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

Phase 3

Completed

• Conditions: Acute Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Natural Killer Cell Lymphoblastic Leukemia/Lymphoma; Myelodysplastic Syndrome; Acute Myelogenous Leukemia
• Interventions: 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

• Registration Number: NCT00412360
• Lead Sponsor: Medical College of Wisconsin

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.

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 Timeline

• Study Start: 2006-12
• Study First Submitted: 2006-12-14
• Study First Submitted QC: 2006-12-14
• Study First Posted: 2006-12-18
• Primary Completion: 2014-03
• Study Completion: 2014-10
• Results First Submitted: 2015-08-28
• Results First Submitted QC: 2015-11-17
• Results First Posted: 2015-12-21
• Status Verified: 2021-10
• Last Update Submitted: 2021-10-13
• Last Update Posted: 2021-10-28

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 224

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single Cord Blood Transplant	Cyclosporine A	Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Double Cord Blood Transplant	Total Body Irradiation	Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Single Cord Blood Transplant	Single Umbilical Cord Blood Unit Transplant	Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Single Cord Blood Transplant	Total Body Irradiation	Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Double Cord Blood Transplant	Double Umbilical Cord Blood Unit Transplant	Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Double Cord Blood Transplant	Cyclosporine A	Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Single Cord Blood Transplant	Fludarabine	Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Single Cord Blood Transplant	Cyclophosphamide	Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Single Cord Blood Transplant	Mycophenolate Mofetil	Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Double Cord Blood Transplant	Cyclophosphamide	Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Double Cord Blood Transplant	Fludarabine	Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
Double Cord Blood Transplant	Mycophenolate Mofetil	Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Treatment-related Mortality	1 year post-randomization	Treatment related mortality is defined as death without relapse of the primary disease.
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.
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.
Percentage of Participants With Disease-free Survival	1 year post-randomization	Disease-free survival is defined as survival without relapse of the primary disease.
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; 1. Rash \<25% of body surface area; 2. Rash on 25-50% of body surface area; 3. Rash on \> 50% of body surface area; 4. Generalized erythroderma with bullous formation; Liver stage (based on bilirubin level)\*: 0: \<2 mg/dL; 1. 2-3 mg/dL; 2. 3.01-6 mg/dL; 3. 6.01-15.0 mg/dL; 4. \>15 mg/dL; GI stage\*: 0: No diarrhea or diarrhea \<500 mL/day; 1. Diarrhea 500-999 mL/day or persistent nausea with histologic evidence of GVHD; 2. Diarrhea 1000-1499 mL/day; 3. Diarrhea \>1500 mL/day; 4. Severe abdominal pain with or without ileus \* If multiple etiologies are listed for liver or GI, the organ system is downstaged by 1.; GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4
Percentage of Participants With Chronic GVHD	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.
Number of Infections Per Participant	2 years post-randomization
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.
Number of Participants With Engraftment Syndrome	Day 100 post-transplant

Trial Locations

Locations (38)

University of Mississippi; 🇺🇸 Jackson, Mississippi, United States

Children's Medical Center of Dallas; 🇺🇸 Dallas, Texas, United States

New York Medical College; 🇺🇸 Valhalla, New York, United States

Childrens Hospital at Oakland; 🇺🇸 Oakland, California, United States

Children's National Medical Center; 🇺🇸 Washington, District of Columbia, United States

University of Florida College of Medicine (Shands); 🇺🇸 Gainesville, Florida, United States

Nemours Childrens Clinic; 🇺🇸 Jacksonville, Florida, United States

Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

All Children's Hospital; 🇺🇸 Saint Petersburg, Florida, United States

University of Michigan Medical Center; 🇺🇸 Ann Arbor, Michigan, United States

University of Louisville/Kosiar Children's Hospital; 🇺🇸 Louisville, Kentucky, United States

Children's Mercy Hospital and Clinics; 🇺🇸 Kansas City, Missouri, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Cook Childrens Medical Center; 🇺🇸 Fort Worth, Texas, United States

Virgina Commonwealth University; 🇺🇸 Richmond, Virginia, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Children's Hospital at Westmead; 🇦🇺 Westmead, New South Wales, Australia

BC Cancer Agency; 🇨🇦 Vancouver, British Columbia, Canada

UCSD/Rady Childrens Hospital; 🇺🇸 San Diego, California, United States

University of California, San Francisco (Peds); 🇺🇸 San Francisco, California, United States

The Children's Hospital of Denver; 🇺🇸 Denver, Colorado, United States

University of Alabama; 🇺🇸 Birmingham, Alabama, United States

Utah BMT/University of Utah Medical School; 🇺🇸 Salt Lake City, Utah, United States

Indiana University Medical Center; 🇺🇸 Indianapolis, Indiana, United States

University of Miami; 🇺🇸 Miami, Florida, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

Oregon Health Sciences University; 🇺🇸 Portland, Oregon, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Fred Hutchinson Cancer Research Center; 🇺🇸 Seattle, Washington, United States

DFCI/Children's Hospital of Boston; 🇺🇸 Boston, Massachusetts, United States

Karmanos Cancer Institute/Children's Hospital of Michigan; 🇺🇸 Detroit, Michigan, United States

Texas Transplant Institute; 🇺🇸 San Antonio, Texas, United States

Phoenix Children's Hospital; 🇺🇸 Phoenix, Arizona, United States

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Children's of New Orleans; 🇺🇸 New Orleans, Louisiana, United States