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

Acute Myeloid Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00795548
• Other study ID #: AZARELA_HHU_2007
• Status: Completed
• Phase: Phase 2
• First received: November 20, 2008
• Last updated: January 20, 2012
• Start date: November 2008
• Est. completion date: August 2011

Study information

• Verified date: January 2012
• Source: Heinrich-Heine University, Duesseldorf
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: August 2011
• Est. primary completion date: October 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

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.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Heinrich-Heine University, Duesseldorf

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Best response		within the 6 months of treatment	No
Secondary	Safety and Toxicity of 5-Azacitidine for patients relapsing after allo-SCT		within 3 years	Yes
Secondary	Response rate		within 6 months	No
Secondary	Duration of remissions		within 3 years	No
Secondary	Incidence of acute and chronic GvHD		3 years	Yes
Secondary	Achievement of complete chimerism		6 month	No
Secondary	Toxicity		wtihin 3 years	Yes