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

• ClinicalTrials.gov Identifier: NCT00412360
• Recruitment Status: Completed
• First Posted: December 18, 2006
• Results First Posted: December 21, 2015
• Last Update Posted: October 28, 2021
• Sponsor: Medical College of Wisconsin
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Blood and Marrow Transplant Clinical Trials Network; National Cancer Institute (NCI); National Marrow Donor Program
• Information provided by (Responsible Party): Medical College of Wisconsin

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 (Clinical Trial)
• 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: December 2006
• Actual Primary Completion Date: March 2014
• Actual Study Completion Date: October 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: MMF, Cellcept®

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Overall Survival [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: Day 100 post-randomization ]

   Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995:

   Skin stage:

   0: No rash

   1. Rash <25% of body surface area
   2. Rash on 25-50% of body surface area
   3. Rash on > 50% of body surface area
   4. Generalized erythroderma with bullous formation

   Liver stage (based on bilirubin level)*:

   0: <2 mg/dL

   1. 2-3 mg/dL
   2. 3.01-6 mg/dL
   3. 6.01-15.0 mg/dL
   4. >15 mg/dL

   GI stage*:

   0: No diarrhea or diarrhea <500 mL/day

   1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD
   2. Diarrhea 1000-1499 mL/day
   3. Diarrhea >1500 mL/day
   4. Severe abdominal pain with or without ileus * If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.

   GVHD grade:

   0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4

5. Percentage of Participants With Chronic GVHD [ Time Frame: 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 [ Time Frame: 2 years post-randomization ]
7. Percentage of Participants With Relapse [ Time Frame: 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 [ Time Frame: 1 year post-randomization ]
   Treatment related mortality is defined as death without relapse of the primary disease.
9. Number of Participants With Engraftment Syndrome [ Time Frame: Day 100 post-transplant ]

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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
  2. Second or greater CR
  3. First relapse with less than 25% blasts in bone marrow
  4. 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.

  2. 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.
  3. 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

United States, Alabama

University of Alabama

Birmingham, Alabama, United States, 35294

United States, Arizona

Phoenix Children's Hospital

Phoenix, Arizona, United States, 85016

United States, California

City of Hope National Medical Center

Duarte, California, United States, 91010

Childrens Hospital at Oakland

Oakland, California, United States, 94609

UCSD/Rady Childrens Hospital

San Diego, California, United States, 92123

University of California, San Francisco (Peds)

San Francisco, California, United States, 94143

United States, Colorado

The Children's Hospital of Denver

Denver, Colorado, United States, 80218

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Florida

University of Florida College of Medicine (Shands)

Gainesville, Florida, United States, 32610

Nemours Childrens Clinic

Jacksonville, Florida, United States, 32207

University of Miami

Miami, Florida, United States, 33136

All Children's Hospital

Saint Petersburg, Florida, United States, 33710

United States, Georgia

Children's Healthcare of Atlanta

Atlanta, Georgia, United States, 30322-1062

United States, Indiana

Indiana University Medical Center

Indianapolis, Indiana, United States, 46202

United States, Kentucky

University of Louisville/Kosiar Children's Hospital

Louisville, Kentucky, United States, 40202

United States, Louisiana

Children's of New Orleans

New Orleans, Louisiana, United States, 70118

United States, Massachusetts

DFCI/Children's Hospital of Boston

Boston, Massachusetts, United States, 02115

United States, Michigan

University of Michigan Medical Center

Ann Arbor, Michigan, United States, 48109

Karmanos Cancer Institute/Children's Hospital of Michigan

Detroit, Michigan, United States, 48201

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, Mississippi

University of Mississippi

Jackson, Mississippi, United States, 39216

United States, Missouri

Children's Mercy Hospital and Clinics

Kansas City, Missouri, United States, 64108

United States, New York

New York Medical College

Valhalla, New York, United States, 10595

United States, North Carolina

Duke University Medical Center

Durham, North Carolina, United States, 27705

United States, Ohio

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205-2696

United States, Oregon

Oregon Health Sciences University

Portland, Oregon, United States, 97239

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232-7610

United States, Texas

Children's Medical Center of Dallas

Dallas, Texas, United States, 75235

Cook Childrens Medical Center

Fort Worth, Texas, United States, 76104

Texas Transplant Institute

San Antonio, Texas, United States, 78229

United States, Utah

Utah BMT/University of Utah Medical School

Salt Lake City, Utah, United States, 84132

United States, Virginia

Virgina Commonwealth University

Richmond, Virginia, United States, 23298

United States, Washington

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States, 98109

United States, Wisconsin

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53211

Australia, New South Wales

Children's Hospital at Westmead

Westmead, New South Wales, Australia, 2145

Canada, British Columbia

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)

Documents provided by Medical College of Wisconsin:

Study Protocol, Statistical Analysis Plan, and Informed Consent Form  [PDF] March 18, 2010

More Information

Additional Information:

Blood and Marrow Transplant Clinical Trials Network 

National Marrow Donor Program 

Publications of Results:

Wagner JE Jr, Eapen M, Carter S, Wang Y, Schultz KR, Wall DA, Bunin N, Delaney C, Haut P, Margolis D, Peres E, Verneris MR, Walters M, Horowitz MM, Kurtzberg J; Blood and Marrow Transplant Clinical Trials Network. One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med. 2014 Oct 30;371(18):1685-94. doi: 10.1056/NEJMoa1405584.

Other 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. doi: 10.1016/0002-9343(80)90380-0.

• Responsible Party: Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT00412360
• Obsolete Identifiers: NCT00429598
• Other Study ID Numbers: BMTCTN0501; 2U01HL069294 ( U.S. NIH Grant/Contract ); 5U24CA076518 ( U.S. NIH Grant/Contract )
• First Posted: December 18, 2006
• Results First Posted: December 21, 2015
• Last Update Posted: October 28, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Findings were published in a manuscript.
• Time Frame: Within 6 months of official study closure at participating sites.
• Access Criteria: Available to the public.
• URL: https://biolincc.nhlbi.nih.gov/home/

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; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Cyclosporine; Mycophenolic Acid; Cyclophosphamide; Fludarabine; Cyclosporins; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents