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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: 5-Azacitidine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 01220
    • Charite´-Campus Benjamin Franklin, Medizinische Klinik III
  • Hamburg, Germany, 20246
    • Bone Marrow Transplantation Unit, University Hospital Hamburg-Eppendorf
  • Baden-Wuertemberg
    • Heidelberg, Baden-Wuertemberg, Germany, 69120
      • Universitaetsklinik Heidelberg, Medizinische Klinik und Poliklinik V
  • Hessen
    • Frankfurt, Hessen, Germany, 60590
      • Klinikum der Johann-Wolfgang-Goethe Universität, Medizinische Klinik II
  • NW
    • Duesseldorf, NW, Germany, 40225
      • Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
      • Universitaetsklinikum Dresden, Medizinische Klinik und Poliklinik I

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 5-Azacitidine; 5-Azacitidine in addition to standard donor lymphocyte infusions.

Drug: 5-Azacitidine; 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.; Other Names: Vidaza

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Investigators: Principal Investigator: Guido Kobbe, PD Dr., Department of Hematology, Oncology and Clinical Immunology

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: November 20, 2008
• First Submitted That Met QC Criteria: November 20, 2008
• First Posted (Estimate): November 21, 2008

Study Record Updates

• Last Update Posted (Estimate): January 23, 2012
• Last Update Submitted That Met QC Criteria: January 20, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Myelodysplastic syndrome (MDS); Acute myeloid leukemia (AML); Stem cell transplantation; Donor lymphocyte infusion; 5-Azacitidine; MDS or AML relapsed after stem cell transplantation
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Azacitidine
• Other Study ID Numbers: AZARELA_HHU_2007