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Cyclophosphamide

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Fludarabine phosphate

Melphalan

Busulfan

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One of two different regimens in RIC will be administered; fludarabine and busulfan, or fludarabine and melphalan.

One of three different regimens in MAC will be administered; busulfan and fludarabine, busulfan and cyclophosphamide, or cyclophosphamide and total body irradiation.

(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 Busulfan

(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

Fludarabine and Melphalan

(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 Fludarabine

(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)

Busulfan and Cyclophosphamide

(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)

Cyclophosphamide and Total Body Irradiation

Mary Horowitz, MD

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.

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.

Reduced Intensity Regimen vs Myeloablative Regimen for Myeloid Leukemia or Myelodysplastic Syndrome (BMT CTN 0901)

A Randomized, Multi-Center, Phase III Study of Allogeneic Stem Cell Transplantation Comparing Regimen Intensity in Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia (BMT CTN #0901)

Findings will be published in a manuscript

Overall survival is defined as survival of death from any cause.

Relapse-free survival is defined as survival without relapse of the primary disease.

Disease Relapse is defined as relapse of the primary disease.

Treatment-related mortality is defined as death without a previous relapse of the primary disease.

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.

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.

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

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.

Chronic GVHD is classified per 2005 NIH Consensus Criteria (Filipovich et al. 2005) into categories of severity: none, mild, moderate, and severe.

Primary graft failure is defined by lack of neutrophil engraftment.

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.

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

The number and types of infection events reported are tabulated.

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.

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.

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

Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grade 3-5 AEs were required to be reported through the AE system per protocol.

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)

Myeloablative Conditioning Regimen (MAC)

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

Reduced Intensity Conditioning (RIC)

Total

Age, Continuous

Sex: Female, Male

Primary Disease

Participants with MDS are categorized per 2008 WHO classification (Vardiman et al. 2009). Major features of each class are given below:

Refractory Anemia (RA): Anemia without marrow blasts or sideroblasts; Refractory Anemia with Ringed Sideroblasts (RARS): \> 15% marrow sideroblasts; Refractory Cytopenias with Multilineage Dysplasia (RCMD): Dysplasia in \>10% marrow cells; Isolated del(5q) (Del-5q): Isolated del(5q) in marrow; Unclassified (MDS-U) Refractory Anemia with Excess Blasts-1 (RAEB-1): 5-9% marrow blasts; Refractory Anemia with Excess Blasts-2 (RAEB-2): 10-19% marrow blasts;

MDS WHO Classification

Participants with AML are categorized per 2008 WHO classification (Vardiman et al. 2009). Major features of each class are given below:

AML with recurrent genetic abnormalities: Presence of specific genetic abnormalities known to be prognostic; AML with multilineage dysplasia: \> 50% of cells in at least 2 myeloid lineages are dysplastic; AML and MDS, therapy related: development of myeloid neoplasms in response to therapy that is diagnosed as either AML or MDS; AML not otherwise specified: AML that does not satisfy criteria for other classes

AML WHO Classification

Disease Duration

Disease risk status is defined according to cytogenetic and molecular abnormalities identified prior to transplantation and classified as standard or high risk. Among AML participants, high-risk disease is defined as the presence of cytogenetic abnormalities at 3q, 9q, 11q, 20q, 21q, or 17p; the presence of del(5q)/-5, -7/del(7q), t(6;9), or t(9;22); and/or FLT-3 internal tandem duplication mutation. Among MDS participants, high-risk disease is defined as the presence of \> 10% blasts in bone marrow.

Disease Risk Status

The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) (Sorror et al., 2005) summarizes relevant comorbidities present in participants prior to allogeneic transplant. Each comorbidity reported at the time of transplant is given a score of 0, 1, 2, or 3 and the overall HCT-CI score is the sum of the comorbidity scores, ranging from 0 - 26.

HCT-CI

Flu/Bu4: busulfan (16 mg/kg oral or 12.8 mg/kg IV) and fludarabine (120-180 mg/m2); Bu/Cy: busulfan (16 mg/kg oral or 12.8 mg/kg IV) and cyclophosphamide (120 mg/kg) ; Cy/TBI: cyclophosphamide (120 mg/kg) and total body irradiation (1200-1420 cGy); Flu/Mel: fludarabine (120-180 mg/m2) and melphalan (≤ 150 mg/m2); Flu/Bu2: fludarabine (120-180 mg/m2) with busulfan (≤ 8 mg/kg oral or 6.4 mg/kg IV);

Flu/Bu4, Bu/Cy, and Cy/TBI are myeloablative conditioning regimens, while Flu/Mel and Flu/Bu2 are reduced intensity conditioning regimens.

Conditioning Regimen

Prophylaxis for Graft Versus Host Disease

GVHD Prophylaxis

ATG Use

Donor Type

Donor Source

Adam Mendizabal, PhD

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.

Percentage of Participants With Overall Survival (OS)

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.

Percentage of Participants With Relapse-Free Survival (RFS)

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.

Percentage of Participants With Disease Relapse

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.

Percentage of Participants With Treatment-related Mortality

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.

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.

Neutrophil Engraftment at Day 28

Platelet Engraftment at Day 60

Percentage of Participants With Neutrophil and Platelet Engraftment

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.

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.

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.

Day 28

Day 100

18 Months

Number of Participants With Donor Cell Engraftment

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.

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.

Grade II-IV Acute GVHD

Grade III-IV Acute GVHD

Percentage of Participants With Acute Graft Versus Host Disease (GVHD)

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.

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