, PhD
Celgene Corporation
Belgian Hematological Society

Investigators

Principal Investigator: Xavier Poiré, MD, Cliniques universitaires Saint-Luc
Principal Investigator: Carlos Graux, MD, PhD, Cliniques Universitaires Mont-Godinne