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
Conditions
Brief summary
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
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.
Interventions
OTHERlaboratory biomarker analysis
Correlative studies
DRUGdecitabine
Given IV
DRUGfludarabine phosphate
Given IV
DRUGbusulfan
Given IV
DRUGcyclophosphamide
Given IV
DRUGtacrolimus
Given PO or IV
DRUGmycophenolate mofetil
Given PO
BIOLOGICALfilgrastim
Given SC
RADIATIONtotal-body irradiation
Undergo total-body irradiation
PROCEDUREallogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplantation
Sponsors
National Cancer Institute (NCI)
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Day 100 | Will be analyzed using Kaplan-Meier (KM) method, and OS will be obtained from the KM estimates along with 95% confidence intervals. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Platelet Recovery by Day 30 | Up to 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. |
| Number of Participants With Primary Graft Failure | Day 30 | 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. |
| Cumulative Incidence of Grade III-IV Acute GVHD | Day 100 | 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. |
| Time to Neutrophil Recovery | Up to 1 year | 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. |
| Number of Participants With Complete Remission After Transplantation | Up to 1 year | — |
| Progression Free Survival | Up to 1 year | — |
| Cumulative Incidence of Chronic GVHD According to BMTCTN | Up to 1 year | Will be summarized with a proportion and a 95% confidence interval. |
Countries
United States
Participant flow
Recruitment details
Recruitment of high risk BMT patients with active disease at time of transplant or very high risk to relapse post-transplant.
Participants by arm
| Arm | Count |
|---|---|
| Decitabine + Bone Marrow Transplant Pre-transplant Decitabine followed by Bone Marrow Transplant. | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 3 |
Baseline characteristics
| Characteristic | Decitabine + Bone Marrow Transplant |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Disease Risk by DRI High Risk | 13 Participants |
| Disease Risk by DRI Intermediate Risk | 2 Participants |
| Disease Risk by DRI Low Risk | 0 Participants |
| Disease Risk by DRI Very High Risk | 5 Participants |
| Disease Status AML | 15 participants |
| Disease Status CR1 with high risk features | 2 participants |
| Disease Status MDS | 5 participants |
| Disease Status Primary Induction Failure | 6 participants |
| Disease Status Relapsed Disease | 7 participants |
| Donor Type Haplo-identical | 12 Participants |
| Donor Type Matched Related | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| HCT-CI Score 0 | 5 Participants |
| HCT-CI Score 1-2 | 7 Participants |
| HCT-CI Score 3+ | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 15 / 20 | 13 / 17 |
| other Total, other adverse events | 20 / 20 | 17 / 17 |
| serious Total, serious adverse events | 0 / 20 | 12 / 17 |
Outcome results
Primary
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.
Time frame: Day 100
Population: (2 patients did not receive a transplant due to infectious complications, 1 patient received transplant off protocol)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Overall Survival (OS) | 64.7 percentage of participants |
Secondary
Cumulative Incidence of Chronic GVHD According to BMTCTN
Will be summarized with a proportion and a 95% confidence interval.
Time frame: Up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Cumulative Incidence of Chronic GVHD According to BMTCTN | 40.7 percentage |
Secondary
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.
Time frame: Day 100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Cumulative Incidence of Grade III-IV Acute GVHD | 27.8 percentage of participants |
Secondary
Number of Participants With Complete Remission After Transplantation
Time frame: Up to 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Number of Participants With Complete Remission After Transplantation | 14 Participants |
Secondary
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.
Time frame: Day 30
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Number of Participants With Primary Graft Failure | 0 Participants |
Secondary
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.
Time frame: Up to day 30
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Percentage of Participants With Platelet Recovery by Day 30 | 58 percentage with plt engraftment, day 30 |
Secondary
Progression Free Survival
Time frame: Up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Progression Free Survival | 141 days |
Secondary
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.
Time frame: Up to 1 year
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Decitabine + Bone Marrow Transplant | Time to Neutrophil Recovery | 16 days |