Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT00412360
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Blood and Marrow Transplant Clinical Trials Network (Other), National Cancer Institute (NCI) (NIH), National Marrow Donor Program (Other)
• Enrollment: 224
• Locations: 38
• Arms: 2
• Duration (Months): 94
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is a Phase III, randomized, open-label, multi-center, prospective study of single umbilical cord blood (UCB) transplantation versus double UCB transplantation in pediatric patients with hematologic malignancies.

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia; Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Myelodysplastic Syndrome; Natural Killer Cell Lymphoblastic Leukemia/Lymphoma	Biological: Single Umbilical Cord Blood Unit Transplant; Biological: Double Umbilical Cord Blood Unit Transplant; Radiation: Total Body Irradiation; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Cyclosporine A; Drug: Mycophenolate Mofetil	Phase 3

Detailed Description

BACKGROUND:

In nearly every large single center or registry analysis of outcomes after UCB transplantation, cell dose is identified as an important factor influencing the incidence and rate of hematopoietic recovery, risk of transplant-related mortality, and probability of survival. Pilot data suggest that infusion of two partially human leukocyte antigen (HLA)-matched UCB units, which always augments the graft cell dose, is safe and may improve neutrophil recovery and survival. To determine whether the infusion of two UCB units enhances survival, a multi-center, open-label, randomized trial is proposed. As adequate single UCB units can be identified for more than 80% of pediatric recipients (in contrast to less than 30% for adults), this study will be open only to pediatric patients. The population will be restricted to patients with high-risk hematologic malignancy, the most common indication of UCB transplantation in children.

DESIGN NARRATIVE:

Participants will include patients 1 to 21 years of age with a diagnosis of hematological malignancy and with two partially HLA-matched UCB units. Units must be HLA-matched at 3 of 6 HLA-A and B (intermediate resolution molecular typing) and DRB1 (high resolution molecular typing) with each other and 4 of 6 with the recipient. Two appropriately HLA-matched units must be available such that one unit delivers a pre-cryopreserved, nucleated cell dose of at least 2.5 x 10^{7 per kilogram and the second unit delivers at least 1.5 x 10}7 per kilogram.

Patients will be randomized no more than 14 days prior to initiation of conditioning. UCB units will be shipped prior to initiation of conditioning.

The preparative regimen will consist of the following:

• Fludarabine: 25 mg/m2/day IV on Days -10, -9, and -8.

• Total Body Irradiation (TBI): 165 cGy twice daily on Days -7, -6, -5, and -4.

• Cyclophosphamide: 60 mg/kg/day x 2 on Days -3 and -2.

• Day 0 will be the day of the UCB transplant. The Graft-vs-Host-Disease (GVHD) prophylaxis regimen will be mycophenolate mofetil (MMF) 15 mg/kg IV BID on Day -3 to Day

• 45 and cyclosporine A (CSA) to maintain level 200-400 ng/mL beginning on Day -3.

Patients will be followed for at least 24 months post-transplant.

Study Design

• Study Type: Interventional
• Actual Enrollment: 224 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multi-center, Open Label, Randomized Trial Comparing Single Versus Double Umbilical Cord Blood (UCB) Transplantation in Pediatric Patients With High Risk Leukemia and Myelodysplasia (BMT CTN #0501)
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Cord Blood Transplant Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil	Biological: Single Umbilical Cord Blood Unit Transplant; Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF; Radiation: Total Body Irradiation; The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.; Other Names: TBI ; Drug: Cyclophosphamide; Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.; Other Names: Cytoxan® ; Drug: Fludarabine; Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8. Fludarabine will not be dose adjusted for body weight.; Other Names: Fludara ; Drug: Cyclosporine A; CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods). CSA can be administered per institutional practice.; Other Names: CSA ; Drug: Mycophenolate Mofetil; MMF will be given at a dose of 1 gram IV q 8 hours if > 50 kg or 15 mg/kg IV q 8 hours if < 50 kg beginning the morning of Day -3.; Other Names: MMF, Cellcept®
Experimental: Double Cord Blood Transplant Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil	Biological: Double Umbilical Cord Blood Unit Transplant; Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF; Radiation: Total Body Irradiation; The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.; Other Names: TBI ; Drug: Cyclophosphamide; Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.; Other Names: Cytoxan® ; Drug: Fludarabine; Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8. Fludarabine will not be dose adjusted for body weight.; Other Names: Fludara ; Drug: Cyclosporine A; CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods). CSA can be administered per institutional practice.; Other Names: CSA ; Drug: Mycophenolate Mofetil; MMF will be given at a dose of 1 gram IV q 8 hours if > 50 kg or 15 mg/kg IV q 8 hours if < 50 kg beginning the morning of Day -3.; Other Names: MMF, Cellcept®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Overall Survival [1 year post-randomization]

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

Secondary Outcome Measures

1. Percentage of Participants With Disease-free Survival [1 year post-randomization]

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

2. Percentage of Participants With Neutrophil and Platelet Engraftment [Days 42 and 100]

   Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10^6/liter for three consecutive measurements on different days. The first of the three days will be designated the day of neutrophil engraftment. Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days.

3. Time to Neutrophil and Platelet Engraftment [2 years post-transplant]

   Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days.

4. Percentage of Participants With Acute Graft-versus-host Disease (GVHD) [Day 100 post-randomization]

   Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash Rash <25% of body surface area Rash on 25-50% of body surface area Rash on > 50% of body surface area Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)*: 0: <2 mg/dL 2-3 mg/dL 3.01-6 mg/dL 6.01-15.0 mg/dL >15 mg/dL GI stage*: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4

5. Percentage of Participants With Chronic GVHD [1 year post-randomization]

   Incidences of chronic GVHD will be graded per Shulman et al. 1980. This reference categorizes chronic GVHD as either limited or extensive. For this outcome, participants developing either type are considered to have a chronic GVHD event.

6. Number of Infections Per Participant [2 years post-randomization]

7. Percentage of Participants With Relapse [1 year post-randomization]

   Relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, or MDS consistent with pre-transplant features. Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation.

8. Percentage of Participants With Treatment-related Mortality [1 year post-randomization]

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

9. Number of Participants With Engraftment Syndrome [Day 100 post-transplant]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Two partially HLA-matched UCB units. Units must be HLA-matched minimally at 4 of 6 HLA-A and B (at intermediate resolution by molecular typing) and DRB1 (at high resolution by molecular typing) loci with the patient, and the units must be HLA-matched at 3 of 6 HLA- A, B, DRB1 loci with each other (using same resolution of molecular typing as indicated above). Two appropriately HLA-matched units must be available such that one unit delivers a pre-cryopreserved nucleated cell dose of at least 2.5 x 10^{7 per kilogram and the second unit at least 1.5 x 10}7 per kilogram.

• Acute myelogenous leukemia (AML) at the following stages:

1. High risk first complete remission (CR1), defined as the following:

• Having preceding myelodysplasia (MDS)

• High risk cytogenetics (high risk cytogenetics: del (5q) -5, -7, abn (3q), t (6;9) complex karyotype [at least 5 abnormalities],)the presence of a high FLT3 ITD-AR (> 0.4)

• Requiring more than 1 cycle of chemotherapy to obtain complete remission (CR);

• FAB M6

1. Second or greater CR

2. First relapse with less than 25% blasts in bone marrow

3. Morphologic complete remission with incomplete blood count recovery

• Therapy-related AML for which prior malignancy has been in remission for at least 12 months

• Acute lymphocytic leukemia (ALL) at the following stages:

1. High risk first remission, defined as one of the following conditions:

• Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)

• Mixed lineage leukemia (MLL) rearrangement with slow early response (defined as having M2 [5-25% blasts] or M3 [more than 25% blasts on bone marrow examination on Day 14 of induction therapy])

• Hypodiploidy (less than 44 chromosomes or DNA index less than 0.81)

• End of induction M3 bone marrow

• End of induction M2 with M2-3 at Day 42

• Evidence of minimal residual disease (MRD). If a patient's only high risk criterion is MRD, approval by a protocol chair or protocol officer is required for enrollment. For COG centers, this will only be for MRD greater than 1 percent by flow MRD at the end of extended induction.

1. High risk second remission, defined as one of the following conditions:

• Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)

• Bone marrow relapse less than 36 months from induction

• T-lineage relapse at any time

• Very early isolated central nervous system (CNS) relapse (6 months from diagnosis)

• Slow reinduction (M2-3 at Day 28) after relapse at any time

• Evidence of minimal residual disease (MRD). If a patient's only high risk criterion is MRD, approval by a protocol chair or protocol officer is required for enrollment. For COG centers, this will only be for MRD greater than 1 percent by flow MRD at the end of extended induction.

1. Any third or subsequent CR

• NK cell lymphoblastic leukemia in any CR

• Biphenotypic or undifferentiated leukemia in any CR or if in first relapse must have less than 25% blasts in bone marrow (BM)

• Myelodysplastic syndrome (MDS) at any stage

• Chronic myelogenous leukemia (CML) in chronic or accelerated phase

• All patients with evidence of CNS leukemia must be treated and be in CNS CR to be eligible for study.

• Patients 16 years old or older must have a Karnofsky score of at least 70% and patients younger than 16 years old must have a Lansky score of at least 70%.

• Patients with adequate physical function as measured by:

1. Cardiac: Left ventricular ejection fraction greater than 40% or shortening fraction greater than 26%

2. Hepatic: Bilirubin no more than 2.5 mg/dL; alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) no more than 5 times the upper limit of normal (ULN)

3. Renal: Serum creatinine within normal range for age, or if serum creatinine is outside normal range for age, then renal function (creatinine clearance or GFR) greater than 70 mL/min/1.73 m^2

4. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50% of predicted value (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation greater than 92% of room air

Exclusion Criteria:

• Pregnant (β-positive human chorionic gonadotropin [HCG]) or breastfeeding

• Evidence of HIV infection or HIV positive serology

• Current uncontrolled bacterial, viral, or fungal infection (currently taking medication and progression of clinical symptoms)

• Autologous transplant less than 12 months prior to enrollment

• Prior autologous transplant for the disease for which the UCB transplant will be performed

• Prior allogeneic hematopoietic stem cell transplant

• Active malignancy other than the one for which the UCB transplant is being performed within 12 months of enrollment

• Inability to receive TBI

• Requirement of supplemental oxygen

• HLA-matched related donor able to donate

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	City of Hope National Medical Center	Duarte	California	United States	91010
4	Childrens Hospital at Oakland	Oakland	California	United States	94609
5	UCSD/Rady Childrens Hospital	San Diego	California	United States	92123
6	University of California, San Francisco (Peds)	San Francisco	California	United States	94143
7	The Children's Hospital of Denver	Denver	Colorado	United States	80218
8	Children's National Medical Center	Washington	District of Columbia	United States	20010
9	University of Florida College of Medicine (Shands)	Gainesville	Florida	United States	32610
10	Nemours Childrens Clinic	Jacksonville	Florida	United States	32207
11	University of Miami	Miami	Florida	United States	33136
12	All Children's Hospital	Saint Petersburg	Florida	United States	33710
13	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322-1062
14	Indiana University Medical Center	Indianapolis	Indiana	United States	46202
15	University of Louisville/Kosiar Children's Hospital	Louisville	Kentucky	United States	40202
16	Children's of New Orleans	New Orleans	Louisiana	United States	70118
17	DFCI/Children's Hospital of Boston	Boston	Massachusetts	United States	02115
18	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
19	Karmanos Cancer Institute/Children's Hospital of Michigan	Detroit	Michigan	United States	48201
20	University of Minnesota	Minneapolis	Minnesota	United States	55455
21	University of Mississippi	Jackson	Mississippi	United States	39216
22	Children's Mercy Hospital and Clinics	Kansas City	Missouri	United States	64108
23	New York Medical College	Valhalla	New York	United States	10595
24	Duke University Medical Center	Durham	North Carolina	United States	27705
25	Nationwide Children's Hospital	Columbus	Ohio	United States	43205-2696
26	Oregon Health Sciences University	Portland	Oregon	United States	97239
27	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
28	Medical University of South Carolina	Charleston	South Carolina	United States	29425
29	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232-7610
30	Children's Medical Center of Dallas	Dallas	Texas	United States	75235
31	Cook Childrens Medical Center	Fort Worth	Texas	United States	76104
32	Texas Transplant Institute	San Antonio	Texas	United States	78229
33	Utah BMT/University of Utah Medical School	Salt Lake City	Utah	United States	84132
34	Virgina Commonwealth University	Richmond	Virginia	United States	23298
35	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
36	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53211
37	Children's Hospital at Westmead	Westmead	New South Wales	Australia	2145
38	BC Cancer Agency	Vancouver	British Columbia	Canada	V5Z 4E3

Sponsors and Collaborators

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

Investigators

• Study Director: Mary Horowitz, MD, MS, Center for International Blood and Marrow Transplant Research

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Mar 18, 2010

More Information

Additional Information:

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

Publications

• Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi MS, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980 Aug;69(2):204-17.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT00412360
• Other Study ID Numbers: BMTCTN0501; 2U01HL069294; 5U24CA076518; NCT00429598
• First Posted: Dec 18, 2006
• Last Update Posted: Oct 28, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Medical College of Wisconsin: Double cord blood
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Fludarabine; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Cord Blood Unit Transplantation: Unrelated donor, single cord blood unit	Double Cord Blood Unit Transplantation: Unrelated donor, double cord blood unit
Period Title: Overall Study
STARTED	113	111
COMPLETED	112	108
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Single UCB Transplant	Double UCB Transplant	Total
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation	Total of all reporting groups
Overall Participants	113	111	224
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.4 (5.1)	10.4 (5.1)	10.4 (5.1)
Sex: Female, Male (Count of Participants)
Female	55 48.7%	41 36.9%	96 42.9%
Male	58 51.3%	70 63.1%	128 57.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	22 19.5%	20 18%	42 18.8%
Not Hispanic or Latino	88 77.9%	88 79.3%	176 78.6%
Unknown or Not Reported	3 2.7%	3 2.7%	6 2.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%	0 0%	1 0.4%
Asian	4 3.5%	5 4.5%	9 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	13 11.5%	11 9.9%	24 10.7%
White	80 70.8%	85 76.6%	165 73.7%
More than one race	3 2.7%	3 2.7%	6 2.7%
Unknown or Not Reported	12 10.6%	7 6.3%	19 8.5%
Primary Disease (Count of Participants)
Acute Myelogenous Leukemia (AML)	39 34.5%	38 34.2%	77 34.4%
Acute Lymphoblastic Leukemia (ALL)	61 54%	58 52.3%	119 53.1%
Acute Biphenotypic Leukemia	6 5.3%	2 1.8%	8 3.6%
Acute Undifferentiated Leukemia	1 0.9%	0 0%	1 0.4%
Myelodysplastic Syndrome (MDS)	5 4.4%	13 11.7%	18 8%
Chronic Myelogenous Leukemia (CML)	1 0.9%	0 0%	1 0.4%
AML Disease Status (Count of Participants)
First Complete Remission (CR)	17 15%	14 12.6%	31 13.8%
Second or Later CR	16 14.2%	19 17.1%	35 15.6%
First Relapse	1 0.9%	3 2.7%	4 1.8%
Morphologic CR before Complete-Blood-Count Recover	2 1.8%	2 1.8%	4 1.8%
Secondary or Therapy-related	3 2.7%	0 0%	3 1.3%
ALL Disease Status (Count of Participants)
First Complete Remission (CR)	19 16.8%	19 17.1%	38 17%
Second CR	29 25.7%	28 25.2%	57 25.4%
Subsequent CR	13 11.5%	10 9%	23 10.3%
Morphologic CR before Complete-Blood-Count Recover	0 0%	1 0.9%	1 0.4%
Acute Biphenotypic Leukemia Disease Status (Count of Participants)
First Complete Remission (CR)	5 4.4%	1 0.9%	6 2.7%
Second CR	1 0.9%	1 0.9%	2 0.9%
MDS Disease Status (Count of Participants)
Refractory Anemia	2 1.8%	0 0%	2 0.9%
Refractory Cytopenia with Multilineage Dysplasia	2 1.8%	3 2.7%	5 2.2%
Refractory Anemia with Excess Blasts 1 (RAEB1)	0 0%	3 2.7%	3 1.3%
Refractory Anemia with Excess Blasts 2 (RAEB2)	0 0%	4 3.6%	4 1.8%
Unclassified	1 0.9%	3 2.7%	4 1.8%
Karnofsky Performance Score (Count of Participants)
100%	58 51.3%	57 51.4%	115 51.3%
90%	38 33.6%	43 38.7%	81 36.2%
80%	13 11.5%	9 8.1%	22 9.8%
70%	4 3.5%	2 1.8%	6 2.7%
Recipient CMV Status (Count of Participants)
Positive	58 51.3%	66 59.5%	124 55.4%
Negative	51 45.1%	39 35.1%	90 40.2%
Inconclusive	1 0.9%	1 0.9%	2 0.9%
Unknown	3 2.7%	5 4.5%	8 3.6%
Weight at Infusion (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	39.6 (20.2)	38.7 (19.2)	39.15 (19.7)
Recipient to First Cord Blood Unit HLA Match (Count of Participants)
3/6	1 0.9%	2 1.8%	3 1.3%
4/6	44 38.9%	33 29.7%	77 34.4%
5/6	51 45.1%	59 53.2%	110 49.1%
6/6	16 14.2%	14 12.6%	30 13.4%
Recipient to Second Cord Blood Unit HLA Match (Count of Participants)
3/6	1 0.9%	1 0.9%
4/6	43 38.1%	43 38.7%
5/6	43 38.1%	43 38.7%
6/6	21 18.6%	21 18.9%
Recipient to First Cord Blood Unit ABO Match (Count of Participants)
Major Mismatch	30 26.5%	25 22.5%	55 24.6%
Minor Mismatch	24 21.2%	35 31.5%	59 26.3%
Bidirectional Mismatch	10 8.8%	8 7.2%	18 8%
No Mismatch	44 38.9%	36 32.4%	80 35.7%
Unknown	4 3.5%	4 3.6%	8 3.6%
Recipient to Second Cord Blood Unit ABO Match (Count of Participants)
Major mismatch	31 27.4%	31 27.9%
Minor mismatch	29 25.7%	29 26.1%
Bidirectional mismatch	4 3.5%	4 3.6%
No mismatch	38 33.6%	38 34.2%
Unknown	6 5.3%	6 5.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Overall Survival
Description	Overall survival is defined as survival of death from any cause.
Time Frame	1 year post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	113	111
Number (95% Confidence Interval) [percentage of participants]	73 64.6%	65 58.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in overall survival at one year post-randomization between participants receiving single- and double-unit cord blood transplant. The targeted sample size of 110 participants per treatment group was sufficient to maintain a type I error rate of 5% and provide more than 86% power to detect an increase in overall survival from 57% among participants receiving a single unit graft to 77% for those receiving a double-unit graft.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments	Testing was performed at a significance level of 0.05
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Percentage of Participants With Disease-free Survival
Description	Disease-free survival is defined as survival without relapse of the primary disease.
Time Frame	1 year post-randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	113	111
Number (95% Confidence Interval) [percentage of participants]	70 61.9%	64 57.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in disease-free survival at one year post-randomization between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments	Testing was performed at a significance level of 0.05
	Method	Log Rank
	Comments

3. Secondary Outcome

Title	Percentage of Participants With Neutrophil and Platelet Engraftment
Description	Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10^6/liter for three consecutive measurements on different days. The first of the three days will be designated the day of neutrophil engraftment. Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days.
Time Frame	Days 42 and 100

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
Neutrophil Engraftment at Day 42	89 78.8%	88 79.3%
Platelet Engraftment at Day 100	76 67.3%	65 58.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of neutrophil engraftment between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.29
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of platelet engraftment between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

4. Secondary Outcome

Title	Time to Neutrophil and Platelet Engraftment
Description	Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions. The first of the 7 days will be designated the day of platelet engraftment. Subjects must not have had platelet transfusions during the preceding 7 days.
Time Frame	2 years post-transplant

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
Neutrophil Engraftment	21	23
Platelet Engraftment	58	84

5. Secondary Outcome

Title	Percentage of Participants With Acute Graft-versus-host Disease (GVHD)
Description	Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash Rash <25% of body surface area Rash on 25-50% of body surface area Rash on > 50% of body surface area Generalized erythroderma with bullous formation Liver stage (based on bilirubin level)*: 0: <2 mg/dL 2-3 mg/dL 3.01-6 mg/dL 6.01-15.0 mg/dL >15 mg/dL GI stage*: 0: No diarrhea or diarrhea <500 mL/day Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD Diarrhea 1000-1499 mL/day Diarrhea >1500 mL/day Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1. GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
Time Frame	Day 100 post-randomization

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
Acute GVHD Grade II-IV	57 50.4%	56 50.5%
Acute GVHD Grade III-IV	13 11.5%	23 20.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of Grade II-IV acute GVHD between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.78
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of Grade III-IV acute GVHD between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

6. Secondary Outcome

Title	Percentage of Participants With Chronic GVHD
Description	Incidences of chronic GVHD will be graded per Shulman et al. 1980. This reference categorizes chronic GVHD as either limited or extensive. For this outcome, participants developing either type are considered to have a chronic GVHD event.
Time Frame	1 year post-randomization

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
Chronic GVHD	30 26.5%	32 28.8%
Extensive Chronic GVHD	9 8%	15 13.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of chronic GVHD between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of extensive chronic GVHD between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

7. Secondary Outcome

Title	Number of Infections Per Participant
Time Frame	2 years post-randomization

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
0	10 8.8%	9 8.1%
1	15 13.3%	13 11.7%
2	12 10.6%	15 13.5%
3	19 16.8%	10 9%
4	17 15%	15 13.5%
5	7 6.2%	12 10.8%
6-10	19 16.8%	24 21.6%
More than 10	13 11.5%	10 9%

8. Secondary Outcome

Title	Percentage of Participants With Relapse
Description	Relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, or MDS consistent with pre-transplant features. Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation.
Time Frame	1 year post-randomization

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
Number (95% Confidence Interval) [percentage of participants]	12 10.6%	14 12.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of relapse between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.12
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

9. Secondary Outcome

Title	Percentage of Participants With Treatment-related Mortality
Description	Treatment related mortality is defined as death without relapse of the primary disease.
Time Frame	1 year post-randomization

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
Number (95% Confidence Interval) [percentage of participants]	19 16.8%	22 19.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single UCB Transplant, Double UCB Transplant
	Comments	The null hypothesis is that there is no difference in the cumulative incidence of treatment-related mortality between participants receiving single- and double-unit cord blood transplant.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.43
	Comments	Testing was performed at a significance level of 0.05
	Method	Gray's test
	Comments

10. Secondary Outcome

Title	Number of Participants With Engraftment Syndrome
Time Frame	Day 100 post-transplant

Outcome Measure Data

Analysis Population Description

Transplanted participants

Arm/Group Title	Single UCB Transplant	Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation	Double Umbilical Cord Blood Unit Transplantation
Measure Participants	112	108
Count of Participants [Participants]	11 9.7%	7 6.3%

Adverse Events

Time Frame	2 years post-transplant
Adverse Event Reporting Description	Serious Adverse Events (AE) are defined as events associated with death, life-threatening event, disability, congenital anomaly, required intervention to prevent permanent impairment or damage, hospitalization or other serious adverse event. Only unexpected grades 3-5 adverse events were required to be reported through the AE system per protocol.
Arm/Group Title	Single UCB Transplant		Double UCB Transplant
Arm/Group Description	Single Umbilical Cord Blood Unit Transplantation		Double Umbilical Cord Blood Unit Transplantation
All Cause Mortality
	Single UCB Transplant		Double UCB Transplant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Single UCB Transplant		Double UCB Transplant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/112 (4.5%)		14/108 (13%)
Blood and lymphatic system disorders
Hemolytic anemia	0/112 (0%)	0	2/108 (1.9%)	2
Cardiac disorders
Congestive heart failure	1/112 (0.9%)	1	1/108 (0.9%)	1
Gastrointestinal disorders
Abdominal pain	0/112 (0%)	0	1/108 (0.9%)	1
Infections and infestations
Pneumonia	0/112 (0%)	0	1/108 (0.9%)	1
Septic shock	0/112 (0%)	0	1/108 (0.9%)	1
Metabolism and nutrition disorders
Hyperglycemia	2/112 (1.8%)	2	0/108 (0%)	0
Nervous system disorders
Acute intracranial Hemorrage	0/112 (0%)	0	1/108 (0.9%)	1
Seizure/aspiration Pneumonia	1/112 (0.9%)	1	0/108 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/112 (0%)	0	2/108 (1.9%)	2
Pulmonary Hemorrage	0/112 (0%)	0	1/108 (0.9%)	1
Aspiration	0/112 (0%)	0	1/108 (0.9%)	1
Aspiration Pneumonia	1/112 (0.9%)	1	0/108 (0%)	0
Vascular disorders
Hypotension	0/112 (0%)	0	1/108 (0.9%)	1
Hypertension	0/112 (0%)	0	1/108 (0.9%)	1
Hematoma	0/112 (0%)	0	1/108 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Single UCB Transplant		Double UCB Transplant
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/112 (0%)		0/108 (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.