Allo vs Hypomethylating/Best Supportive Care in MDS (BMTCTN1102)

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT02016781
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Cancer Institute (NCI) (NIH), Blood and Marrow Transplant Clinical Trials Network (Other), National Marrow Donor Program (Other)
• Enrollment: 384
• Locations: 37
• Arms: 2
• Actual Duration (Months): 93.6
• Patients Per Site: 10.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is designed as a multicenter trial, with biological assignment to one of two study arms; Arm 1: Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT), Arm 2: Non-Transplant Therapy/Best Supportive Care.

Condition or Disease	Intervention/Treatment	Phase
MDS	Procedure: Allogeneic Hematopoietic Cell Transplant; Procedure: Hypomethylating Therapy / Best Supportive Care	Phase 2

Detailed Description

Background: MDS is a clonal disorder of hematopoietic precursors and stem cells, which may evolve to a terminal phase resembling acute leukemia. A subject of clinical urgency for researchers, clinicians, patients, and health care underwriters such as Medicare, is the role of allogeneic hematopoietic cell transplantation (alloHCT) in the treatment of older patients with higher risk myelodysplastic syndromes (MDS). The use of reduced intensity conditioning (RIC) regimens has extended HCT to the care of older patients with acute myelogenous leukemia (AML) and lymphoma and a number of retrospective and phase II trials for patients with MDS now show the curative potential of RIC alloHCT in selected patients.

This protocol is designed to evaluate the relative benefits of RIC alloHCT compared to non-transplant therapies focusing on overall survival. This will be done by having patients biologically assigned to the alloHCT arm or the hypomethylating therapy/best supportive care arm and following them for survival at 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 384 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Two arms will enroll and have data collected on them simultaneously.Two arms will enroll and have data collected on them simultaneously.
• Masking: None (Open Label)
• Masking Description: No parties are masked in this trial.
• Primary Purpose: Treatment
• Official Title: A Multi-Center Biologic Assignment Trial Comparing Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients w/Intermediate-2 & High Risk Myelodysplastic Syndrome (BMTCTN1102)
• Actual Study Start Date: Dec 16, 2013
• Actual Primary Completion Date: Oct 5, 2021
• Actual Study Completion Date: Oct 5, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Transplant Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT)	Procedure: Allogeneic Hematopoietic Cell Transplant; Bone marrow or peripheral blood stem cell transplant.from a fully matched related (6/6) or unrelated (8/8) donor. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity.; Other Names: RIC alloHCT
Active Comparator: Hypomethylating Therapy / Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician.	Procedure: Hypomethylating Therapy / Best Supportive Care; The specific non-transplant treatment regimen will be at the discretion of the treating physician.; Other Names: Non-transplant

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Overall Survival (OS) [3 years]

   The primary endpoint for this study is overall survival (OS) at three years post-consent. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. Three year OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. The results posted are from the February 2020 interim analysis per protocol study design. Two interim analyses for efficacy were performed previously in January and November 2019 and presented to the Data and Safety Monitoring Board (DSMB). Results at the second analysis was crossing the efficacy boundary. Subsequently, the DSMB approved early release of study data as of February 2020.

Secondary Outcome Measures

1. Percentage of Participants With Leukemia-free Survival (LFS) [3 years]

   LFS is defined as the time from the date of patient consent to the date of progression to AML or death from any cause, whichever comes first. Progression to AML is defined as > 20% leukemic blasts in bone marrow or in the peripheral blood. Death from any cause or transformation of MDS to AML are considered events for this endpoint. Participants without either event are censored at the time of last follow-up. Three year leukemia-free survival probability estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.

2. Quality of Life (QOL) - Functional Assessment of Cancer Therapy-General (FACT-G) [3 years]

   QOL will be compared between the 2 arms using the FACT-G instrument. FACT-G evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer. FACT-G consists of four subscales developed and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Well-being, and Functional Well-being. The FACT-G score ranges 0-108. Each subscale is positively scored, with higher scores indicating better functioning. The self-reported questionnaire will be completed at enrollment and at 6, 12, 18, 24, and 36 months from consent. Results shown are FACT-G total scores.

3. Quality of Life (QOL) - Medical Outcomes Study Short Form (MOS SF-36) [3 years]

   SF36 is being used in this protocol as a generic measure of quality of life (QOL). The self-reported questionnaires are completed at enrollment and at 6, 12, 18, 24, and 36 months from consent. The MOS SF-36 instrument is a general assessment of health QOL with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index. The sub scores for each of the eight components were computed based on the raw categorical values from the survey and range 0-100 with higher scores indicating better outcomes for each domain. Then overall Physical Component Summary (PCS) and Mental Component Summary (MCS) are computed using standardized algorithm for SF36. MCS and PCS scores range 0-100 with higher score indicating positive outcome. To facilitate comparison of the results with published norms, PCS and MCS are used as the outcome measures in summarizing the SF-36 data.

4. Quality of Life (QOL) - EQ-5D [3 years]

   QOL will be compared between the 2 arms using the EQ-5D survey. The EQ-5D contains a five-item survey with three response levels per item measuring mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D takes approximately 1 minute to complete (Agency for Healthcare Research and Quality, 2005). The EQ-5D score ranges -0.224 to 1. The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions, where higher scores indicate more severe or frequent problems. The self-reported questionnaire will be completed at enrollment and at 6, 12, 18, 24, and 36 months from consent.

5. Percentage of Participants With Overall Survival (OS) in As-treated Population [3 years]

   Time to event outcomes will be analyzed from the time of consent. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. Three-year OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.

6. Percentage of Participants With Leukemia-free Survival (LFS) in As-treated Population [3 years]

   LFS is defined as the time from the date of patient consent to the date of progression to AML or death from any cause, whichever comes first. Progression to AML is defined as > 20% leukemic blasts in bone marrow or in the peripheral blood. Death from any cause or transformation of MDS to AML are considered events for this endpoint. Participants without either event are censored at the time of last follow-up. Three year leukemia-free survival probability estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.

7. Percentage of Participants on HCT Arm With Overall Survival (OS) [27 months post-transplant]

   The time to event outcomes is evaluated from the time of transplant. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.

8. Percentage of Participants on HCT Arm With Disease Relapse [27 months post-transplant]

   Outcome Measure Description: The time to event outcomes is evaluated from the time of transplant. Disease relapse is defined as: Satisfying criteria for evolution into acute leukemia; or reappearance of pre-transplant morphologic abnormalities, detected in bone marrow specimens; or reappearance of pre-transplant cytogenetic abnormality in at least one metaphase on each of two separate consecutive examinations at least one month apart, regardless of the number of metaphases analyzed; or institution of any therapy to treat relapsed disease (institution of any therapy not meant for maintenance or prevention), including withdrawal of immunosuppressive therapy or DLI. Relapse estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.

9. Percentage of Participants on HCT Arm With Disease-free Survival (DFS) [27 months post-transplant]

   The time to event outcomes is evaluated from the time of transplant. Death or disease relapse/progression will be considered as events for this endpoint. Surviving participants are censored at the time of last follow-up. DFS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.

10. Percentage of Participants on HCT Arm With Treatment-related Mortality [27 months post-transplant]

    The time to event outcomes is evaluated from the time of transplant. The events are deaths prior to disease relapse. TRM estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.

11. Percentage of Participants on HCT Arm With Grade II-IV Acute GVHD (aGVHD) [27 months post-transplant]

    Grade II-IV aGVHD is the event. aGVHD will be graded according to the BMT CTN Manual of Procedures (MOP). Staging for skin: Stage 1. <25% rash; 2. 25-50%; 3. >50%; 4. generalized erythroderma with bullae. Staging for GI: Stage 1. Diarrhea>500ml/d or persistent nausea; 2. >1000ml/d; 3. >1500ml/d; 4. Large volume diarrhea and severe abdominal pain +- ileus. Staging for Liver: Stage 1. bilirubin 2-3mg/dl; 2. bilirubin 3-6 mg/dl; 3. bilirubin 6-15 mg/dl; 4. bilirubin>15mg/dl. aGVHD grading is performed by the consensus conference criteria (Przepiorka et al. 1995). Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver.

12. Percentage of Participants on HCT Arm With Grade III-IV Acute GVHD [27 months post-transplant]

    The time to event outcomes is evaluated from the time of transplant. Grade III-IV Acute GVHD will be considered as events for this endpoint.

13. Percentage of Participants on HCT Arm With Chronic GVHD [27 months post-transplant]

    The time to event outcomes is evaluated from the time of transplant. Chronic GVHD will be considered as events for this endpoint. Data will be collected and reviewed according to the recommendations of the NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients fulfilling the following criteria will be eligible for entry into this study:

1. Patients with de novo MDS who have, or have previously had, Intermediate-2 or High risk disease as determined by the International Prognostic Scoring System (IPSS). Current Intermediate-2 or High risk disease is NOT a requirement.

2. Patients must have an acceptable MDS subtype:

• Refractory cytopenia with unilineage dysplasia (RCUD) (includes refractory anemia (RA))

• Refractory anemia with ringed sideroblasts (RARS)

• Refractory anemia with excess blasts (RAEB-1)

• Refractory anemia with excess blasts (RAEB-2)

• Refractory cytopenia with multilineage dysplasia (RCMD)

• Myelodysplastic syndrome with isolated del(5q) (5q-syndrome)

• Myelodysplastic syndrome (MDS), unclassifiable

1. Patients must have fewer than 20% marrow blasts within 60 days of consent.

2. Patients may have received prior therapy for the treatment of MDS, including but not limited to: growth factor, transfusion support, immunomodulatory (IMID) therapy, DNA hypomethylating therapy, or cytotoxic chemotherapy prior to enrollment.

3. Age 50.0-75.0 years.

4. Karnofsky performance status > 70 or Eastern Cooperative Oncology Group (ECOG) ≤

6. Patients are eligible if no formal unrelated donor search has been activated prior to date of consent. A formal unrelated donor search begins at the time at which samples are requested from potential National Marrow Donor Program (NMDP) donors. Patients who have started a sibling donor search or who have found a matched sibling donor are eligible.

7. Patients and physicians must be willing to comply with treatment assignment:

8. No intent to proceed with alloHCT using donor sources not specified in this protocol, including human leukocyte antigen (HLA)-mismatched related or unrelated donors (< 6/6 HLA related matched or < 8/8 HLA unrelated matched) or umbilical cord blood unit(s).

9. No intent to use myeloablative conditioning regimens.

10. Intent to proceed with RIC alloHCT if a matched sibling or matched unrelated donor is identified. There is no requirement as to the timing of the transplantation.

11. Patients must be considered to be suitable RIC alloHCT candidates at the time of enrollment based on medical history, physical examination, and available laboratory tests. Specific testing for organ function is not required for eligibility but, if available, these tests should be used to judge eligibility.

12. Signed informed consent

Exclusion Criteria:

• Patients with the following will be ineligible for registration onto this study:

1. Therapy-related MDS (defined as the occurrence of MDS due to prior exposure to systemic chemotherapy and/or radiation for malignancy)

2. Current or prior diagnosis of AML

3. Chronic myelomonocytic leukemia or myelodysplastic/myeloproliferative neoplasm (unacceptable MDS subtypes); uncontrolled bacterial, viral or fungal infection (currently taking medication and with progression or no clinical improvement) at time of enrollment.

4. Patients with prior malignancies, except treated non-melanoma skin cancer or treated cervical carcinoma in situ. Cancer treated with curative surgery without chemotherapy/radiation therapy > 5 years previously will be allowed. Cancer treated with curative surgery < 5 years previously will not be allowed unless approved by the Protocol Officer or one of the Protocol Chairs.

5. Prior autologous or allogeneic HCT

6. Human Immunodeficiency Virus (HIV) infection

7. Patients of childbearing potential unwilling to use contraceptive techniques

8. Patients with psychosocial conditions that would prevent study compliance

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010
2	Stanford Hospital and Clinics	Stanford	California	United States	94305
3	University of Florida College of Medicine	Gainesville	Florida	United States	32610-0277
4	H. Lee Moffitt Cancer Center	Tampa	Florida	United States	33624
5	Emory University	Atlanta	Georgia	United States	30322
6	University of Chicago	Chicago	Illinois	United States	60637-1470
7	University of Kansas Hospital	Kansas City	Kansas	United States	66160
8	University of Kentucky	Lexington	Kentucky	United States	40536
9	University of Maryland Medical Systems - Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
10	Johns Hopkins	Baltimore	Maryland	United States	21231
11	Dana Farber Cancer Institute/Brigham & Women's	Boston	Massachusetts	United States	02115
12	Dana Farber Cancer Institute/Massachusetts General Hospital	Boston	Massachusetts	United States	02115
13	Karmanos Cancer Institute/BMT	Detroit	Michigan	United States	48201
14	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
15	Washington University/Barnes Jewish Hospital	Saint Louis	Missouri	United States	63110
16	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
17	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
18	Mount Sinai Hospital	New York	New York	United States	10029
19	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
20	University of North Carolina Hospital at Chapel Hill	Chapel Hill	North Carolina	United States	27599
21	University of North Carolina	Chapel Hill	North Carolina	United States	27599
22	Duke University Medical Center	Durham	North Carolina	United States	27705
23	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
24	Jewish Hospital BMT Program	Cincinnati	Ohio	United States	45236
25	University Hospitals of Cleveland/ Case Western	Cleveland	Ohio	United States	44106
26	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
27	Ohio State/Arthur G. James Cancer Hospital	Columbus	Ohio	United States	43210
28	Oregon Health & Science University	Portland	Oregon	United States	97239-3098
29	University of Pennsylvania Cancer Center	Philadelphia	Pennsylvania	United States	19104
30	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232-8210
31	Baylor College of Medicine/The Methodist Hospital	Houston	Texas	United States	77030
32	University of Texas/MD Anderson CRC	Houston	Texas	United States	77030
33	University of Utah Med School	Salt Lake City	Utah	United States	84132
34	Virginia Commonwealth University MCV Hospitals	Richmond	Virginia	United States	23298
35	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
36	West Virginia University Hospital	Morgantown	West Virginia	United States	26506
37	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53211

Sponsors and Collaborators

• Medical College of Wisconsin
• National Heart, Lung, and Blood Institute (NHLBI)
• National Cancer Institute (NCI)
• Blood and Marrow Transplant Clinical Trials Network
• National Marrow Donor Program

Investigators

• Study Director: Mary Horowitz, MD, MS, Center for International Blood and Marrow Transplant Research (CIBMTR), Medical College of Wisconsin

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Nov 28, 2018

More Information

Additional Information:

• Blood and Marrow Transplant Clinical Trials Network Website
• National Marrow Donor Program

Publications

• Saber W, Le Rademacher J, Sekeres M, Logan B, Lewis M, Mendizabal A, Leifer E, Appelbaum FR, Horowitz MM, Nakamura R, Cutler CS. Multicenter biologic assignment trial comparing reduced-intensity allogeneic hematopoietic cell transplant to hypomethylating therapy or best supportive care in patients aged 50 to 75 with intermediate-2 and high-risk myelodysplastic syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 study rationale, design, and methods. Biol Blood Marrow Transplant. 2014 Oct;20(10):1566-72. doi: 10.1016/j.bbmt.2014.06.010. Epub 2014 Jun 24.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT02016781
• Other Study ID Numbers: BMTCTN1102; 2U10HL069294-11; 5U24CA076518
• First Posted: Dec 20, 2013
• Last Update Posted: Jul 29, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Medical College of Wisconsin: Myelodysplastic Syndrome
• Additional relevant MeSH terms: Myelodysplastic Syndromes

Study Results

Participant Flow

Recruitment Details	Participants were recruited from 34 centers between December 2013 and November 2018. The study opened to accrual on December 16, 2013 with 36 centers activated for enrollment. The study closed to accrual on November 9, 2018 and study completed on October 5, 2021.
Pre-assignment Detail	Participants whose donors were found during the search were assigned to HCT arm. Participants whose donors were not found by the end of the search were assigned to Non-HCT arm.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Period Title: Interim Look for Primary Analysis
STARTED	260	124
COMPLETED	187	100
NOT COMPLETED	73	24
Period Title: Interim Look for Primary Analysis
STARTED	261	123
COMPLETED	248	115
NOT COMPLETED	13	8

Baseline Characteristics

Arm/Group Title	HCT Arm	Non-HCT Arm	Total
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.	Total of all reporting groups
Overall Participants	260	124	384
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	105 40.4%	44 35.5%	149 38.8%
>=65 years	155 59.6%	80 64.5%	235 61.2%
Age (year) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [year]	65.6 (5.6)	66.0 (5.9)	65.7 (5.7)
Sex: Female, Male (Count of Participants)
Female	95 36.5%	48 38.7%	143 37.2%
Male	165 63.5%	76 61.3%	241 62.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	11 4.2%	9 7.3%	20 5.2%
Not Hispanic or Latino	233 89.6%	108 87.1%	341 88.8%
Unknown or Not Reported	16 6.2%	7 5.6%	23 6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	1 0.8%	2 0.5%
Asian	8 3.1%	2 1.6%	10 2.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 2.3%	9 7.3%	15 3.9%
White	234 90%	105 84.7%	339 88.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	11 4.2%	7 5.6%	18 4.7%
Karnofsky Performance Score (KPS) (Count of Participants)
>=90	99 38.1%	35 28.2%	134 34.9%
<90	81 31.2%	49 39.5%	130 33.9%
ECOG Performance Score (Count of Participants)
0	24 9.2%	16 12.9%	40 10.4%
> 0	56 21.5%	24 19.4%	80 20.8%
MDS Subtype (Count of Participants)
Refractory cytopenia with unilineage dysplasia (RCUD)	5 1.9%	1 0.8%	6 1.6%
Refractory anemia with ringed sideroblasts (RARS)	5 1.9%	2 1.6%	7 1.8%
Refractory anemia with excess blasts (RAEB-1)	61 23.5%	31 25%	92 24%
Refractory anemia with excess blasts (RAEB-2)	132 50.8%	63 50.8%	195 50.8%
Refractory cytopenia with multilineage dysplasia (RCMD)	36 13.8%	14 11.3%	50 13%
Myelodysplastic syndrome with isolated del(5q) (5q-syndrome)	6 2.3%	7 5.6%	13 3.4%
Myelodysplastic syndrome (MDS), unclassifiable	15 5.8%	6 4.8%	21 5.5%
MDS Duration from Diagnosis to Enrollment (months) (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	8.4 (21.6)	11.0 (27.1)	9.2 (23.5)
Identified Donor Type (HCT Arm only) (Count of Participants)
HLA Matched Related	80 30.8%	0 0%	80 20.8%
HLA Matched Unrelated	180 69.2%	0 0%	180 46.9%
Donor Gender (HCT Arm only) (Count of Participants)
Female	73 28.1%	0 0%	73 19%
Male	130 50%	0 0%	130 33.9%
Missing	57 21.9%	0 0%	57 14.8%
HCT-CI (HCT Arm only) (Count of Participants)
0	41 15.8%	0 0%	41 10.7%
1	31 11.9%	0 0%	31 8.1%
2	35 13.5%	0 0%	35 9.1%
3	98 37.7%	0 0%	98 25.5%
Missing	55 21.2%	0 0%	55 14.3%
Highest IPSS Score (Count of Participants)
Intermediate-2 (1.5-2.0)	173 66.5%	81 65.3%	254 66.1%
High Risk (>=2.5)	87 33.5%	43 34.7%	130 33.9%
Highest IPSS-R Score (Count of Participants)
Very Low	4 1.5%	0 0%	4 1%
Low	2 0.8%	0 0%	2 0.5%
Intermediate	79 30.4%	34 27.4%	113 29.4%
High	82 31.5%	51 41.1%	133 34.6%
Very High	93 35.8%	39 31.5%	132 34.4%
Response to Hypomethylating Therapy (Count of Participants)
Complete Response	10 3.8%	7 5.6%	17 4.4%
Partial Response	46 17.7%	23 18.5%	69 18%
No Response	79 30.4%	42 33.9%	121 31.5%
Never had therapy	88 33.8%	33 26.6%	121 31.5%
Unknown	37 14.2%	19 15.3%	56 14.6%
Cytogenetics Tested (Count of Participants)
Yes	241 92.7%	112 90.3%	353 91.9%
No	12 4.6%	8 6.5%	20 5.2%
Unknown or Missing	7 2.7%	4 3.2%	11 2.9%
Results of Cytogenetics Test (Count of Participants)
Abnormalities Identified	151 58.1%	81 65.3%	232 60.4%
No Evaluable Metaphases	4 1.5%	0 0%	4 1%
No Abnormalities	84 32.3%	31 25%	115 29.9%
Missing	2 0.8%	0 0%	2 0.5%
Number of Distinct Cytogenetic Abnormalities (Count of Participants)
1	43 16.5%	28 22.6%	71 18.5%
2	31 11.9%	19 15.3%	50 13%
3	20 7.7%	14 11.3%	34 8.9%
>=4	52 20%	20 16.1%	72 18.8%
Missing	5 1.9%	0 0%	5 1.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Overall Survival (OS)
Description	The primary endpoint for this study is overall survival (OS) at three years post-consent. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. Three year OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy. The results posted are from the February 2020 interim analysis per protocol study design. Two interim analyses for efficacy were performed previously in January and November 2019 and presented to the Data and Safety Monitoring Board (DSMB). Results at the second analysis was crossing the efficacy boundary. Subsequently, the DSMB approved early release of study data as of February 2020.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The enrolled participants are included in the analyses.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	260	124
Number (95% Confidence Interval) [percentage of participants]	47.9 18.4%	26.6 21.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the rates of three-year OS are the same for both treatments. The results posted are from the interim analysis per protocol study design.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	Wald test
	Comments	Wald test of difference in adjusted OS estimates.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of response to hypomethylating therapy (No Response to Hypomethylation vs. Any Response or Hematologic Improvement to Hypomethylation vs. No Prior Hypomethylation) on the treatment effect for OS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3345
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments	Overall Wald test of interaction terms between response to hypomethylating therapy and treatment assignment in regression model.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of patient age (< vs. >= 65) on the treatment effect for OS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7328
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments	Overall Wald test of interaction terms between patient age and treatment assignment in regression model.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of disease duration (less than vs. 3 months or more) on the treatment effect for OS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6261
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments	Overall Wald test of interaction terms between disease duration and treatment assignment in regression model.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of IPSS score (Intermediate-2 vs. High) on the treatment effect for OS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4134
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments	Overall Wald test of interaction terms between IPSS score and treatment assignment in regression model.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	Statistical Analysis 6: This subgroup analysis investigated the differential impact of IPSS-R score (Very Low, Low, or Intermediate vs. High vs. Very High) on the treatment effect for OS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3147
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments	Overall Wald test of interaction terms between IPSS-R score and treatment assignment in regression model.

2. Secondary Outcome

Title	Percentage of Participants With Leukemia-free Survival (LFS)
Description	LFS is defined as the time from the date of patient consent to the date of progression to AML or death from any cause, whichever comes first. Progression to AML is defined as > 20% leukemic blasts in bone marrow or in the peripheral blood. Death from any cause or transformation of MDS to AML are considered events for this endpoint. Participants without either event are censored at the time of last follow-up. Three year leukemia-free survival probability estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The enrolled participants are included in the analyses.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	260	124
Number (95% Confidence Interval) [percentage of participants]	35.8 13.8%	20.6 16.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the rates of three-year LFS are the same for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0030
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	Wald test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of response to hypomethylating therapy on the treatment effect for LFS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9908
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of patient age (< or >= 65) on the treatment effect for LFS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8981
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of disease duration (less than vs. 3 months or more) on the treatment effect for LFS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1465
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of IPSS score (Intermediate-2 vs. High) on the treatment effect for LFS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
Statistical Test of Hypothesis	p-Value	0.4991
	Comments
	Method	pseudo-value regression models
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	This subgroup analysis investigated the differential impact of IPSS-R score on the treatment effect for LFS at three years post-consent for the HCT arm vs. the non-HCT arm. The analysis was conducted using pseudo-value regression models via an interaction term between the factor and the treatment group with a logit link function.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4953
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	pseudo-value regression models
	Comments

3. Secondary Outcome

Title	Quality of Life (QOL) - Functional Assessment of Cancer Therapy-General (FACT-G)
Description	QOL will be compared between the 2 arms using the FACT-G instrument. FACT-G evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer. FACT-G consists of four subscales developed and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Well-being, and Functional Well-being. The FACT-G score ranges 0-108. Each subscale is positively scored, with higher scores indicating better functioning. The self-reported questionnaire will be completed at enrollment and at 6, 12, 18, 24, and 36 months from consent. Results shown are FACT-G total scores.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The enrolled participants are included in the analyses. Only English and Spanish speaking patients were eligible to participate in the QOL component of this trial.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	260	124
Enrollment	81.5 (1.1)	79.3 (1.9)
6 Months	81.4 (1.1)	78.6 (2.0)
12 Months	84.0 (1.2)	80.8 (2.2)
18 Months	87.7 (1.5)	83.8 (2.8)
24 Months	89.0 (1.6)	87.0 (3.4)
36 Months	90.3 (2.0)	79.7 (5.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the FACT-G scores are the same at Enrollment for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2777
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in FACT-G scores from enrollment are the same at 6 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2250
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in FACT-G scores from enrollment are the same at 12 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1048
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in FACT-G scores from enrollment are the same at 18 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0888
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in FACT-G scores from enrollment are the same at 24 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5844
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in FACT-G scores from enrollment are the same at 36 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0344
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

4. Secondary Outcome

Title	Quality of Life (QOL) - Medical Outcomes Study Short Form (MOS SF-36)
Description	SF36 is being used in this protocol as a generic measure of quality of life (QOL). The self-reported questionnaires are completed at enrollment and at 6, 12, 18, 24, and 36 months from consent. The MOS SF-36 instrument is a general assessment of health QOL with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, and Mental Health Index. The sub scores for each of the eight components were computed based on the raw categorical values from the survey and range 0-100 with higher scores indicating better outcomes for each domain. Then overall Physical Component Summary (PCS) and Mental Component Summary (MCS) are computed using standardized algorithm for SF36. MCS and PCS scores range 0-100 with higher score indicating positive outcome. To facilitate comparison of the results with published norms, PCS and MCS are used as the outcome measures in summarizing the SF-36 data.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The enrolled participants are included in the analyses. Only English and Spanish speaking patients were eligible to participate in the QOL component of this trial.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	260	124
PCS at Enrollment	38.8 (0.8)	37.9 (1.2)
PCS at 6 Months	38.1 (0.7)	37.8 (1.2)
PCS at 12 Months	39.9 (0.8)	37.7 (1.8)
PCS at 18 Months	42.1 (0.9)	40.5 (1.6)
PCS at 24 Months	43.2 (1.1)	41.2 (2.3)
PCS at 36 Months	44.0 (1.3)	39.3 (3.9)
MCS at Enrollment	49.9 (0.8)	50.7 (1.0)
MCS at 6 Months	50.1 (0.8)	50.7 (1.4)
MCS at 12 Months	52.6 (0.8)	53.4 (1.2)
MCS at 18 Months	54.4 (0.9)	52.0 (1.7)
MCS at 24 Months	54.4 (0.9)	53.2 (1.4)
MCS at 36 Months	54.0 (1.1)	53.6 (4.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the MOS SF-36 PCS scores are the same at Enrollment for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5583
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 PCS scores from enrollment are the same at 6 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6690
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 PCS scores from enrollment are the same at 12 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2089
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 PCS scores from enrollment are the same at 18 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4343
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 PCS scores from enrollment are the same at 24 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5942
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 PCS scores from enrollment are the same at 36 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1615
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the MOS SF-36 MCS scores are the same at Enrollment for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5659
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 MCS scores from enrollment are the same at 6 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8555
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 MCS scores from enrollment are the same at 12 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8995
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 MCS scores from enrollment are the same at 18 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0105
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 MCS scores from enrollment are the same at 24 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2596
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in MOS SF-36 MCS scores from enrollment are the same at 36 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5022
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

5. Secondary Outcome

Title	Quality of Life (QOL) - EQ-5D
Description	QOL will be compared between the 2 arms using the EQ-5D survey. The EQ-5D contains a five-item survey with three response levels per item measuring mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D takes approximately 1 minute to complete (Agency for Healthcare Research and Quality, 2005). The EQ-5D score ranges -0.224 to 1. The maximum score of 1 indicates the best health state, by contrast with the scores of individual questions, where higher scores indicate more severe or frequent problems. The self-reported questionnaire will be completed at enrollment and at 6, 12, 18, 24, and 36 months from consent.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The enrolled participants are included in the analyses. Only English and Spanish speaking patients were eligible to participate in the QOL component of this trial.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	260	124
Enrollment	0.800 (0.010)	0.823 (0.015)
6 Months	0.779 (0.013)	0.792 (0.020)
12 Months	0.792 (0.014)	0.772 (0.028)
18 Months	0.826 (0.016)	0.812 (0.025)
24 Months	0.845 (0.016)	0.858 (0.034)
36 Months	0.835 (0.024)	0.789 (0.061)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the EQ-5D scores are the same at Enrollment for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1768
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in EQ-5D scores from enrollment are the same at 6 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8318
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in EQ-5D scores from enrollment are the same at 12 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4752
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in EQ-5D scores from enrollment are the same at 18 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5671
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in EQ-5D scores from enrollment are the same at 24 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3009
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the changes in EQ-5D scores from enrollment are the same at 36 Months for both treatments.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3403
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	ANOVA
	Comments	Changes in scores from enrollment were compared between arms using ANOVA models with treatment arm as main effect and enrollment score as a covariate

6. Secondary Outcome

Title	Percentage of Participants With Overall Survival (OS) in As-treated Population
Description	Time to event outcomes will be analyzed from the time of consent. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. Three-year OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The treated participants are included in the analyses. This secondary analysis includes only treated participants who were compliant with their biologic assignment during the first six months following final assignment and excludes participants from the analysis if they died or dropped out before 90 days without a donor identified.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	216	85
Number (95% Confidence Interval) [percentage of participants]	49.4 19%	17.4 14%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the rates of three-year OS are the same for both treatments in treated population.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	Wald test
	Comments

7. Secondary Outcome

Title	Percentage of Participants With Leukemia-free Survival (LFS) in As-treated Population
Description	LFS is defined as the time from the date of patient consent to the date of progression to AML or death from any cause, whichever comes first. Progression to AML is defined as > 20% leukemic blasts in bone marrow or in the peripheral blood. Death from any cause or transformation of MDS to AML are considered events for this endpoint. Participants without either event are censored at the time of last follow-up. Three year leukemia-free survival probability estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

The treated participants are included in the analyses. This secondary analysis includes only treated participants who were compliant with their biologic assignment during the first six months following final assignment and excludes participants from the analysis if they died or dropped out before 90 days without a donor identified.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	216	85
Number (95% Confidence Interval) [percentage of participants]	39.5 15.2%	11.2 9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	HCT Arm, Non-HCT Arm
	Comments	The null hypothesis is that the rates of three-year LFS are the same for both treatments in treated population.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments	Statistical significance was determined using a pre-specified threshold of 0.05.
	Method	Wald test
	Comments

8. Secondary Outcome

Title	Percentage of Participants on HCT Arm With Overall Survival (OS)
Description	The time to event outcomes is evaluated from the time of transplant. Death from any cause will be considered an event for this endpoint. Surviving participants are censored at the time of last follow-up. OS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.
Time Frame	27 months post-transplant

Outcome Measure Data

Analysis Population Description

The enrolled participants in the HCT arm who received HCT from their assigned donor.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	216	0
Number (95% Confidence Interval) [percentage of participants]	55.7 21.4%

9. Secondary Outcome

Title	Percentage of Participants on HCT Arm With Disease Relapse
Description	Outcome Measure Description: The time to event outcomes is evaluated from the time of transplant. Disease relapse is defined as: Satisfying criteria for evolution into acute leukemia; or reappearance of pre-transplant morphologic abnormalities, detected in bone marrow specimens; or reappearance of pre-transplant cytogenetic abnormality in at least one metaphase on each of two separate consecutive examinations at least one month apart, regardless of the number of metaphases analyzed; or institution of any therapy to treat relapsed disease (institution of any therapy not meant for maintenance or prevention), including withdrawal of immunosuppressive therapy or DLI. Relapse estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.
Time Frame	27 months post-transplant

Outcome Measure Data

Analysis Population Description

The enrolled participants in the HCT arm who received HCT from their assigned donor.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	216	0
Number (95% Confidence Interval) [percentage of participants]	29.6 11.4%

10. Secondary Outcome

Title	Percentage of Participants on HCT Arm With Disease-free Survival (DFS)
Description	The time to event outcomes is evaluated from the time of transplant. Death or disease relapse/progression will be considered as events for this endpoint. Surviving participants are censored at the time of last follow-up. DFS estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.
Time Frame	27 months post-transplant

Outcome Measure Data

Analysis Population Description

The enrolled participants in the HCT arm who received HCT from their assigned donor.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	216	0
Number (95% Confidence Interval) [percentage of participants]	49.7 19.1%

11. Secondary Outcome

Title	Percentage of Participants on HCT Arm With Treatment-related Mortality
Description	The time to event outcomes is evaluated from the time of transplant. The events are deaths prior to disease relapse. TRM estimates are adjusted for age, race/ethnicity, performance status, IPSS score, duration of disease, and response to prior hypomethylating therapy.
Time Frame	27 months post-transplant

Outcome Measure Data

Analysis Population Description

The enrolled participants in the HCT arm who received HCT from their assigned donor.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	216	0
Number (95% Confidence Interval) [percentage of participants]	20.6 7.9%

12. Secondary Outcome

Title	Percentage of Participants on HCT Arm With Grade II-IV Acute GVHD (aGVHD)
Description	Grade II-IV aGVHD is the event. aGVHD will be graded according to the BMT CTN Manual of Procedures (MOP). Staging for skin: Stage 1. <25% rash; 2. 25-50%; 3. >50%; 4. generalized erythroderma with bullae. Staging for GI: Stage 1. Diarrhea>500ml/d or persistent nausea; 2. >1000ml/d; 3. >1500ml/d; 4. Large volume diarrhea and severe abdominal pain +- ileus. Staging for Liver: Stage 1. bilirubin 2-3mg/dl; 2. bilirubin 3-6 mg/dl; 3. bilirubin 6-15 mg/dl; 4. bilirubin>15mg/dl. aGVHD grading is performed by the consensus conference criteria (Przepiorka et al. 1995). Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver.
Time Frame	27 months post-transplant

Outcome Measure Data

Analysis Population Description

Enrolled participants in the HCT arm who received HCT from their assigned donor and who had Grade II-IV Acute GVHD data from CIBMTR are included.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	201	0
Number (95% Confidence Interval) [percentage of participants]	43.1 16.6%

13. Secondary Outcome

Title	Percentage of Participants on HCT Arm With Grade III-IV Acute GVHD
Description	The time to event outcomes is evaluated from the time of transplant. Grade III-IV Acute GVHD will be considered as events for this endpoint.
Time Frame	27 months post-transplant

Outcome Measure Data

Analysis Population Description

Enrolled participants in the HCT arm who received HCT from their assigned donor and who had Grade III-IV Acute GVHD data from CIBMTR are included.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	201	0
Number (95% Confidence Interval) [percentage of participants]	17.1 6.6%

14. Secondary Outcome

Title	Percentage of Participants on HCT Arm With Chronic GVHD
Description	The time to event outcomes is evaluated from the time of transplant. Chronic GVHD will be considered as events for this endpoint. Data will be collected and reviewed according to the recommendations of the NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria.
Time Frame	27 months post-transplant

Outcome Measure Data

Analysis Population Description

Enrolled participants in the HCT arm who received HCT from their assigned donor and who had Chronic GVHD data from CIBMTR are included.

Arm/Group Title	HCT Arm	Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2	Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
Measure Participants	202	0
Number (95% Confidence Interval) [percentage of participants]	55.5 21.3%

Adverse Events

Time Frame	Adverse event reporting and monitoring were conducted throughout the study, up to 3 years.
Adverse Event Reporting Description	Per Protocol 4.4.5. AE Reporting, no other therapy is mandated in this study, AE associated with transplantation or non-transplantation will not be collected nor reported for this protocol. Only AE related to the study consent process, collection of the optional research samples, or completing QOL Surveys will be reported. A few AEs were initially reported by sites but later were assessed by the Medical Monitor and determined to be report filed in error. Such AEs are not included in this report.
Arm/Group Title	HCT Arm		Non-HCT Arm
Arm/Group Description	Reduced intensity conditioning allogeneic hematopoietic cell transplantation (RIC-alloHCT) All subjects are initially assigned to the non-transplant arm. Subjects are re-assigned to the transplant arm should a suitable donor be identified within 90 days of informed consent. Bone marrow or peripheral blood stem cell transplant from a fully matched related (6/6) or unrelated (8/8) donor. Donors must meet institutional selection criteria, and there is no age restriction for sibling donors. The specific transplant treatment regimen will be at the discretion of the treating physician but is required to be reduced-intensity. The following limits on conditioning dose intensity delineate myeloablative regimens: TBI doses of ≥ 500 (unfractionated) cGy and ≥ 800 cGy (fractionated) All supportive care will be given in keeping with the BMT CTN Manual of Procedures (MOP) and local institutional guidelines. All patients will receive prophylaxis against bacterial, fungal, and viral infections during the post-HCT period according to institutional standards. Busulfan dose ≥ 9.5 mg/kg Melphalan ≥ 150 mg/m2		Non-Transplant Therapy/Best Supportive Care The specific non-transplant treatment regimen will be at the discretion of the treating physician. Hypomethylating therapy is the accepted standard therapy of treatment naïve patients with Int-2/High Risk MDS not undergoing transplantation. Azacytidine: 75 mg/m2 by subcutaneous injection or IV for 7 days; 28 day cycles. Or Decitabine: 20 mg/m2 IV daily for 5 days; 28 day cycles. All supportive care will be given in keeping with local institutional guidelines.
All Cause Mortality
	HCT Arm		Non-HCT Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	125/260 (48.1%)		86/124 (69.4%)
Serious Adverse Events
	HCT Arm		Non-HCT Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/260 (0%)		0/124 (0%)
Other (Not Including Serious) Adverse Events
	HCT Arm		Non-HCT Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/260 (0%)		0/124 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.