Leukemia, Myelocytic, Acute
Conditions
Keywords
Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Brief summary
The study is designed as a Phase III, multicenter trial comparing outcomes after allogeneic hematopoietic stem cell transplantation (HCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) between patients receiving myeloablative conditioning (MAC) versus reduced intensity conditioning (RIC) regimens.
Detailed description
Patients randomized to RIC will receive one of two regimen types: the combination of fludarabine (120-180 mg/m\^2) and busulfan (less than or equal to 8 mg/kg or IV equivalent) (Flu/Bu) or fludarabine (120-180 mg/m\^2) and melphalan (less than 150 mg/m\^2) (Flu/Mel). Patient randomized to MAC will receive one of three regimens: busulfan (16 mg/kg oral or 12.8 mg/kg IV equivalent) and cyclophosphamide (120 mg/kg) (Bu/Cy); or, busulfan (16 mg/kg PO or 12.8 mg/kg IV) and fludarabine (120-180 mg/m\^2) (Bu/Flu); or, cyclophosphamide (120 mg/kg) and total body irradiation (greater than 1200-1420cGy) (CyTBI). A total of 356 patients (178 to each arm) will be accrued on this study over a period of four years. Patients will be followed for up to 18 months from transplantation.
Interventions
(Flu/Bu) * Fludarabine: 30 mg/m\^2/day on Days -6 to -2 (total dose of 150 mg/m\^2) * Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4
(Flu/Mel) * Fludarabine: 30 mg/m\^2/day on Days -5 to -2 (total dose of 120 mg/m\^2) * Melphalan: 140 mg/m\^2 on Day -2
(Bu/Flu) * Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m\^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -5 to -2 * Fludarabine: 30 mg/m\^2/day on Days -5 to -2: Flu (total dose of 120 mg/m\^2)
DRUGBusulfan and Cyclophosphamide
(Bu/Cy) * Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m\^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -7 to -4 * Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)
(Cy/TBI) * TBI: 1200-1420 cGy on Days -7 to -4 * Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Blood and Marrow Transplant Clinical Trials Network
National Marrow Donor Program
Medical College of Wisconsin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Age equal or less than 65 years old and equal to or greater than 18 years old. * Patients with the diagnosis of MDS or AML with fewer than 5% myeloblasts in the bone marrow and no leukemic myeloblasts in the peripheral blood on morphologic analysis performed within 30 days of start of the conditioning regimen enrollment. * For patients receiving treatment of their MDS or AML prior to transplantation: a)Interval between the start of the most recent cycle of conventional cytotoxic chemotherapy and enrollment must be at least 30 days; b)Interval between completing treatment with a hypomethylating agent or other non-cytotoxic chemotherapy and enrollment must be at least 10 days. * Patients must have a related or unrelated bone marrow or peripheral blood donor who is human leukocyte antigen (HLA)-matched at 7 or 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. * HCT-Specific Comorbidity Index Score (HCT-CI) less than or equal to 4. * Organ function: a) Cardiac function: Ejection fraction greater than or equal to 40%; b) Hepatic function: total bilirubin less than or equal to 2 times the upper limit of normal and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal to 3 times the upper limit of normal.; c)Pulmonary function: Diffusing capacity of the lung for carbon monoxide (DLCO) greater than or equal to 40% and forced expiratory volume in one second (FEV1) greater than or equal to 50% (corrected for hemoglobin). * Creatinine clearance greater than or equal to 50mL/min based on the Cockcroft-Gault formula. * Signed informed consent.
Exclusion criteria
* Prior allograft or prior autograft. * Symptomatic coronary artery disease. * Leukemia involvement in the central nervous system (CNS) within 4 weeks of enrollment for patients with a history of prior CNS leukemia involvement (i.e., leukemic blasts previously detected in the cerebral spinal fluid). * Karnofsky Performance Score less than 70. * Patients receiving supplemental oxygen. * Planned use of donor lymphocyte infusion (DLI) therapy. * Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms). * Patients seropositive for the human immunodeficiency virus (HIV). * Patients with prior malignancies, except resected basal cell carcinoma or treated cervical carcinoma in situ. Cancer treated with curative intent greater than 5 years previously. Cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs. * Females who are pregnant or breastfeeding. * Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Overall Survival (OS) | 18 months post-randomization | Overall survival is defined as survival of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Disease Relapse | 18 months post-randomization | Disease Relapse is defined as relapse of the primary disease. |
| Percentage of Participants With Treatment-related Mortality | 18 months post-randomization | Treatment-related mortality is defined as death without a previous relapse of the primary disease. |
| Percentage of Participants With Neutrophil and Platelet Engraftment | Days 28 and 60 post-transplant | Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10\^6/liter for 3 consecutive measurements on different days. The first of the 3 days will be designated the day of neutrophil engraftment. Platelet engraftment is defined as achieving platelet counts greater than 20,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days. |
| Number of Participants With Donor Cell Engraftment | Days 28 and 100 and 18 months post-transplant | Donor cell engraftment will be assessed by donor-recipient chimerism assays. Full donor chimerism is defined as the presence of at least 95% donor cells as a proportion of the total population in the peripheral blood or bone marrow. Graft rejection is defined as the presence of no more than 5% donor cells as a proportion of the total population. Mixed chimerism is defined as the presence of between 5% and 95% donor cells. Mixed or full donor chimerism will be considered evidence of donor engraftment. |
| Percentage of Participants With Acute Graft Versus Host Disease (GVHD) | Day 100 post-transplant | Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash 1. Rash \<25% of body surface area 2. Rash on 25-50% of body surface area 3. Rash on \> 50% of body surface area 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 |
| Percentage of Participants With Chronic GVHD | 18 months post-transplant | Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification. |
| Percentage of Participants With Relapse-Free Survival (RFS) | 18 months post-randomization | Relapse-free survival is defined as survival without relapse of the primary disease. |
| Number of Participants With Primary Graft Failure | 28 days post-transplant | Primary graft failure is defined by lack of neutrophil engraftment. |
| Number of Participants With Secondary Graft Failure | 18 months post-transplant | Secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts to less than 500x10\^6/liter that is unresponsive to growth factor therapy. |
| Number of Participants With Maximum Grade 3-5 Toxicities | 18 months | The maximum grade of toxicities reported by participants over the study duration are tabulated. Per the CTCAE criteria, toxicities are graded on a scale of 0-5, with higher numbers indicating greater severity. The categories correspond as follows: 3 - severe; 4 - life-threatening; 5 - fatal |
| Infection Type | 18 months post-transplant | The number and types of infection events reported are tabulated. |
| Number of Participants With Infections | 18 months post-transplant | The maximum severity of infections reported by participants are tabulated. The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of severe, life-threatening, or fatal infections will be compared between the two treatment arms at 6, 12, and 18 months from transplant or until death. |
| Number of Participants With Cause of Death | 18 months post-randomization | Primary cause of death was adjudicated using previously described criteria (Copelan et al. 2007). When relapse occurred, it was considered the primary cause of death regardless of other events. |
| Number of Participants With Chronic GVHD Severity | 18 months post-transplant | Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between June 2011 and April 2014 from 32 transplant centers
Participants by arm
| Arm | Count |
|---|---|
| Myeloablative Conditioning Regimen (MAC) One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation.
Busulfan and Fludarabine: (Bu/Flu)
* Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or mg/m\^2/day with Bu Css 900±100 ng/mL (total dose of 16 mg/kg, 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -5 to -2
* Fludarabine: 30 mg/m\^2/day on Days -5 to -2: Flu (total dose of 120 mg/m\^2)
Busulfan and Cyclophosphamide: (Bu/Cy)
* Busulfan: 4 mg/kg/day PO, 3.2 mg/kg/day IV or 130 mg/m\^2/day with Bu Css 900 ± 100 ng/mL (total dose of 16 mg/kg or 12.8 mg/kg or 520 mg/m\^2, respectively) on Days -7 to -4
* Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg)
Cyclophosphamide and Total Body Irradiation: (Cy/TBI)
* TBI: 1200-1420 cGy on Days -7 to -4
* Cyclophosphamide: 60 mg/kg/day on Days -3 to -2 (total dose of 120 mg/kg) | 135 |
| Reduced Intensity Conditioning (RIC) One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan.
Fludarabine and Busulfan: (Flu/Bu)
* Fludarabine: 30 mg/m\^2/day on Days -6 to -2 (total dose of 150 mg/m\^2)
* Busulfan: 4 mg/kg/day PO or 3.2 mg/kg/day (total dose of 8 mg/kg or 6.4 mg/kg, respectively) on Days -5 to -4
Fludarabine and Melphalan: (Flu/Mel)
* Fludarabine: 30 mg/m\^2/day on Days -5 to -2 (total dose of 120 mg/m\^2)
* Melphalan: 140 mg/m\^2 on Day -2 | 137 |
| Total | 272 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease relapse | 1 | 4 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Myeloablative Conditioning Regimen (MAC) | Reduced Intensity Conditioning (RIC) |
|---|---|---|---|
| Age, Continuous | 54.8 years | 54.8 years | 54.8 years |
| AML WHO Classification AML and MDS, therapy related | 5 Participants | 2 Participants | 3 Participants |
| AML WHO Classification AML, not otherwise specified | 161 Participants | 86 Participants | 75 Participants |
| AML WHO Classification AML with multilineage dysplasia | 20 Participants | 8 Participants | 12 Participants |
| AML WHO Classification AML with recurrent genetic abnormalities | 32 Participants | 12 Participants | 20 Participants |
| ATG Use No | 232 Participants | 117 Participants | 115 Participants |
| ATG Use Yes | 40 Participants | 18 Participants | 22 Participants |
| Conditioning Regimen Bu/Cy | 40 Participants | 40 Participants | 0 Participants |
| Conditioning Regimen Cy/TBI | 8 Participants | 8 Participants | 0 Participants |
| Conditioning Regimen Flu/Bu2 | 110 Participants | 0 Participants | 110 Participants |
| Conditioning Regimen Flu/Bu4 | 87 Participants | 87 Participants | 0 Participants |
| Conditioning Regimen Flu/Mel | 27 Participants | 0 Participants | 27 Participants |
| Disease Duration | 6 months | 6 months | 6 months |
| Disease Risk Status High | 115 Participants | 54 Participants | 61 Participants |
| Disease Risk Status Standard | 145 Participants | 74 Participants | 71 Participants |
| Disease Risk Status Unknown | 12 Participants | 7 Participants | 5 Participants |
| Donor Source Bone Marrow | 22 Participants | 8 Participants | 14 Participants |
| Donor Source Peripheral Blood | 250 Participants | 127 Participants | 123 Participants |
| Donor Type Matched Related | 115 Participants | 57 Participants | 58 Participants |
| Donor Type Matched Unrelated | 124 Participants | 66 Participants | 58 Participants |
| Donor Type Mismatched Related | 7 Participants | 2 Participants | 5 Participants |
| Donor Type Mismatched Unrelated | 26 Participants | 10 Participants | 16 Participants |
| GVHD Prophylaxis Cyclosporine / Methotrexate | 6 Participants | 3 Participants | 3 Participants |
| GVHD Prophylaxis Cyclosporine / Mycophenolate mofetil | 1 Participants | 1 Participants | 0 Participants |
| GVHD Prophylaxis Other | 8 Participants | 3 Participants | 5 Participants |
| GVHD Prophylaxis Sirolimus / Tacrolimus | 22 Participants | 10 Participants | 12 Participants |
| GVHD Prophylaxis TAC / Mycophenolate mofetil | 13 Participants | 8 Participants | 5 Participants |
| GVHD Prophylaxis Tacrolimus / Methotrexate | 222 Participants | 110 Participants | 112 Participants |
| HCT-CI 0 | 86 Participants | 46 Participants | 40 Participants |
| HCT-CI 1-2 | 97 Participants | 45 Participants | 52 Participants |
| HCT-CI 3 or more | 86 Participants | 42 Participants | 44 Participants |
| HCT-CI Unknown | 3 Participants | 2 Participants | 1 Participants |
| MDS WHO Classification RAEB-1 | 10 Participants | 5 Participants | 5 Participants |
| MDS WHO Classification RAEB-2 | 11 Participants | 6 Participants | 5 Participants |
| MDS WHO Classification RA/RARS/RCMD/RCMD-RS/Del-5q/MDS-U | 33 Participants | 16 Participants | 17 Participants |
| Primary Disease Acute Myeloid Leukemia (AML) | 218 Participants | 108 Participants | 110 Participants |
| Primary Disease Myelodysplastic Syndrome (MDS) | 54 Participants | 27 Participants | 27 Participants |
| Sex: Female, Male Female | 129 Participants | 59 Participants | 70 Participants |
| Sex: Female, Male Male | 143 Participants | 76 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 132 | 4 / 133 |
| serious Total, serious adverse events | 21 / 132 | 16 / 133 |
Outcome results
Primary
Percentage of Participants With Overall Survival (OS)
Overall survival is defined as survival of death from any cause.
Time frame: 18 months post-randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Overall Survival (OS) | 77.5 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Overall Survival (OS) | 67.7 percentage |
Comparison: The null hypothesis is that there is no difference in overall survival at 18 months post-randomization between AML/MDS participants receiving MAC and RIC conditioning regimens. 18 month overall survival was compared between treatment arms using the difference in Kaplan-Meier estimators, which should be close to 0 under the null hypothesis.p-value: 0.0795% CI: [-0.8, 20.3]Difference in Kaplan-Meier estimators
Secondary
Infection Type
The number and types of infection events reported are tabulated.
Time frame: 18 months post-transplant
Population: Infection events
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Infection Type | Viral | 117 Infection events |
| Myeloablative Conditioning Regimen (MAC) | Infection Type | Protozoal | 1 Infection events |
| Myeloablative Conditioning Regimen (MAC) | Infection Type | Fungal | 37 Infection events |
| Myeloablative Conditioning Regimen (MAC) | Infection Type | Other | 6 Infection events |
| Myeloablative Conditioning Regimen (MAC) | Infection Type | Bacterial | 192 Infection events |
| Reduced Intensity Conditioning (RIC) | Infection Type | Other | 15 Infection events |
| Reduced Intensity Conditioning (RIC) | Infection Type | Bacterial | 161 Infection events |
| Reduced Intensity Conditioning (RIC) | Infection Type | Viral | 95 Infection events |
| Reduced Intensity Conditioning (RIC) | Infection Type | Fungal | 12 Infection events |
| Reduced Intensity Conditioning (RIC) | Infection Type | Protozoal | 0 Infection events |
Secondary
Number of Participants With Cause of Death
Primary cause of death was adjudicated using previously described criteria (Copelan et al. 2007). When relapse occurred, it was considered the primary cause of death regardless of other events.
Time frame: 18 months post-randomization
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Cause of Death | Organ failure | 3 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Cause of Death | Infection | 2 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Cause of Death | Relapse | 10 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Cause of Death | Sudden death | 0 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Cause of Death | GVHD | 15 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Cause of Death | Still alive | 105 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Cause of Death | GVHD | 4 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Cause of Death | Relapse | 38 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Cause of Death | Organ failure | 1 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Cause of Death | Still alive | 93 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Cause of Death | Infection | 0 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Cause of Death | Sudden death | 1 Participants |
Secondary
Number of Participants With Chronic GVHD Severity
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.
Time frame: 18 months post-transplant
Population: Transplanted participants
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Chronic GVHD Severity | Moderate | 33 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Chronic GVHD Severity | None | 47 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Chronic GVHD Severity | Severe | 12 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Chronic GVHD Severity | Mild | 40 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Chronic GVHD Severity | Severe | 12 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Chronic GVHD Severity | None | 70 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Chronic GVHD Severity | Moderate | 17 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Chronic GVHD Severity | Mild | 34 Participants |
Secondary
Number of Participants With Donor Cell Engraftment
Donor cell engraftment will be assessed by donor-recipient chimerism assays. Full donor chimerism is defined as the presence of at least 95% donor cells as a proportion of the total population in the peripheral blood or bone marrow. Graft rejection is defined as the presence of no more than 5% donor cells as a proportion of the total population. Mixed chimerism is defined as the presence of between 5% and 95% donor cells. Mixed or full donor chimerism will be considered evidence of donor engraftment.
Time frame: Days 28 and 100 and 18 months post-transplant
Population: Transplanted participants
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 28 | Unknown (relapsed or missing assay) | 36 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 100 | Death Prior to Assessment | 6 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 28 | Mixed Chimerism | 9 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 100 | Unknown (relapsed or missing assay) | 6 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 100 | Full Donor Chimerism | 106 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | 18 Months | Full Donor Chimerism | 71 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 28 | Death Prior to Assessment | 0 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | 18 Months | Mixed Chimerism | 4 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 100 | Mixed Chimerism | 12 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | 18 Months | Graft Rejection | 1 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 28 | Graft Rejection | 1 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | 18 Months | Death Prior to Assessment | 31 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 100 | Graft Rejection | 2 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | 18 Months | Unknown (relapsed or missing assay) | 25 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Donor Cell Engraftment | Day 28 | Full Donor Chimerism | 86 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | 18 Months | Unknown (relapsed or missing assay) | 19 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 28 | Full Donor Chimerism | 80 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 28 | Mixed Chimerism | 30 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 28 | Graft Rejection | 1 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 28 | Death Prior to Assessment | 0 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 28 | Unknown (relapsed or missing assay) | 22 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 100 | Full Donor Chimerism | 86 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 100 | Mixed Chimerism | 30 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 100 | Graft Rejection | 1 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 100 | Death Prior to Assessment | 8 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | Day 100 | Unknown (relapsed or missing assay) | 8 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | 18 Months | Full Donor Chimerism | 66 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | 18 Months | Mixed Chimerism | 5 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | 18 Months | Graft Rejection | 1 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Donor Cell Engraftment | 18 Months | Death Prior to Assessment | 42 Participants |
Comparison: The null hypothesis is that there is no difference in the proportions of participants with full chimerism, mixed chimerism, graft rejection, and death prior to assessment at Day 28 post-transplant between AML/MDS participants receiving MAC and RIC conditioning regimens.p-value: 0.005Chi-squared
Comparison: The null hypothesis is that there is no difference in the proportions of participants with full chimerism, mixed chimerism, graft rejection, and death prior to assessment at Day 100 post-transplant between AML/MDS participants receiving MAC and RIC conditioning regimens.p-value: 0.011Chi-squared
Comparison: The null hypothesis is that there is no difference in the proportions of participants with full chimerism, mixed chimerism, graft rejection, and death prior to assessment at 18 months post-transplant between AML/MDS participants receiving MAC and RIC conditioning regimens.p-value: 0.39Chi-squared
Secondary
Number of Participants With Infections
The maximum severity of infections reported by participants are tabulated. The number of infections and the number of patients experiencing infections will be tabulated by type of infection, severity, and time period after transplant. The cumulative incidence of severe, life-threatening, or fatal infections will be compared between the two treatment arms at 6, 12, and 18 months from transplant or until death.
Time frame: 18 months post-transplant
Population: Transplanted participants
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Infections | None | 38 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Infections | Moderate | 42 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Infections | Severe | 40 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Infections | Life Threatening or Fatal | 12 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Infections | Life Threatening or Fatal | 10 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Infections | None | 43 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Infections | Severe | 43 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Infections | Moderate | 37 Participants |
Secondary
Number of Participants With Maximum Grade 3-5 Toxicities
The maximum grade of toxicities reported by participants over the study duration are tabulated. Per the CTCAE criteria, toxicities are graded on a scale of 0-5, with higher numbers indicating greater severity. The categories correspond as follows: 3 - severe; 4 - life-threatening; 5 - fatal
Time frame: 18 months
Population: Transplanted participants
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Maximum Grade 3-5 Toxicities | 0-2 | 34 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Maximum Grade 3-5 Toxicities | 3 | 66 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Maximum Grade 3-5 Toxicities | 4 | 22 Participants |
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Maximum Grade 3-5 Toxicities | 5 | 10 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Maximum Grade 3-5 Toxicities | 5 | 9 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Maximum Grade 3-5 Toxicities | 0-2 | 59 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Maximum Grade 3-5 Toxicities | 4 | 18 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Maximum Grade 3-5 Toxicities | 3 | 47 Participants |
Secondary
Number of Participants With Primary Graft Failure
Primary graft failure is defined by lack of neutrophil engraftment.
Time frame: 28 days post-transplant
Population: Transplanted participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Primary Graft Failure | 1 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Primary Graft Failure | 3 Participants |
Secondary
Number of Participants With Secondary Graft Failure
Secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in neutrophil counts to less than 500x10\^6/liter that is unresponsive to growth factor therapy.
Time frame: 18 months post-transplant
Population: Transplanted participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Number of Participants With Secondary Graft Failure | 1 Participants |
| Reduced Intensity Conditioning (RIC) | Number of Participants With Secondary Graft Failure | 4 Participants |
Secondary
Percentage of Participants With Acute Graft Versus Host Disease (GVHD)
Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash 1. Rash \<25% of body surface area 2. Rash on 25-50% of body surface area 3. Rash on \> 50% of body surface area 4. Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL 1. 2-3 mg/dL 2. 3.01-6 mg/dL 3. 6.01-15.0 mg/dL 4. \>15 mg/dL GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD 2. Diarrhea 1000-1499 mL/day 3. Diarrhea \>1500 mL/day 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
Time frame: Day 100 post-transplant
Population: Transplanted participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Acute Graft Versus Host Disease (GVHD) | Grade II-IV Acute GVHD | 44.7 percentage |
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Acute Graft Versus Host Disease (GVHD) | Grade III-IV Acute GVHD | 13.6 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Acute Graft Versus Host Disease (GVHD) | Grade II-IV Acute GVHD | 31.6 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Acute Graft Versus Host Disease (GVHD) | Grade III-IV Acute GVHD | 6.8 percentage |
Comparison: The null hypothesis is that there is no difference in the cumulative incidence of grade II-IV acute GVHD during the first 100 days post-randomization between AML/MDS participants receiving MAC and RIC conditioning regimens. Cumulative incidence of grade II-IV acute GVHD was compared between treatment arms using Gray's test, treating death as a competing risk.p-value: 0.024Gray's test
Comparison: The null hypothesis is that there is no difference in the cumulative incidence of grade III-IV acute GVHD during the first 100 days post-randomization between AML/MDS participants receiving MAC and RIC conditioning regimens. Cumulative incidence of grade III-IV acute GVHD was compared between treatment arms using Gray's test, treating death as a competing risk.p-value: 0.066Gray's test
Secondary
Percentage of Participants With Chronic GVHD
Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe. Occurrence of chronic GVHD is defined as the occurrence of mild, moderate, or severe chronic GVHD per this classification.
Time frame: 18 months post-transplant
Population: Transplanted participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Chronic GVHD | 64.0 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Chronic GVHD | 47.6 percentage |
Comparison: The null hypothesis is that there is no difference in the cumulative incidence of chronic GVHD during the first 18 months post-randomization between AML/MDS participants receiving MAC and RIC conditioning regimens. Cumulative incidence of chronic GVHD was compared between treatment arms using Gray's test, treating death as a competing risk.p-value: 0.019Gray's test
Secondary
Percentage of Participants With Disease Relapse
Disease Relapse is defined as relapse of the primary disease.
Time frame: 18 months post-randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Disease Relapse | 13.5 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Disease Relapse | 48.3 percentage |
Comparison: The null hypothesis is that there is no difference in the cumulative incidence of disease relapse during the first 18 months post-randomization between AML/MDS participants receiving MAC and RIC conditioning regimens. Cumulative incidence of disease relapse was compared between treatment arms using Gray's test, treating death as a competing risk.p-value: <0.001Gray's test
Secondary
Percentage of Participants With Neutrophil and Platelet Engraftment
Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10\^6/liter for 3 consecutive measurements on different days. The first of the 3 days will be designated the day of neutrophil engraftment. Platelet engraftment is defined as achieving platelet counts greater than 20,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days.
Time frame: Days 28 and 60 post-transplant
Population: Transplanted participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Neutrophil and Platelet Engraftment | Neutrophil Engraftment at Day 28 | 98.5 percentage |
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Neutrophil and Platelet Engraftment | Platelet Engraftment at Day 60 | 95.5 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Neutrophil and Platelet Engraftment | Neutrophil Engraftment at Day 28 | 97.8 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Neutrophil and Platelet Engraftment | Platelet Engraftment at Day 60 | 96.2 percentage |
Comparison: The null hypothesis is that there is no difference in the cumulative incidence of neutrophil engraftment at Day 28 post-transplant between AML/MDS participants receiving MAC and RIC conditioning regimens. Cumulative incidence of neutrophil engraftment at Day 28 was compared between treatment arms using the difference in Aalen-Johansen estimators, which should be close to 0 under the null hypothesis. Death was treated as a competing risk.p-value: 0.002Difference in Aalen-Johansen estimators
Comparison: The null hypothesis is that there is no difference in the cumulative incidence of platelet engraftment at Day 60 post-transplant between AML/MDS participants receiving MAC and RIC conditioning regimens. Cumulative incidence of platelet engraftment at Day 60 was compared between treatment arms using the difference in Aalen-Johansen estimators, which should be close to 0 under the null hypothesis. Death was treated as a competing risk.p-value: 0.065Difference in Aalen-Johansen estimators
Secondary
Percentage of Participants With Relapse-Free Survival (RFS)
Relapse-free survival is defined as survival without relapse of the primary disease.
Time frame: 18 months post-randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Relapse-Free Survival (RFS) | 67.8 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Relapse-Free Survival (RFS) | 47.3 percentage |
Comparison: The null hypothesis is that there is no difference in relapse-free survival at 18 months post-randomization between AML/MDS participants receiving MAC and RIC conditioning regimens. 18 month relapse-free survival was compared between treatment arms using the difference in Kaplan-Meier estimators, which should be close to 0 under the null hypothesis.p-value: <0.0195% CI: [8.9, 32]Difference in Kaplan-Meier estimators
Secondary
Percentage of Participants With Treatment-related Mortality
Treatment-related mortality is defined as death without a previous relapse of the primary disease.
Time frame: 18 months post-randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Myeloablative Conditioning Regimen (MAC) | Percentage of Participants With Treatment-related Mortality | 15.8 percentage |
| Reduced Intensity Conditioning (RIC) | Percentage of Participants With Treatment-related Mortality | 4.4 percentage |
Comparison: The null hypothesis is that there is no difference in the cumulative incidence of treatment-related mortality during the first 18 months post-randomization between AML/MDS participants receiving MAC and RIC conditioning regimens. Cumulative incidence of treatment-related mortality was compared between treatment arms using Gray's test, treating disease relapse as a competing risk.p-value: 0.002Gray's test