Clinical trial NCT02017457: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: University Hospital of Mont-Godinne
Sponsor class: OTHER
Collaborators: name: Celgene Corporation
name: Belgian Hematological Society
First posted: 2013-12-20
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Response rate
timeFrame: 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 outcomes:
measure: Disease-free survival
timeFrame: 2 years after cycle 6
measure: Overall survival
timeFrame: 2 years after cycle 6
measure: Evaluation of the treatment Toxicity
timeFrame: 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
measure: Incidence and severity of GvHD
timeFrame: 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
measure: Incidence and severity of infections
timeFrame: 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 outcomes:
measure: Immune reconstitution
timeFrame: 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
measure: Immune reconstitution
timeFrame: 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
measure: Treg expansion
timeFrame: 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
Locations:
city: Antwerpen
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen
city: Brugge
country: Belgium
facility: AZ Sint-Jan Brugge
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Haine-St-Paul
country: Belgium
facility: Hopital de Jolimont
city: Jette
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Leuven
city: Liège
country: Belgium
facility: CHU Liège
city: Roeselare
country: Belgium
facility: Hartziekenhuis Roeselare Menen
city: Woluwe-Saint-Lambert
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Yvoir
country: Belgium
facility: CHU Mont-Godinne
Study officials:
affiliation: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
name: Xavier Poiré, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cliniques Universitaires Mont-Godinne
name: Carlos Graux, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: