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

Conditions: Myelodysplastic Syndrome; Acute Myeloid Leukemia

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.

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 criteria:
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 \ 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.

Keywords: myelodysplastic syndrome (mds) acute myeloid leukemia (aml) stem cell transplantation 5-azacitidine donor lymphocyte infusion mds or aml relapsed after stem cell transplantation