Safety Study of 5-Azacitidine and Standard Donor Lymphocyte Infusion (DLI) to Treat Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) Relapsing After Allogeneic Stem Cell Transplantation

Study Overview
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Brief Summary
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This open label phase-II trial evaluates hematological response of an additional treatment with 5-Azacitidine to common DLI in patients with MDS or AML relapsing after allogeneic stem cell transplantation.

Detailed Description
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Relapse after allogeneic stem cell transplantation is a major problem in patients with poor prognosis AML or MDS. Donor lymphocyte infusions alone re-induce remission in a minority of these patients, which may be the result of poor differentiation of the leukemic cells. The study drug 5-Aza is effective in AML and MDS.In addition to direct cytotoxicity, it alters gene expression and induces differentiation of leukemic blast cells. Furthermore, DNA-demethylating treatment results in an induction of transcription and cell surface expression of formerly unexpressed KIRs (killer Ig-like receptors) in NK cells, which are involved in the specific recognition of leukemic target cells and who are able to generate a specific graft-versus leukemia effect. The increased expression of MHC class I and II molecules on the surface of the recipient's leukemic cells and the de novo expression of formerly silenced KIR genes in donor NK cells due to treatment with 5-Aza may result in an increased susceptibility of myeloid leukemic cells to the allogeneic graft versus leukemia effect. Therefore, the graft-versus leukemia effect by donor lymphocyte infusions and NK cells from the original donor may be supported by additional therapy with 5-Azacitidine.

Official Title
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Phase-II Trial to Assess the Efficacy and Toxicity of 5-Azacitidine in Addition to Standard DLI for the Treatment of Patients With AML or MDS Relapsing After Allogeneic Stem Cell Transplantation

Conditions
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Myelodysplastic Syndrome, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: 5-Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Primary and secondary MDS, AML after MDS, and de novo AML relapsing after allogeneic stem cell transplantation Eligibility for Donor Lymphocyte Infusions Performance status according to the WHO scale: 0, 1 or 2. Adequate renal and liver function: bilirubin < 1.5 times the upper limit of normal and a GFR > 50 ml/min Absence of severe cardiovascular disease, i.e., arrhythmias requiring chronic treatment, congestive heart failure (NYHA Class III or IV) or symptomatic ischemic heart disease, where New-York Heart Association (NYHA) HIV negative and HBs-Ag negative. Absence of active uncontrolled infection (Septicaemia). No prior history or current evidence of central nervous system and psychiatric disorders requiring hospitalization. Age at least 18 years. Negative pregnancy test for women with reproductive potential. Signed written informed consent must be given according to national/local regulations. Exclusion Criteria: - Have malignant hepatic tumors. Severe liver dysfunction CHILD B and C. Renal insufficiency with a GFR < 50 ml/min Radiation therapy, chemotherapy, or cytotoxic therapy, given to treat conditions other than MDS, AML or applied for conditioning prior allogeneic stemcell transplantation. Psychiatric illness that would prevent granting of informed consent. Treatment with androgenic hormones during the previous 14 days prior Day 1. Active viral infection with known human immunodeficiency virus (HIV) or viral Hepatitis B or C. Hypersensitivity to Mannitol or 5-Azacitidine. Treatment with other investigational drugs following relapse after allogeneic stemcell transplantation or ongoing adverse events from previous treatment with investigational drugs regardless of time period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-Azacitidine<br>5-Azacitidine in addition to standard donor lymphocyte infusions. | Drug: 5-Azacitidine<br>* 5-Aza will be administered at doses of 100mg/m2 via subcutaneous injection over a period of 5 days. The total amount per treatment cycle, consisting of 5 days, is 500mg/m². Each treatment cycle is repeated every 28 days, with a treatment pause of 23 days between each 5-Aza cycle, to a total of 6 (optional 8 cycles) cycles. DLI will be transfused on day +34 with a total count of CD3+ cells of DLI 1-5x10E6CD3+/kg bodyweight. In absence of GvHD DLI transfusion is repeated on day +90 with DLI 1-5x10E7CD3+/kg bodyweight and on day +142 with DLI 1-5x10E8CD3+/kg bodyweight. Additional DLI may be given.<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best response |  | within the 6 months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Toxicity of 5-Azacitidine for patients relapsing after allo-SCT |  | within 3 years | 
| Response rate |  | within 6 months | 
| Duration of remissions |  | within 3 years | 
| Incidence of acute and chronic GvHD |  | 3 years | 
| Achievement of complete chimerism |  | 6 month | 
| Toxicity |  | wtihin 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic syndrome (MDS), Acute myeloid leukemia (AML), Stem cell transplantation, 5-Azacitidine, Donor lymphocyte infusion, MDS or AML relapsed after stem cell transplantation