Myelodysplastic Syndrome, Acute Myeloid Leukemia
Conditions
Keywords
Myelodysplastic syndrome (MDS), Acute myeloid leukemia (AML), Stem cell transplantation, 5-Azacitidine, Donor lymphocyte infusion, MDS or AML relapsed after stem cell transplantation
Brief 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.
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.
Interventions
DRUG5-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.
Sponsors
Heinrich-Heine University, Duesseldorf
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Best response | within the 6 months of treatment |
Secondary
| Measure | Time frame |
|---|---|
| Response rate | within 6 months |
| Duration of remissions | within 3 years |
| Safety and Toxicity of 5-Azacitidine for patients relapsing after allo-SCT | within 3 years |
| Achievement of complete chimerism | 6 month |
| Toxicity | wtihin 3 years |
| Incidence of acute and chronic GvHD | 3 years |
Countries
Germany
Outcome results
None listed