Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR

Study Overview
=================
Brief 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).

Detailed Description
-----------------
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.

Official Title
-----------------
Epigenetic Priming With 5-Azacytidine Prior to in Vivo T-cell Depleted Allogeneic Stem Cell Transplantation for Patients With High Risk Myeloid Malignancies in Morphologic Remission

Conditions
-----------------
Leukemia, Erythroblastic, Acute, Myelodysplastic Syndromes

Intervention / Treatment
-----------------
* Drug: 5-Azacytidine
* Drug: Fludarabine
* Drug: Melphalan
* Drug: Alemtuzumab
* Radiation: Total Body Irradiation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically or cytologically confirmed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) as specified below: 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 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 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 Acute myeloid leukemia in first complete morphologic remission, having required more than one course of induction chemotherapy to attain remission status; or Acute myeloid leukemia, all types, excluding M3 (Promyelocytic leukemia) in second or higher complete morphologic remission; or Myelodysplastic syndromes (intermediate-2, high risk and chronic myelomonocytic leukemia (CMML) with bone marrow blasts <5%); or 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5 Azacytidine<br>Patients will be given a five day course of subcutaneous 5-azacytidine, followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. | Drug: 5-Azacytidine<br>* Patients will be given a five day course of subcutaneous 5-azacytidine followed by a reduced intensity conditioning regimen of fludarabine and melphalan with or without total body irradiation prior to an allogeneic hematopoietic stem cell transplantation from a related or unrelated HLA matched donor. 5-Azacytidine 75 mg/m2 subcutaneously daily at the same time on days -11, -10, -9, -8 and -7. This will be administered on an outpatient basis if possible.<br>* Other names: Vidaza;Drug: Fludarabine<br>* Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Fludarabine will be given at 40 mg/m2 intravenously daily at the same time over 30 minutes on days -6,-5,-4,-3.<br>* Other names: Fludara;Drug: Melphalan<br>* Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Melphalan will be given at 140 mg/m2 IV on day -3.<br>* Other names: Alkeran;Drug: Alemtuzumab<br>* Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Alemtuzumab will be given at 30 mg subcutaneously on Days -4 and -2 for unrelated donors, and Day -2 for related donors.<br>* Other names: Campath, Lemtrada;Radiation: Total Body Irradiation<br>* Conditioning regimen: Hospital admission will usually take place on the first day of the conditioning regimen. Total Body Irradiation (TBI) will be given at 2 doses of 200 cGy each on one day of the conditioning regimen (between days -6 and -3).<br>* Other names: TBI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival at 1 Year Post-transplant | Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 1 year post-transplant. | 1 year post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival at 6 Months Post-transplant | Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 6 months post-transplant | 6 months post-transplant | 
| Disease Free Survival at 2 Years Post-transplant | Number of participants without evidence of progression of underlying malignancy for which the transplant was performed, assessed at 2 years post-transplant. | 2 years post-transplant | 
| Overall Survival at 6 Months Post-transplant | Number of participants alive at 6 months post-transplant | 6 months post-transplant | 
| Overall Survival at 1 Year Post-Transplant | Number of participants alive at 1 year post-transplant | 1 year post-transplant | 
| Overall Survival at 2 Years Post-Transplant | Number of participants alive at 2 years post-transplant | 2 years post-transplant | 
| Graft Failure | Number of patients who experience graft failure, defined as the absence of neutrophil engraftment by Day +21 or a drop in the absolute neutrophil count to <0.3 cells/microL for five consecutive days occurring after initial neutrophil engraftment within the first 3 weeks post-transplantation. | 21 days post-transplant | 
| Acute Graft-versus-Host Disease (GVHD) | Number of patients who develop acute graft-versus-host disease of any grade. | 2 years post-transplant | 
| High-Risk Extensive Chronic Graft-versus-Host-Disease | Number of patients who develop high-risk extensive chronic graft-versus-host disease. Extensive chronic GVHD is defined as generalized skin or multiple organ involvement. High risk chronic GVHD is defined as platelet count of less than 100k/microL | 2 years post-transplant |