Azacytidine Prior to in Vivo T-cell Depleted Allo Stem Cell Transplant for Patients With Myeloid Malignancies in CR
- Conditions
- Leukemia, Erythroblastic, AcuteMyelodysplastic Syndromes
- Interventions
- Radiation: Total Body Irradiation
- Registration Number
- NCT02497404
- Lead Sponsor
- Weill Medical College of Cornell University
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
-
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.
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 5 Azacytidine Total Body Irradiation 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 5-Azacytidine 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 Fludarabine 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 Melphalan 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 Alemtuzumab 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.
- Primary Outcome Measures
Name Time Method Disease Free Survival at 1 Year Post-transplant 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.
- Secondary Outcome Measures
Name Time Method Graft Failure 21 days post-transplant 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.
Acute Graft-versus-Host Disease (GVHD) 2 years post-transplant Number of patients who develop acute graft-versus-host disease of any grade.
Overall Survival at 6 Months Post-transplant 6 months post-transplant Number of participants alive at 6 months post-transplant
Overall Survival at 1 Year Post-Transplant 1 year post-transplant Number of participants alive at 1 year post-transplant
Disease Free Survival at 6 Months Post-transplant 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
Disease Free Survival at 2 Years Post-transplant 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.
Overall Survival at 2 Years Post-Transplant 2 years post-transplant Number of participants alive at 2 years post-transplant
High-Risk Extensive Chronic Graft-versus-Host-Disease 2 years post-transplant 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
Trial Locations
- Locations (1)
Weill Cornell Medical College
🇺🇸New York, New York, United States