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
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Myelodysplastic Syndrome Acute Myeloid Leukemia |
Drug: 5-Azacitidine |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | 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 |
- Best response [ Time Frame: within the 6 months of treatment ] [ Designated as safety issue: No ]
- Safety and Toxicity of 5-Azacitidine for patients relapsing after allo-SCT [ Time Frame: within 3 years ] [ Designated as safety issue: Yes ]
- Response rate [ Time Frame: within 6 months ] [ Designated as safety issue: No ]
- Duration of remissions [ Time Frame: within 3 years ] [ Designated as safety issue: No ]
- Incidence of acute and chronic GvHD [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
- Achievement of complete chimerism [ Time Frame: 6 month ] [ Designated as safety issue: No ]
- Toxicity [ Time Frame: wtihin 3 years ] [ Designated as safety issue: Yes ]
| Enrollment: | 30 |
| Study Start Date: | November 2008 |
| Study Completion Date: | August 2011 |
| Primary Completion Date: | October 2010 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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 Name: Vidaza
|
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.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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.
Contacts and Locations| Germany | |
| Universitaetsklinik Heidelberg, Medizinische Klinik und Poliklinik V | |
| Heidelberg, Baden-Wuertemberg, Germany, 69120 | |
| Klinikum der Johann-Wolfgang-Goethe Universität, Medizinische Klinik II | |
| Frankfurt, Hessen, Germany, 60590 | |
| Department of Hematology, Oncology and Clinical Immunology, University Hospital Duesseldorf | |
| Duesseldorf, NW, Germany, 40225 | |
| Universitaetsklinikum Dresden, Medizinische Klinik und Poliklinik I | |
| Dresden, Sachsen, Germany, 01307 | |
| Charite´-Campus Benjamin Franklin, Medizinische Klinik III | |
| Berlin, Germany, 01220 | |
| Bone Marrow Transplantation Unit, University Hospital Hamburg-Eppendorf | |
| Hamburg, Germany, 20246 | |
| Principal Investigator: | Guido Kobbe, PD Dr. | Department of Hematology, Oncology and Clinical Immunology |
More Information
No publications provided
| Responsible Party: | Heinrich-Heine University, Duesseldorf |
| ClinicalTrials.gov Identifier: | NCT00795548 History of Changes |
| Other Study ID Numbers: | AZARELA_HHU_2007 |
| Study First Received: | November 20, 2008 |
| Last Updated: | January 20, 2012 |
| Health Authority: | Germany: Federal Institute for Drugs and Medical Devices |
Keywords provided by Heinrich-Heine University, Duesseldorf:
|
Myelodysplastic syndrome (MDS) Acute myeloid leukemia (AML) Stem cell transplantation |
5-Azacitidine Donor lymphocyte infusion MDS or AML relapsed after stem cell transplantation |
Additional relevant MeSH terms:
|
Leukemia Leukemia, Myeloid, Acute Leukemia, Myeloid Myelodysplastic Syndromes Preleukemia Neoplasms by Histologic Type Neoplasms Bone Marrow Diseases Hematologic Diseases |
Precancerous Conditions Azacitidine Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Pharmacologic Actions Antineoplastic Agents Therapeutic Uses Enzyme Inhibitors |
ClinicalTrials.gov processed this record on June 18, 2013