Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation
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Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL); however, human leukocyte antigen (HLA)-matched donor availability continues to be a major hurdle. Historically, HLA haploidentical donor hematopoietic cell transplantation (haplo-HCT) was associated with high incidences of graft rejection and excessive non-relapse mortality (NRM), but recent advances utilizing post-transplant cyclophosphamide (PT-Cy) have revolutionized haplo-HCT and the outcomes are now comparable to allo-HCT using more traditional HLA matched related and unrelated donors. However, graft-versus-host disease (GvHD) continues to be a problem and is associated with significant morbidity and mortality in allo-HCT patients including those who receive haplo-HCT on PT-Cy platform. The aim of this early phase study is to investigate the safety and overall efficacy of azacitidine in reducing the incidence and severity of GvHD when added to PT-Cy based haplo-HCT platform for patients with AML, ALL, or advanced MDS.
Drug: FludarabineRadiation: Fractionated total body irradiationDrug: BusulfanDrug: CyclophosphamideRadiation: Single dose total body irradiationDrug: MelphalanDrug: Granulocyte-colony stimulating factorProcedure: Stem cell transplantDrug: Azacitidine
Safety of azacitidine (Phase I only) as measured by frequency and grade of adverse events [ Time Frame: Up to Day 35 ]
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
Maximum tolerated dose of azacitidine (Phase I only) [ Time Frame: Estimated to be 3-4 months (completion of all Phase I patients through Day 35) ]
Grade II-IV acute GvHD rate of azacitidine (Phase II only) [ Time Frame: Up to Day 100 ]
Secondary Outcome Measures :
Event-free survival (EFS) [ Time Frame: Up to 48 months ]
EFS is defined as the time from date of first dose of the preparative regimen until failure to engraft, treatment failure, disease progression/relapse, or death from any cause (whichever occurs first).
Overall survival (OS) [ Time Frame: Up to 48 months ]
OS is defined as the time from the date of Day 0 until death from any cause.
Disease-free survival (DFS) [ Time Frame: Up to 48 months ]
Non-relapse mortality (NRM) [ Time Frame: Up to Day 100 ]
NRM is defined as death that results from a transplant procedure-related complication (e.g. infection, organ failure, hemorrhage, GvHD) rather than from relapse of the underlying disease prior to Day +100 visit.
Time to neutrophil engraftment [ Time Frame: Up to 12 months ]
Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/ul following conditioning regimen-induced nadir.
Time to platelet engraftment [ Time Frame: Up to 12 months ]
Time to platelet engraftment is measured by determining the first of 3 consecutive measurements of platelet count ≥ 20,000/ul without platelet transfusion support for 7 days.
Rate of acute GvHD [ Time Frame: Up to Day 100 ]
Incidence and severity of acute GvHD will be assessed based on the modified Glucksberg criteria and Seattle criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).
Rate of chronic GvHD [ Time Frame: Day 100 through Day 365 ]
Incidence and severity of chronic GvHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).
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Layout table for eligibility information
Ages Eligible for Study:
18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:
Accepts Healthy Volunteers:
Diagnosis of acute leukemia (AML/ALL) or advanced MDS (INT-2 or high risk) in complete remission (CR/CRc/CRi) documented by bone marrow biopsy done within 30 days prior to the initiation of conditioning regimen.
Available HLA-haploidentical donor that meets the following criteria:
Immediate family member (sibling, offspring, or parent)
At least 18 years of age
HLA-haploidentical donor/recipient match by class I serologic typing at the A&B locus.
In the treating physician's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting HSC
No active hepatitis (B, C), HTLV, and HIV infections
Karnofsky performance status ≥ 70 %
Adequate organ function as defined below:
Total bilirubin ≤ 2.5 mg/dl (unless the patient has a history of Gilbert's syndrome)
AST(SGOT) and ALT(SGPT) ≤ 3.0 x IULN
Creatinine ≤ 2.0 x IULN OR estimated creatinine clearance ≥ 30 mL/min/1.73 m^2 by Cockcroft-Gault Formula