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Myeloablative Umbilical Cord Blood Transplantation in Hematological Diseases

Primary Purpose

Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Chronic Myelogenous Leukemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
filgrastim
cyclophosphamide
cyclosporine
fludarabine phosphate
mycophenolate mofetil
umbilical cord blood transplantation
total-body irradiation
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring blastic phase chronic myelogenous leukemia, primary myelofibrosis, chronic myelomonocytic leukemia, myelodysplastic syndromes, juvenile myelomonocytic leukemia, recurrent adult Burkitt lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent lymphoblastic lymphoma, recurrent childhood acute myeloid leukemia, recurrent childhood large cell lymphoma, recurrent follicular lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, refractory multiple myeloma, chronic myelogenous leukemia, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, multiple myeloma, adult lymphoblastic lymphoma, refractory anemia with excess blasts, refractory anemia, Burkitt lymphoma, childhood large cell lymphoma, adult Burkitt lymphoma, mantle cell lymphoma, childhood lymphoblastic lymphoma, childhood myelodysplastic syndromes

Eligibility Criteria

undefined - 55 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Acute myeloid leukemia (AML): high risk CR1 (as evidenced by preceding myelodysplastic syndrome [MDS], high risk cytogenetics, ≥ 2 cycles to obtain complete remission [CR], erythroblastic or megakaryocytic leukemia; CR2+. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Very high risk pediatric patients with AML. Patients <21 years, however, are eligible with (M2 marrow) with < or = 25% blasts in marrow after having failed one or more cycles of chemotherapy. This group of patients will be analyzed separately. Acute lymphocytic leukemia (ALL): high risk CR1 [t(9;22), t (1:19), t(4;11) or other MLL rearrangements] hypodiploidy, or IKZF1 abnormalities), DNA index < 0.81, > 1 cycle to obtain CR or presence minimal residual disease (MRD). Patients in CR2+ are eligible. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Very high risk pediatric patients with ALL. patients <21 years are also considered high risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of induction or M3 marrow at the end of induction. They are eligible once they achieved a complete remission Chronic myelogenous leukemia (CML) excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate. Plasma Cell leukemia after initial therapy, who achieved at least a partial remission Advanced myelofibrosis Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a representative bone marrow aspirate morphology. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma are eligible if there was disease progression/relapse within 12 of achieving a partial or complete remission. Patients who had remissions lasting > 12 months, are eligible after at least two prior therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant. Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or PR1+. Large cell NHL > CR2/> PR2. Patients in CR2/PR2 with initial short remission (<6 months) are eligible. Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial therapy if stage III/IV in CR1/PR1 or after progression if stage I/II < 1 year. Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered for this protocol after initial therapy. Recipients must have a Karnofsky score (adults) ≥ 80 % or Lansky score ≥ 50% (pediatrics), and proper organ function. Exclusion Criteria Active infection at time of transplantation History of human immunodeficiency virus (HIV) infection Pregnant or breast feeding. Chemotherapy refractory large cell and high grade NHL If < or = 18 years old, prior myeloablative transplant within the last 6 months. If >18 years old prior myeloablative allotransplant or autologous transplant Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation. Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy.

Sites / Locations

  • Masonic Cancer Center at University of Minnesota
  • Fred Hutchinson Cancer Research Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Unrelated UCBT for Blood Cancers

Arm Description

Patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine phosphate, mycophenolate mofetil, filgrastim, cyclophosphamide, cyclosporine and fractionated total-body irradiation.

Outcomes

Primary Outcome Measures

Number of Participants Who Were Alive at 1 Year Transplant Overall Survival
Number of patients alive at 1 year after transplant.

Secondary Outcome Measures

Number of Participants Who Died Due to Transplant
Determine the incidence of transplant-related mortality at 6 months after UCBT
Number of Participants With Platelet Engraftment
Determine the incidence of platelet engraftment (platelet recovery >50,000/uL) at 6 months after UCBT.
Number of Participants With Neutrophil Engraftment
Determine the incidence of neutrophil engraftment at day 42 after UCBT Patients diagnosed with graft failure (failure of absolute neutrophil count ANC > 5 x 10^8/L of donor origin by day +42)
Number of Participants With Acute Graft-Versus-Host Disease
Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria following Przepiorka et al, 1995, Consensus Clinical Stage and Grade of Acute GVHD. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.
Number of Participants With Chronic Graft-Versus-Host Disease
Determine the incidence of chronic GVHD at 1 year after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.
Percentage Chimerism on Day 21
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Percentage Chimerism on Day 100
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Percentage Chimerism at 6 Months
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Percentage Chimerism at 1 Year
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Percentage Chimerism at 2 Years
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.

Full Information

First Posted
March 29, 2006
Last Updated
September 9, 2020
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT00309842
Brief Title
Myeloablative Umbilical Cord Blood Transplantation in Hematological Diseases
Official Title
Transplantation of Unrelated Umbilical Cord Blood for Patients With Hematological Diseases With Cyclophosphamide/Fludarabine/Total Body Irradiation Myeloablative Preparative Regimen
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Completed
Study Start Date
July 28, 2005 (Actual)
Primary Completion Date
July 29, 2019 (Actual)
Study Completion Date
November 22, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
RATIONALE: Giving chemotherapy drugs, such as fludarabine and cyclophosphamide, and total-body irradiation before a donor umbilical cord blood stem cell transplant helps stop the growth of cancer cells and prepares the patient's bone marrow for the stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclosporine and mycophenolate mofetil may stop this from happening. PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing an umbilical cord blood transplant for hematologic cancer.
Detailed Description
OBJECTIVES: Primary Determine the 1-year survival of patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine, cyclophosphamide, and fractionated total-body irradiation. Secondary Determine the incidence of transplant-related mortality at 6 months after UCBT. Evaluate the pattern of chimerism after double UCBT. Determine the incidence of neutrophil engraftment at day 42 after UCBT. Determine the incidence of platelet engraftment at 6 months after UCBT. Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT. Determine the incidence of chronic GVHD at 1 year after UCBT. Determine the disease-free survival at 1 and 2 years after UCBT. Determine the incidence of relapse at 1 year after UCBT. OUTLINE: This is a nonrandomized, open-label, multicenter study. Preparative Regimen: Patients receive fludarabine IV over 1 hour on days -8 to -6 and cyclophosphamide IV on days -7 and -6. Patients also undergo total-body irradiation twice daily on days -4 to -1. Umbilical Cord Blood Transplantation (UCBT): Patients undergo 1 or 2 units of UCBT on day 0. Patients receive filgrastim (G-CSF) IV once daily beginning on day 1 and continuing until blood counts recover. Graft-versus-host disease (GVHD) prophylaxis: Patients receive cyclosporine IV over 2 hours 2 or 3 times daily beginning on day -3 and continuing until day 100 followed by a taper until day 180. Patients also receive mycophenolate mofetil IV or orally 2 or 3 times a day beginning on day -3 and continuing until day 30 or 7 days after engraftment in the absence of acute GVHD. After completion of study treatment, patients are followed periodically for at least 5 years. PROJECTED ACCRUAL: A total of 150 patients will be accrued for this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Myelofibrosis, MDS, Refractory Anemia, Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Non-Hodgkin's Lymphoma, Leukemia, Lymphoma, Multiple Myeloma, Myelodysplastic Syndromes
Keywords
blastic phase chronic myelogenous leukemia, primary myelofibrosis, chronic myelomonocytic leukemia, myelodysplastic syndromes, juvenile myelomonocytic leukemia, recurrent adult Burkitt lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent lymphoblastic lymphoma, recurrent childhood acute myeloid leukemia, recurrent childhood large cell lymphoma, recurrent follicular lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, refractory multiple myeloma, chronic myelogenous leukemia, secondary acute myeloid leukemia, secondary myelodysplastic syndromes, multiple myeloma, adult lymphoblastic lymphoma, refractory anemia with excess blasts, refractory anemia, Burkitt lymphoma, childhood large cell lymphoma, adult Burkitt lymphoma, mantle cell lymphoma, childhood lymphoblastic lymphoma, childhood myelodysplastic syndromes

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
213 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Unrelated UCBT for Blood Cancers
Arm Type
Experimental
Arm Description
Patients undergoing unrelated umbilical cord blood transplantation (UCBT) for hematologic malignancies treated with myeloablative preparative regimen comprising fludarabine phosphate, mycophenolate mofetil, filgrastim, cyclophosphamide, cyclosporine and fractionated total-body irradiation.
Intervention Type
Biological
Intervention Name(s)
filgrastim
Other Intervention Name(s)
G-CSF
Intervention Description
All patients will receive G-CSF 5 mcg/kg/day intravenously(IV) (dose rounded to vial size) based on the actual body weight IV beginning on day +1 after umbilical cord blood (UCB) infusion. G-CSF will be administered daily until the absolute neutrophil count (ANC) exceeds 2.5 x 10^9/L for three consecutive days.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Cyclophosphamide to be administered with high volume fluid flush and mesna (MT(S) 9006) at 10:00am, or per institutional routine, on days-7 and -6 after fludarabine. Cyclophosphamide 60mg/kg/day intravenous (IV) x 2 days, total dose 120 mg/kg (days -7 and -6) Dosing is calculated based on Actual BodyWeight (ABW) unless ABW > 30 kg above Ideal BodyWeight (IBW), in which case the dose should be computed using adjusted body weight.
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
CSA
Intervention Description
Patients will receive cyclosporine (CSA) therapy beginning on day -3 maintaining a level of > 200 ng/mL. For adults the initial dose will be 2.5 mg/kg intravenously (IV) over 2 hours every 12 hours. For children < 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours.
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
Fludara
Intervention Description
Fludarabine 25 mg/m2/day intravenously (IV) x 3 days, total dose 75 mg/m2 (days -8 to -6);
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
MMF
Intervention Description
All patients will begin mycophenolate mofetil (MMF) on day -3. Patients ≥ 40 kilograms will receive MMF at the dose of 3 grams/day divided into 2 or 3 doses (every 12 or 8 hours). Pediatric patient (<40 kilograms) will receive MMF at the dose of 15 mg/kg three times a day.
Intervention Type
Procedure
Intervention Name(s)
umbilical cord blood transplantation
Other Intervention Name(s)
UCBT
Intervention Description
The product is infused via intravenous (IV) drip directly into the central line without a needle, pump or filter.
Intervention Type
Radiation
Intervention Name(s)
total-body irradiation
Other Intervention Name(s)
TBI
Intervention Description
The recommended TBI is 165 cGy given twice daily for a total dose of 1320 cGy (days -4 to -1).
Primary Outcome Measure Information:
Title
Number of Participants Who Were Alive at 1 Year Transplant Overall Survival
Description
Number of patients alive at 1 year after transplant.
Time Frame
at 1 year
Secondary Outcome Measure Information:
Title
Number of Participants Who Died Due to Transplant
Description
Determine the incidence of transplant-related mortality at 6 months after UCBT
Time Frame
At Month 6
Title
Number of Participants With Platelet Engraftment
Description
Determine the incidence of platelet engraftment (platelet recovery >50,000/uL) at 6 months after UCBT.
Time Frame
6 months
Title
Number of Participants With Neutrophil Engraftment
Description
Determine the incidence of neutrophil engraftment at day 42 after UCBT Patients diagnosed with graft failure (failure of absolute neutrophil count ANC > 5 x 10^8/L of donor origin by day +42)
Time Frame
Day 42
Title
Number of Participants With Acute Graft-Versus-Host Disease
Description
Determine the incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at day 100 after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria following Przepiorka et al, 1995, Consensus Clinical Stage and Grade of Acute GVHD. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.
Time Frame
Day 100
Title
Number of Participants With Chronic Graft-Versus-Host Disease
Description
Determine the incidence of chronic GVHD at 1 year after UCBT. Patients will be staged weekly between days 0 and 100 after transplantation using standard criteria. Patients will be assigned an overall GVHD score based on extent of skin rash, volume of diarrhea and maximum bilirubin level.
Time Frame
Year 1
Title
Percentage Chimerism on Day 21
Description
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Time Frame
Day 21
Title
Percentage Chimerism on Day 100
Description
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Time Frame
Day 100
Title
Percentage Chimerism at 6 Months
Description
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Time Frame
Month 6
Title
Percentage Chimerism at 1 Year
Description
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Time Frame
1 Year
Title
Percentage Chimerism at 2 Years
Description
Chimerism studies will be performed on the bone marrow on days 21 and 100 and at 6 months, 1 year and 2 years. In cases of slow engraftment a bone marrow biopsy may be repeated on day +28.
Time Frame
2 Years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Acute myeloid leukemia (AML): high risk CR1 (as evidenced by preceding myelodysplastic syndrome [MDS], high risk cytogenetics, ≥ 2 cycles to obtain complete remission [CR], erythroblastic or megakaryocytic leukemia; CR2+. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Very high risk pediatric patients with AML. Patients <21 years, however, are eligible with (M2 marrow) with < or = 25% blasts in marrow after having failed one or more cycles of chemotherapy. This group of patients will be analyzed separately. Acute lymphocytic leukemia (ALL): high risk CR1 [t(9;22), t (1:19), t(4;11) or other MLL rearrangements] hypodiploidy, or IKZF1 abnormalities), DNA index < 0.81, > 1 cycle to obtain CR or presence minimal residual disease (MRD). Patients in CR2+ are eligible. All patients must be in CR as defined by hematological recovery, AND <5% blasts by light microscopy within the bone marrow with a cellularity of ≥15%. Very high risk pediatric patients with ALL. patients <21 years are also considered high risk CR1 if they had M2 or M3 marrow at day 42 from the initiation of induction or M3 marrow at the end of induction. They are eligible once they achieved a complete remission Chronic myelogenous leukemia (CML) excluding refractory blast crisis. To be eligible in first chronic phase (CP1) patient must have failed or be intolerant to imatinib mesylate. Plasma Cell leukemia after initial therapy, who achieved at least a partial remission Advanced myelofibrosis Myelodysplasia (MDS) IPSS Int-2 or High risk (i.e. RAEB, RAEBt) or refractory anemia with severe pancytopenia or high risk cytogenetics. Blasts must be < 10% by a representative bone marrow aspirate morphology. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), marginal zone B-cell lymphoma or follicular lymphoma are eligible if there was disease progression/relapse within 12 of achieving a partial or complete remission. Patients who had remissions lasting > 12 months, are eligible after at least two prior therapies. Patients with bulky disease (nodal mass greater than 5 cm) should be considered for debulking chemotherapy before transplant. Lymphoplasmacytic lymphoma, mantle-cell lymphoma, prolymphocytic leukemia are eligible after initial therapy in CR1+ or PR1+. Large cell NHL > CR2/> PR2. Patients in CR2/PR2 with initial short remission (<6 months) are eligible. Lymphoblastic lymphoma, Burkitt's lymphoma, and other high-grade NHL after initial therapy if stage III/IV in CR1/PR1 or after progression if stage I/II < 1 year. Multiple myeloma beyond PR2. Patients with chromosome 13 abnormalities, first response lasting less than 6 months, or β-2 microglobulin > 3 mg/L, may be considered for this protocol after initial therapy. Recipients must have a Karnofsky score (adults) ≥ 80 % or Lansky score ≥ 50% (pediatrics), and proper organ function. Exclusion Criteria Active infection at time of transplantation History of human immunodeficiency virus (HIV) infection Pregnant or breast feeding. Chemotherapy refractory large cell and high grade NHL If < or = 18 years old, prior myeloablative transplant within the last 6 months. If >18 years old prior myeloablative allotransplant or autologous transplant Extensive prior therapy including > 12 months alkylator therapy or > 6 months alkylator therapy with extensive radiation. Patients who have received Y-90 ibritumomab (Zevalin) or I-131 tostumomab (Bexxar), as part of their salvage therapy.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Claudio G. Brunstein, MD, PhD
Organizational Affiliation
Masonic Cancer Center, University of Minnesota
Official's Role
Study Chair
Facility Information:
Facility Name
Masonic Cancer Center at University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
19706886
Citation
Verneris MR, Brunstein CG, Barker J, MacMillan ML, DeFor T, McKenna DH, Burke MJ, Blazar BR, Miller JS, McGlave PB, Weisdorf DJ, Wagner JE. Relapse risk after umbilical cord blood transplantation: enhanced graft-versus-leukemia effect in recipients of 2 units. Blood. 2009 Nov 5;114(19):4293-9. doi: 10.1182/blood-2009-05-220525. Epub 2009 Aug 25.
Results Reference
result
PubMed Identifier
18997171
Citation
MacMillan ML, Weisdorf DJ, Brunstein CG, Cao Q, DeFor TE, Verneris MR, Blazar BR, Wagner JE. Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood. 2009 Mar 12;113(11):2410-5. doi: 10.1182/blood-2008-07-163238. Epub 2008 Nov 7.
Results Reference
derived

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Myeloablative Umbilical Cord Blood Transplantation in Hematological Diseases

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