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Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies

Primary Purpose

Beta Thalassemia Major, Sickle Beta 0 Thalassemia, Sickle Beta Plus Thalassemia

Status
Withdrawn
Phase
Early Phase 1
Locations
Study Type
Interventional
Intervention
Bortezomib
Busulfan
Cyclophosphamide
Dexamethasone
Fludarabine Phosphate
Hematopoietic Cell Transplantation
Lapine T-Lymphocyte Immune Globulin
Mycophenolate Mofetil
Plasmapheresis
Rituximab
Tacrolimus
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Beta Thalassemia Major

Eligibility Criteria

2 Years - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients 2-30 years-of-age with confirmed sickle cell disease (SCD) (SS & sickle beta [SB]-thalassemia, both sickle beta 0 [SB0] and sickle beta plus [SB+]) or severe B-thalassemia major are potentially eligible
  • Patients with SCD should also meet the following eligibility criteria as outlined by the Center for Medicaid and Medicare Services: sickle cell disease and at least one of the following:

    • Stroke or neurological deficit lasting > 24 hours
    • Recurrent acute chest syndrome (ACS): 2 or more episodes of ACS in 2-year period preceding enrollment
    • Recurrent vaso-occlusive pain crises: 3 or more episodes per year in 2-year period preceding enrollment or recurrent priapism (3 or more episodes in the 2 years preceding enrollment)
    • Chronic transfusion program defined as 8 or more packed red blood cells (PRBC) transfusions per year to prevent central nervous system and/or vaso-occlusive complications in 1-year period preceding enrollment
    • Impaired neuropsychological function and abnormal cerebral magnetic resonance imaging (MRI) scan (silent strokes)
    • Stage I or II sickle lung disease
    • Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of predicted normal value)
    • Bilateral proliferative retinopathy and major visual impairment in at least one eye
    • Osteonecrosis of multiple joints
    • Echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) >= 2.7 m/sec
  • Patients with B-thalassemia are considered as severe if they are/have any of the following:

    • Transfusion-dependent
    • Evidence of extra-medullary hematopoiesis
    • Pesaro Class III
  • Patients shall not proceed to HCT without confirmation of primary diagnosis by review of available newborn screening results or hemoglobin electrophoresis and/or genetic testing
  • DONOR: High resolution HLA typing will be performed on all willing and available biologic parents and siblings without clinically significant hemoglobinopathy. Preference will be given to donors with the lowest number of HLA-allele mismatches
  • DONOR: Donor-specific anti-HLA antibodies will be obtained and analyzed from all patients. Preference will be given to donors with absent or low titer anti HLA-donor specific antibody levels when possible

Exclusion Criteria:

  • Uncontrolled infection
  • Females who are pregnant and/or unwilling to cease breastfeeding
  • Seropositivity for human immunodeficiency virus (HIV)
  • Lansky or Karnofsky performance status < 70%
  • Life expectancy severely limited by concomitant illness
  • Uncontrolled arrhythmias or symptomatic cardiac disease
  • Uncontrolled symptomatic pulmonary disease
  • Evidence of chronic active hepatitis or cirrhosis
  • Serum conjugated (direct) bilirubin > 2 x upper limit of normal for age. Participants are not excluded if the serum conjugated (direct) bilirubin is > 2 x the upper limit of normal for age as per local laboratory and:

    • There is evidence of a hyperhemolytic reaction after a recent red blood cell (RBC) transfusion, OR
    • There is evidence of moderate direct hyperbilirubinemia defined as direct serum bilirubin < 5 times upper limit of normal (ULN) and not caused by underlying hepatic disease
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 5 x upper limit of normal for age
  • Serum creatinine > 1.5 x upper limit of normal for age AND estimated or measure creatinine clearance < 70 mL/min/1.72 m^2
  • Patient, parent or guardian unable/unwilling to provide consent and when indicated, assent
  • Patients with available HLA-matched related donor
  • Prior receipt of gene therapy
  • DONOR: All potential donors shall be tested by hemoglobin electrophoresis. Any potential donor with a clinically significant hemoglobinopathy will be deemed ineligible. Donors with sickle cell trait and beta thalassemia trait are eligible to donate

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Treatment (PTIS, HCT)

    Arm Description

    See Detailed Description.

    Outcomes

    Primary Outcome Measures

    Event-free survival (EFS)
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.

    Secondary Outcome Measures

    Event-free survival
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
    Event-free survival
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
    Overall survival
    Will be summarized by the Kaplan-Meier method.
    Overall survival
    Will be summarized by the Kaplan-Meier method.
    Transplant-related mortality
    Will be summarized by the Kaplan-Meier method.
    Time to platelet and neutrophil engraftment
    Will be estimated using the method of Gooley et al.
    Incidence of graft failure (primary and secondary)
    Will be estimated using the method of Gooley et al.
    Incidence of acute graft-versus-host disease
    Will be estimated using the method of Gooley et al.
    Incidence of chronic graft-versus-host disease
    Will be estimated using the method of Gooley et al.
    Incidence of chronic graft-versus-host disease
    Will be estimated using the method of Gooley et al.
    Incidence of grade II or greater organ toxicity
    Will be reported as counts with percentages.
    Incidence of hepatic sinusoidal obstruction syndrome
    Will be reported as counts with percentages.
    Incidence of central nervous system toxicities including posterior reversible encephalopathy syndrome
    Will be reported as counts with percentages.
    Incidence of infectious complications
    Will be reported as counts with percentages.

    Full Information

    First Posted
    February 8, 2021
    Last Updated
    February 16, 2023
    Sponsor
    M.D. Anderson Cancer Center
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04776850
    Brief Title
    Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies
    Official Title
    Pre-Transplant Immunosuppression and Related Haploidentical Hematopoietic Cell Transplantation for Patients With Severe Hemoglobinopathies
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2022
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Competing protocol opened in Adult SCT that will include pediatric patients and is now multi-center. No patients enrolled on study.
    Study Start Date
    December 29, 2020 (Actual)
    Primary Completion Date
    December 5, 2022 (Actual)
    Study Completion Date
    December 5, 2022 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    M.D. Anderson Cancer Center

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This clinical trial studies the effect of pre-transplant immunosuppression (PTIS) and donor stem cell transplant in treating patients with severe blood diseases (hemoglobinopathies). PTIS helps prepare the body for the transplant and lowers the risk of developing graft versus host disease (GVHD). Hematopoietic cells are found in the bone marrow and produce blood cells. Hematopoietic cell transplantation (HCT) injects healthy hematopoietic cells into the body to support blood cell production. PTIS and HCT may help to control severe hemoglobinopathies.
    Detailed Description
    PRIMARY OBJECTIVE: I. To estimate event-free survival (EFS) at 2-years post HCT. SECONDARY OBJECTIVES: I. Assess event-free survival (EFS) at 100 days and 1 year post HCT. II. Assess overall survival (OS) at 100 days and 1 year post HCT. III. 30-day transplant-related mortality (TRM). IV. Time to platelet and neutrophil engraftment. V. Rate of graft failure (primary and secondary) through day 100. VI. Incidence of acute graft-versus-host disease (aGVHD) by day 100. VII. Incidence of chronic graft-versus-host disease (cGVHD) by 1 year and 2 years. VIII. Rate of grade II or greater organ toxicity through day 100. IX. Incidence of hepatic sinusoidal obstruction syndrome (SOS) by day 100. X. Incidence of central nervous system (CNS) toxicities including posterior reversible encephalopathy syndrome (PRES) by day 100. XI. Incidence of infectious complications through day 100. EXPLORATORY OBJECTIVES: I. Effect of HCT on clinical and laboratory manifestations of hemoglobinopathies by 1 and 2 years after HCT. II. Assess the pharmacokinetic profile of busulfan and thymoglobulin to better understand post-transplant outcomes. III. Assess immune reconstitution kinetics post HCT. OUTLINE: DONOR-SPECIFIC ANTI-HLA DESENSITIZATION: Patients with donor-specific anti-HLA antibody titers >= 1:3,000 at the start of PTIS receive rituximab intravenously (IV) on days -69, -41, -28, and -13 and bortezomib IV over less than 1 minute on days -68, -65, -40, and -37 in the absence of unacceptable toxicity. Patients with donor-specific anti-HLA antibody titers > 1:15,000 at the start of PTIS receive receive rituximab IV on days -69, -41, -28, and -13 and bortezomib IV over less than 1 minute on days -68, -65, -62, -58, -40, -37, -34, and -31 in the absence of unacceptable toxicity. Patients with donor-specific anti-HLA antibody titers > 1:5,000 at the start of conditioning may also undergo plasmapheresis on day -12. PTIS: Patients receive fludarabine phosphate (fludarabine) IV over 1 hour and dexamethasone IV over less than 1 minute on days -68 to -64 and days -40 to -36 in the absence of disease progression or unacceptable toxicity. CONDITIONING: Patients receive lapine T-lymphocyte immune globulin (rATG) IV over 4-6 hours on days -12 to -10, fludarabine phosphate IV over 1 hour on days -8 to -4, and busulfan IV over 2 hours on days -7 to -4 in the absence of disease progression or unacceptable toxicity. TRANSPLANT: Patients undergo HCT on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 2-3 hours on days 3 and 4 in the absence of unacceptable toxicity. Beginning on day 5, patients also receive tacrolimus IV continuously daily and then orally (PO) twice daily (BID) at the discretion of the treating physician for up to 12 months, and mycophenolate mofetil IV or PO BID up to day 60 in the absence of unacceptable toxicity. After completion of HCT, patients are followed up periodically for up to 2 years.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Beta Thalassemia Major, Sickle Beta 0 Thalassemia, Sickle Beta Plus Thalassemia, Sickle Beta Thalassemia, Sickle Cell Disease, Sickle Cell-SS Disease

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Early Phase 1
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Treatment (PTIS, HCT)
    Arm Type
    Experimental
    Arm Description
    See Detailed Description.
    Intervention Type
    Drug
    Intervention Name(s)
    Bortezomib
    Other Intervention Name(s)
    [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Busulfan
    Other Intervention Name(s)
    1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Cyclophosphamide
    Other Intervention Name(s)
    (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Dexamethasone
    Other Intervention Name(s)
    Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Fludarabine Phosphate
    Other Intervention Name(s)
    2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
    Intervention Description
    Given IV
    Intervention Type
    Procedure
    Intervention Name(s)
    Hematopoietic Cell Transplantation
    Other Intervention Name(s)
    HCT, Hematopoietic Stem Cell Transplantation, HSCT, Stem Cell Transplant, stem cell transplantation
    Intervention Description
    Undergo HCT
    Intervention Type
    Biological
    Intervention Name(s)
    Lapine T-Lymphocyte Immune Globulin
    Other Intervention Name(s)
    Anti-Thymocyte Globulin Rabbit, Grafalon, Rabbit Anti-Human Thymocyte Globulin (RATG), Rabbit Anti-Thymocyte Globulin, Rabbit Antithymocyte Globulin, Rabbit ATG, rATG, Thymoglobulin
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Mycophenolate Mofetil
    Other Intervention Name(s)
    CellCept, MMF
    Intervention Description
    Given IV or PO
    Intervention Type
    Procedure
    Intervention Name(s)
    Plasmapheresis
    Other Intervention Name(s)
    Plasma Exchange, Therapeutic Plasma Exchange, Therapeutic Plasmapheresis
    Intervention Description
    Undergo plasmapheresis
    Intervention Type
    Biological
    Intervention Name(s)
    Rituximab
    Other Intervention Name(s)
    ABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, Rituximab Biosimilar SIBP-02, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, Truxima
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Tacrolimus
    Other Intervention Name(s)
    FK 506, Fujimycin, Hecoria, Prograf, Protopic
    Intervention Description
    Given IV or PO
    Primary Outcome Measure Information:
    Title
    Event-free survival (EFS)
    Description
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
    Time Frame
    At 2 years post-hematopoietic cell transplantation (HCT)
    Secondary Outcome Measure Information:
    Title
    Event-free survival
    Description
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
    Time Frame
    Up to 100 days post-HCT
    Title
    Event-free survival
    Description
    EFS is defined as survival time following HCT without a qualifying event. Will be summarized by the Kaplan-Meier method with 95% confidence intervals.
    Time Frame
    Up to 1 year post-HCT
    Title
    Overall survival
    Description
    Will be summarized by the Kaplan-Meier method.
    Time Frame
    Up to 100 days post-HCT
    Title
    Overall survival
    Description
    Will be summarized by the Kaplan-Meier method.
    Time Frame
    Up to 1 year post-HCT
    Title
    Transplant-related mortality
    Description
    Will be summarized by the Kaplan-Meier method.
    Time Frame
    Up to 30 days post-HCT
    Title
    Time to platelet and neutrophil engraftment
    Description
    Will be estimated using the method of Gooley et al.
    Time Frame
    Up to 2 years post-HCT
    Title
    Incidence of graft failure (primary and secondary)
    Description
    Will be estimated using the method of Gooley et al.
    Time Frame
    Up to 100 days post-HCT
    Title
    Incidence of acute graft-versus-host disease
    Description
    Will be estimated using the method of Gooley et al.
    Time Frame
    Up to 100 days post-HCT
    Title
    Incidence of chronic graft-versus-host disease
    Description
    Will be estimated using the method of Gooley et al.
    Time Frame
    Up to 1 year post-HCT
    Title
    Incidence of chronic graft-versus-host disease
    Description
    Will be estimated using the method of Gooley et al.
    Time Frame
    Up to 2 years post-HCT
    Title
    Incidence of grade II or greater organ toxicity
    Description
    Will be reported as counts with percentages.
    Time Frame
    Up to 100 days post-HCT
    Title
    Incidence of hepatic sinusoidal obstruction syndrome
    Description
    Will be reported as counts with percentages.
    Time Frame
    Up to 100 days post-HCT
    Title
    Incidence of central nervous system toxicities including posterior reversible encephalopathy syndrome
    Description
    Will be reported as counts with percentages.
    Time Frame
    Up to 100 days post-HCT
    Title
    Incidence of infectious complications
    Description
    Will be reported as counts with percentages.
    Time Frame
    Up to 100 days post-HCT

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    2 Years
    Maximum Age & Unit of Time
    30 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients 2-30 years-of-age with confirmed sickle cell disease (SCD) (SS & sickle beta [SB]-thalassemia, both sickle beta 0 [SB0] and sickle beta plus [SB+]) or severe B-thalassemia major are potentially eligible Patients with SCD should also meet the following eligibility criteria as outlined by the Center for Medicaid and Medicare Services: sickle cell disease and at least one of the following: Stroke or neurological deficit lasting > 24 hours Recurrent acute chest syndrome (ACS): 2 or more episodes of ACS in 2-year period preceding enrollment Recurrent vaso-occlusive pain crises: 3 or more episodes per year in 2-year period preceding enrollment or recurrent priapism (3 or more episodes in the 2 years preceding enrollment) Chronic transfusion program defined as 8 or more packed red blood cells (PRBC) transfusions per year to prevent central nervous system and/or vaso-occlusive complications in 1-year period preceding enrollment Impaired neuropsychological function and abnormal cerebral magnetic resonance imaging (MRI) scan (silent strokes) Stage I or II sickle lung disease Sickle nephropathy (moderate or severe proteinuria or a glomerular filtration rate 30-50% of predicted normal value) Bilateral proliferative retinopathy and major visual impairment in at least one eye Osteonecrosis of multiple joints Echocardiographic finding of tricuspid valve regurgitant jet velocity (TRJV) >= 2.7 m/sec Patients with B-thalassemia are considered as severe if they are/have any of the following: Transfusion-dependent Evidence of extra-medullary hematopoiesis Pesaro Class III Patients shall not proceed to HCT without confirmation of primary diagnosis by review of available newborn screening results or hemoglobin electrophoresis and/or genetic testing DONOR: High resolution HLA typing will be performed on all willing and available biologic parents and siblings without clinically significant hemoglobinopathy. Preference will be given to donors with the lowest number of HLA-allele mismatches DONOR: Donor-specific anti-HLA antibodies will be obtained and analyzed from all patients. Preference will be given to donors with absent or low titer anti HLA-donor specific antibody levels when possible Exclusion Criteria: Uncontrolled infection Females who are pregnant and/or unwilling to cease breastfeeding Seropositivity for human immunodeficiency virus (HIV) Lansky or Karnofsky performance status < 70% Life expectancy severely limited by concomitant illness Uncontrolled arrhythmias or symptomatic cardiac disease Uncontrolled symptomatic pulmonary disease Evidence of chronic active hepatitis or cirrhosis Serum conjugated (direct) bilirubin > 2 x upper limit of normal for age. Participants are not excluded if the serum conjugated (direct) bilirubin is > 2 x the upper limit of normal for age as per local laboratory and: There is evidence of a hyperhemolytic reaction after a recent red blood cell (RBC) transfusion, OR There is evidence of moderate direct hyperbilirubinemia defined as direct serum bilirubin < 5 times upper limit of normal (ULN) and not caused by underlying hepatic disease Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 5 x upper limit of normal for age Serum creatinine > 1.5 x upper limit of normal for age AND estimated or measure creatinine clearance < 70 mL/min/1.72 m^2 Patient, parent or guardian unable/unwilling to provide consent and when indicated, assent Patients with available HLA-matched related donor Prior receipt of gene therapy DONOR: All potential donors shall be tested by hemoglobin electrophoresis. Any potential donor with a clinically significant hemoglobinopathy will be deemed ineligible. Donors with sickle cell trait and beta thalassemia trait are eligible to donate
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Kris M Mahadeo
    Organizational Affiliation
    M.D. Anderson Cancer Center
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Links:
    URL
    http://www.mdanderson.org
    Description
    MD Anderson Cancer Center

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    Pre-transplant Immunosuppression and Donor Stem Cell Transplant for the Treatment of Severe Hemoglobinopathies

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