Decitabine and Total-Body Irradiation Followed By Donor Bone Marrow Transplant and Cyclophosphamide in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how well decitabine and total-body irradiation followed by donor bone marrow transplant and cyclophosphamide works in treating patients with relapsed or refractory acute myeloid leukemia. Giving decitabine and total-body irradiation before a donor bone marrow transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving decitabine and total-body irradiation before the transplant together with high-dose cyclophosphamide, tacrolimus, and mycophenolate mofetil after the transplant may stop this from happening.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine overall survival at 100 days after transplantation following decitabine and a bone marrow transplant using a donor that is at least partially-matched and a myeloablative preparative regimen with post-transplantation cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis. SECONDARY OBJECTIVES: I. Patients enrolled in this study will also be followed for the following endpoints: neutrophil and platelet recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, incidence of infection, treatment-related mortality, time to relapse/progression, overall survival, and progression-free survival. OUTLINE: Beginning between days -29 and -22, patients receive decitabine intravenously (IV) over 1 hour daily for 10 days, fludarabine phosphate IV over 30 minutes on days -5 to -2, and busulfan IV over 3 hours on days -5 to -2. PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily (BID) on day -1. TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus orally (PO) BID or IV continuously on days 5-180, mycophenolate mofetil PO three times daily (TID) on days 5-35 and filgrastim subcutaneously (SC) beginning day 5 until absolute neutrophil count (ANC) >= 1,000/mm^3 for 3 consecutive days. After completion of study treatment, patients are followed up at 6 months and 1 year.

Official Title
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Decitabine Followed by Bone Marrow Transplant and High-Dose Cyclophosphamide for the Treatment of Relapsed and Refractory Acute Myeloid Neoplasms

Conditions
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Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), de Novo Myelodysplastic Syndromes, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: decitabine
* Drug: fludarabine phosphate
* Drug: busulfan
* Drug: cyclophosphamide
* Drug: tacrolimus
* Drug: mycophenolate mofetil
* Biological: filgrastim
* Radiation: total-body irradiation
* Procedure: allogeneic bone marrow transplantation
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet one of two disease criteria: Acute myelogenous leukemia (AML) within one of the following categories: Primary induction failure (PIF): patients who have not achieved a complete remission following initial diagnosis and after at least two induction cycles of chemotherapy consisting of cytarabine and an anthracycline or high-dose cytarabine Relapsed AML: Patients are defined as having relapsed disease if they entered a complete remission confirmed with a bone marrow biopsy following initial treatment, and then were found to have morphological or cytogenetic evidence of recurrent disease on a subsequent bone marrow exam Any complete remission (CR) 2 or greater: CR must be defined using a bone marrow exam taken at least 21 days since the last chemotherapy (including a methyltransferase inhibitor), and may include CRp (morphologic CR without peripheral platelet recovery) CR1 with high-risk features: includes patients with treatment-related AML, secondary AML (following myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN)), high-risk cytogenetic or molecular phenotype (by National Comprehensive Cancer Network (NCCN) criteria) Untreated AML (> 20% blasts on a bone marrow) arising from a previous confirmed diagnosis of MDS or MPN (excluding BCR-ABL (a genetic mutation) positive diseases). Myelodysplastic syndromes within one of the following categories: High-risk myelodysplastic syndrome (MDS) at diagnosis as defined by the International Prognostic Scoring System (IPSS) or World Health Organization (WHO) classification based Prognostic Scoring System (WPSS) Transfusion dependent MDS (either red blood cells (RBC) or platelet dependent) without a hematologic response to at least 4 months of methyltransferase inhibitor (MTI) therapy; hematological response is defined as transfusion independence for two or more months Progressive MDS following at least 4 months of MTI therapy; progression is defined as resumption of transfusion dependence after at least two months of transfusion independence OR increase of marrow blasts by 50% from pretreatment OR overall blasts over 10% of marrow cells at any time after treatment Available related donor that is at least an allele level haplotype-match at human leukocyte antigen (HLA)- A, B, C, DP Beta 1 (DRB1) and DPB1 loci (DPB1 matching according to the permissive - non-permissive dichotomy as stated by University of Wisconsin (UW) Histocompatibility Laboratory); a minimum match of 5/10 loci is required; an unrelated donor search is not required for a patient to be eligible for this protocol Karnofsky score of 60% or better (requires occasional assistance, but is able to care for most of his/her needs) Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected for hemoglobin > 40%; and forced expiratory volume in one second (FEV1) > 50% Ejection fraction (EF) >= 50% and no uncontrolled angina, symptomatic ventricular arrhythmias, or electrocardiogram (ECG) evidence of active ischemia Serum creatinine within normal range for age, or if serum creatinine outside normal range, then renal function (estimated glomerular filtration rate (GFR) by modification of diet in renal disease (MDRD) formula) > 40 mL/min/1.73 m^2 Women of child bearing potential must have a negative pregnancy test within 14 days prior to study registration and agree to use adequate birth control during study treatment Voluntary written consent Patients must be 28 days from the end of the last induction course or at least 14 days from completion of previous methyltransferase inhibitor therapy (azacitidine or decitabine) at the time of registration DONOR: Donors must be at least HLA-haploidentical first degree relatives of the patients; eligible donors include biological parents, siblings, half-siblings or children DONOR: Age >= 18 years and =< 60 years DONOR: Donors must meet the selection criteria prior to the start of the recipient's pre-transplant conditioning regimen as defined by the Foundation for the Accreditation of Cell Therapy (FACT) and will be screened according to the American Association of Blood Banks (AABB) guidelines and UW Bone Marrow Transplant (BMT) program standard operating procedure (SOP) Exclusion Criteria: Active central nervous system (CNS) leukemia within two weeks of registration; patients with a history of CNS leukemia must have adequate treatment as defined by at least two negative spinal fluid assessments separated by at least one week; patients who have received cranial radiation therapy (XRT) must still be eligible to receive total body irradiation to 4 Gy New or active infection as determined by fever, unexplained pulmonary infiltrate or sinusitis on radiographic assessment; infections diagnosed within 4 weeks of registration must be determined to be controlled or resolving prior to treatment Active human immunodeficiency virus (HIV), hepatitis A, B or C infection Allergy or hypersensitivity to agents used within the treatment protocol DONOR: Recipient derived anti-donor high-titer (> 3000 MFI) HLA antibody as determined by Luminex assay DONOR: Not suitable for donation according to UW BMT program donor selection SOP

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (donor bone marrow transplant)<br>Beginning between days -29 and -22, patients receive decitabine IV over 1 hour daily for 10 days, fludarabine phosphate IV over 30 minutes on days -5 to -2, and busulfan IV over 3 hours on days -5 to -2. PREPARATIVE REGIMEN: Patients undergo total-body irradiation BID on day -1. TRANSPLANT: Patients undergo allogeneic bone marrow transplant on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2 hours on days 3 and 4, tacrolimus PO BID or IV continuously on days 5-180, mycophenolate mofetil PO TID on days 5-35, and filgrastim SC beginning day 5 until ANC >= 1,000/mm^3 for 3 consecutive days. | Drug: decitabine<br>* Given IV<br>* Other names: decitabine (DAC);Drug: fludarabine phosphate<br>* Given IV<br>* Other names: Fludara;Drug: busulfan<br>* Given IV<br>* Other names: Myeloleukon;Drug: cyclophosphamide<br>* Given IV<br>* Other names: Endoxana;Drug: tacrolimus<br>* Given PO or IV<br>* Other names: Prograf;Drug: mycophenolate mofetil<br>* Given PO<br>* Other names: mycophenolate mofetil (MMF);Biological: filgrastim<br>* Given SC<br>* Other names: Neupogen;Radiation: total-body irradiation<br>* Undergo total-body irradiation<br>* Other names: total body irradiation (TBI);Procedure: allogeneic bone marrow transplantation<br>* Undergo allogeneic bone marrow transplantation<br>* Other names: transplantation, allogenic bone marrow;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Will be analyzed using Kaplan-Meier (KM) method, and OS will be obtained from the KM estimates along with 95% confidence intervals. | Day 100 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Neutrophil Recovery | Defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/ul for three consecutive measurements on different days. Will be summarized with mean and standard deviation or median and interquartile range, and the change will be tested using a one-sample paired t-test at a two-tailed significance level of 0.05. | Up to 1 year | 
| Percentage of Participants With Platelet Recovery by Day 30 | Platelet recovery is defined as the first day of a platelet count greater than 20,000/mm^3 with no platelet transfusions. Will be summarized with mean and standard deviation or median and interquartile range, and the change will be tested using a one-sample paired t-test at a two-tailed significance level of 0.05. | Up to day 30 | 
| Number of Participants With Primary Graft Failure | Defined as less than 5% donor chimerism in the cluster of differentiation (CD)3 and CD33 selected cell populations at any time after transplantation. Will be analyzed using KM method. | Day 30 | 
| Cumulative Incidence of Grade III-IV Acute GVHD | Determined by the standard bone marrow transplant (BMT) Clinical Trials Network criteria (BMTCTN). Will be analyzed using KM method, a Graft versus Host Disease (GVHD) grade III-IV will be obtained from the KM estimates along with 95% confidence intervals. | Day 100 | 
| Cumulative Incidence of Chronic GVHD According to BMTCTN | Will be summarized with a proportion and a 95% confidence interval. | Up to 1 year | 
| Number of Participants With Complete Remission After Transplantation |  | Up to 1 year | 
| Progression Free Survival |  | Up to 1 year |