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

Myelodysplastic Syndrome Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02017457
• Other study ID #: BHS-TC-10
• Status: Completed
• Phase: Phase 2
• Start date: December 2013
• Est. completion date: November 2019

Study information

• Verified date: December 2019
• Source: University Hospital of Mont-Godinne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: November 2019
• Est. primary completion date: November 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Recurrence
• Syndrome

Intervention

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

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.

Locations

Country	Name	City	State
Belgium	Ziekenhuis Netwerk Antwerpen	Antwerpen
Belgium	AZ Sint-Jan Brugge	Brugge
Belgium	Institut Jules Bordet	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	Universitair Ziekenhuis Gent	Gent
Belgium	Hopital de Jolimont	Haine-St-Paul
Belgium	Universitair Ziekenhuis Brussel	Jette
Belgium	Universitair Ziekenhuis Leuven	Leuven
Belgium	CHU Liège	Liège
Belgium	Hartziekenhuis Roeselare Menen	Roeselare
Belgium	Cliniques Universitaires Saint-Luc	Woluwe-Saint-Lambert
Belgium	CHU Mont-Godinne	Yvoir

Sponsors (3)

Lead Sponsor	Collaborator
Carlos Graux, MD, PhD	Belgian Hematological Society, Celgene Corporation

Country where clinical trial is conducted

Belgium, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Immune reconstitution	Immune reconstitution (hemoglobuline in g/dL)	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
Other	Immune reconstitution	Immune reconstitution (ANC, ALC, platelet in cells/µL)	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
Other	Treg expansion	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
Primary	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.	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	Disease-free survival	Disease-free survival of patients	2 years after cycle 6
Secondary	Overall survival	Overall survival of patients	2 years after cycle 6
Secondary	Evaluation of the treatment Toxicity	Evaluate haematological and non-haematological toxicities and safety of the planned therapy.	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
Secondary	Incidence and severity of GvHD	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
Secondary	Incidence and severity of infections	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