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

Myelodysplastic Syndrome Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00412360
• Other study ID #: BMTCTN0501
• Secondary ID: 2U01HL0692945U24
• Status: Completed
• Phase: Phase 3
• Start date: December 2006
• Est. completion date: October 2014

Study information

• Verified date: October 2021
• Source: Medical College of Wisconsin
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Other known NCT identifiers

• NCT00429598

Recruitment information / eligibility

• Status: Completed
• Enrollment: 224
• Est. completion date: October 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 21 Years

Eligibility

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 (ß-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

Related Conditions & MeSH terms

• Acute Lymphocytic Leukemia
• Acute Myelogenous Leukemia
• Chronic Myelogenous Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Natural Killer Cell Lymphoblastic Leukemia/Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Biological:
• Single Umbilical Cord Blood Unit Transplant
Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
• 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.

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.
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
Australia	Children's Hospital at Westmead	Westmead	New South Wales
Canada	BC Cancer Agency	Vancouver	British Columbia
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	University of Alabama	Birmingham	Alabama
United States	DFCI/Children's Hospital of Boston	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Children's Medical Center of Dallas	Dallas	Texas
United States	The Children's Hospital of Denver	Denver	Colorado
United States	Karmanos Cancer Institute/Children's Hospital of Michigan	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Cook Childrens Medical Center	Fort Worth	Texas
United States	University of Florida College of Medicine (Shands)	Gainesville	Florida
United States	Indiana University Medical Center	Indianapolis	Indiana
United States	University of Mississippi	Jackson	Mississippi
United States	Nemours Childrens Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital and Clinics	Kansas City	Missouri
United States	University of Louisville/Kosiar Children's Hospital	Louisville	Kentucky
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Children's of New Orleans	New Orleans	Louisiana
United States	Childrens Hospital at Oakland	Oakland	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Oregon Health Sciences University	Portland	Oregon
United States	Virgina Commonwealth University	Richmond	Virginia
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Utah BMT/University of Utah Medical School	Salt Lake City	Utah
United States	Texas Transplant Institute	San Antonio	Texas
United States	UCSD/Rady Childrens Hospital	San Diego	California
United States	University of California, San Francisco (Peds)	San Francisco	California
United States	Fred Hutchinson Cancer Research Center	Seattle	Washington
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (5)

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

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

References & Publications (2)

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. — View Citation

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 trans — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Overall Survival	Overall survival is defined as survival of death from any cause.	1 year post-randomization
Secondary	Percentage of Participants With Disease-free Survival	Disease-free survival is defined as survival without relapse of the primary disease.	1 year post-randomization
Secondary	Percentage of Participants With Neutrophil and Platelet Engraftment	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.	Days 42 and 100
Secondary	Time to Neutrophil and Platelet 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.	2 years post-transplant
Secondary	Percentage of Participants With Acute Graft-versus-host Disease (GVHD)	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	Day 100 post-randomization
Secondary	Percentage of Participants With Chronic GVHD	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.	1 year post-randomization
Secondary	Number of Infections Per Participant		2 years post-randomization
Secondary	Percentage of Participants With Relapse	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.	1 year post-randomization
Secondary	Percentage of Participants With Treatment-related Mortality	Treatment related mortality is defined as death without relapse of the primary disease.	1 year post-randomization
Secondary	Number of Participants With Engraftment Syndrome		Day 100 post-transplant

External Links

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