azacytidine prior to in vivo t-cell depleted allo stem cell transplant for patients with myeloid malignancies in cr

Conditions: Leukemia, Erythroblastic, Acute; Myelodysplastic Syndromes

Summary: the purpose of this study is to determine whether 5-azacytidine priming before the conditioning regimen for subjects receiving a hematopoietic stem cell transplant is an effective treatment for high risk myeloid malignancies in complete remission (cr).

this open label two-step phase ii study is designed to determine the safety and efficacy of epigenetic priming with 5-azacytidine immediately prior to reduced intensity conditioning for an in vivo t-cell depleted hematopoietic stem cell transplantation for high risk myeloid malignancies in complete remission (cr). subjects will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine, melphalan and total body irradiation (tbi) prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated human leukocyte antigen (hla) matched donor. the effect of 5-azacytidine on global gene methylation will be assessed. evaluations for safety, in particular for graft failure, transplant related mortality and acute graft versus host disease will be made on a weekly basis. efficacy, as defined by disease free survival, will be evaluated with a bone marrow biopsy at the standard time points, which are one-, three-, six-, and twelve-months after transplant and upon clinical suspicion within regular follow-up visits - weekly for the first 3 months, then biweekly for 3 months, then monthly until one-year post-stem cell transplant. thereafter, unless otherwise dictated by the clinical scenario, the follow up visits will be every 3 months.

Eligibility criteria:
inclusion criteria: * patients must have histologically or cytologically confirmed acute myeloid leukemia (aml) or myelodysplastic syndrome (mds) as specified below: 1. acute myeloid leukemia with poor risk cytogenetics in complete morphologic remission. these include: del (5q)/-5, del (7q)/-7, abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (≥ 3 unrelated abnormalities); or 2. acute myeloid leukemia with either flt-3, tet-2, p53, dnmt3a, or asxl1 mutation, mutations of genes involved in the chromatin/spliceosome category (ezh2, srsf2, u2af1, zrsr2), bcor, and runx1, as well as mll rearrangement, evi1 overexpression in complete morphologic remission; or 3. acute myeloid leukemia with a white blood cell count of greater than or equal to 50,000/mcl at presentation in first complete morphologic remission; or 4. acute myeloid leukemia in first complete morphologic remission, having required more than one course of induction chemotherapy to attain remission status; or 5. acute myeloid leukemia, all types, excluding m3 (promyelocytic leukemia) in second or higher complete morphologic remission; or 6. myelodysplastic syndromes (intermediate-2, high risk and chronic myelomonocytic leukemia (cmml) with bone marrow blasts \<5%); or 7. secondary acute myeloid leukemia on the basis of prior mds or prior myeloproliferative neoplasm (mpn) in complete morphologic remission * life expectancy not severely limited by concomitant disease * karnofsky performance score greater than or equal to 70%. * adequate organ function as defined below: serum bilirubin:\ 60 ml/min (egfr as estimated by the modified modification of diet in renal disease study (mdrd) equation) - ability to understand and the willingness to sign a written informed consent document. exclusion criteria: * evidence of chronic active hepatitis or cirrhosis * hiv infection * uncontrolled illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * pregnant and lactating women are excluded from the study because the risks to an unborn fetus or potential risks in nursing infants are unknown. * there are no prior therapies or concomitant medications that would render the patients ineligible