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.
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:<2.0 mg/dL; Alanine Aminotransferase (ALT) (SGPT): <3 x upper limit of
normal; Creatinine Clearance:>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
