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    Clinical Trial Results:
    A Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus Host-Disease

    Summary
    EudraCT number
    2015-000602-18
    Trial protocol
    DE  
    Global end of trial date
    05 Oct 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Aug 2023
    First version publication date
    03 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BMT-CTN#1301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02345850
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    National Heart, Lung, and Blood Institute (NHLBI)
    Sponsor organisation address
    401 N. Washington St., Suite 700, Rockville, United States,
    Public contact
    Clinical Trials Information, EMMES Corporation, 001 301-251-1161,
    Scientific contact
    Clinical Trials Information, EMMES Corporation, 001 301-251-1161,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the randomized trial is to compare chronic GVHD/relapse-free survival (CRFS) after HSCT across two CNI-free interventions and Tac/Mtx control.
    Protection of trial subjects
    The trial compared standard of care interventions using IMPs with marketing authorization/ authorities approval in EEA.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Oct 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    United States: 344
    Worldwide total number of subjects
    346
    EEA total number of subjects
    2
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    344
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    NA

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CD34 Selection Arm
    Arm description
    Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products.
    Arm type
    Experimental

    Investigational medicinal product name
    Allogeneic stem cells from peripheral blood CD34 selected
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.

    Arm title
    Post-Transplant Cyclophosphamide
    Arm description
    Unmanipulated Bone Marrow Graft with Cyclophosphamide
    Arm type
    Experimental

    Investigational medicinal product name
    Human allogeneic hematopoietic stem cells from bone marrow
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).

    Arm title
    Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Arm description
    Unmanipulated bone marrow graft with Tacrolimus(Cyclopsorin)/Methotrexate GVHD prophylaxis. Tacrolimus(Cyclosporin) will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant. Cyclosporine may be substituted for tacrolimus in germany or if the patient is intolerant of tacrolimus or per institutional practice.
    Arm type
    Active comparator

    Investigational medicinal product name
    Cyclosporin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Capsule, soft, Oral solution
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Tacrolimus (Cyclosporin) will be given orally or intravenously per institutional standards starting Day -3. The dose of tacrolimus (Cyclosporin) may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of tacrolimus (Cyclosporin) (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus (Cyclosporin) taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus (Cyclosporin) by Day 180 post HSCT if there is no evidence of active GVHD.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Methotrexate will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. Leucovorin rescue is allowed according to institutional practices.

    Number of subjects in period 1
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Started
    114
    114
    118
    Completed
    101
    106
    112
    Not completed
    13
    8
    6
         Consent withdrawn by subject
    1
    -
    -
         Not transplanted
    10
    5
    4
         Lost to follow-up
    2
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    346 346
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    51.1 (13.1 to 66) -
    Gender categorical
    Units: Subjects
        Female
    149 149
        Male
    197 197
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    21 21
        Not Hispanic or Latino
    314 314
        Unknown or Not Reported
    11 11
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0
        Asian
    9 9
        Native Hawaiian or Other Pacific Islander
    0 0
        Black or African American
    9 9
        White
    311 311
        More than one race
    0 0
        Unknown or Not Reported
    17 17
    Lansky/Karnofsky Performance Score
    KPS describes patient-perceived global quality of life and functioning on a scale of 0-100. 100: No evidence of disease; 90: Normal activity. Minor signs or symptoms of disease; 80: Normal activity with effort. Some signs or symptoms of disease; 70: Cares for self. Unable to continue normal activity; 60: Needs occasional assistance, but cares for most personal needs; 50: Needs considerable assistance and medical care; 40: Disabled. Needs special care and assistance; 30: Severely disabled. Hospital admission indicated; 20: Very sick. Active supportive therapy needed; 10: Moribund; 0: Dead
    Units: Subjects
        90-100
    196 196
        70-80
    150 150
    Primary Disease
    Units: Subjects
        Acute Lymphoblastic Leukemia (ALL)
    80 80
        Acute Myelogenous Leukemia (AML)
    212 212
        Myelodysplastic Syndrome (MDS)
    46 46
        Chronic Myelomonocytic Leukemia (CMML)
    3 3
        Acute Undifferentiated Leukemia
    2 2
        Biphenotypic Leukemia
    3 3
    Disease Risk
    Disease risk data was collected by CIBMTR. For AML and ALL: High risk (not in remission): Never treated, PIF, Relapse; Non-high: CR1, CR2 and CR3+. For MDS (including CMML): High risk: High risk: RAEB, RAEB-T, RAEB-1, RAEB-2, CMML; non-high: RA, RARS, RCMD, RCMD/RS, MDS Unclassifiable, isolated 5q- syndrome.
    Units: Subjects
        Non-high
    205 205
        High
    115 115
        Missing/Unknown
    26 26
    Disease Stage for AML and ALL
    1st CR: meet all for >=4 weeks: no blast cells in the peripheral blood, < 5% blasts in the bone marrow, no blasts with Auer rods, normal maturation of all cellular components in the marrow, normal CBC and ANC of > 1000/µL; Platelets ≥ 100000/µL; No other signs or symptoms of disease. >=2nd CR: after CR, relapsed and achieved CR again. Final is CR. PIF: recipient treated but never achieved durable CR. Relapse: ≥ 5% blasts in the marrow; Extramedullary disease; Reappearance of cytogenetic abnormalities and/or molecular markers associated with the diagnosis at a level representing relapse.
    Units: Subjects
        1st complete remission
    207 207
        >=2nd complete remission
    51 51
        Relapse
    4 4
        Primary induction failure (PIF)/Untreated
    10 10
        Missing
    20 20
        Not Applicable
    54 54
    Donor type
    Units: Subjects
        Related Donor
    131 131
        Unrelated Donor
    215 215
    Cytogenentic
    For Adult acute myeloid leukemia (AML), Favorable: t(15:17), inv(16), del(16q), t(16:16), [t(8:21) without del(9q) or complex]; Intermediate: normal karyotype, +6, +8, -Y, del(12p), 11q23, t(9:11); Poor: complex karyotype, -5/del(5q), -7/del(7q), abn(3q, 9q, 11q, 21q, 17p), t(6:9), t(9:22). For Acute lymphocytic leukemia (ALL), Poor: Ph+/t(9:22), t(4:11), 11q23, MLL, hypodiploid, t(8:14), complex. For Myelodysplastic Syndrome (MDS): Favorable: normal karyotype, isolated del(5q), del(20q), or -Y; Poor: complex karyotype, 7 chromosome abnormalities; Intermediate: other abnormalities.
    Units: Subjects
        Normal
    11 11
        Favorable
    37 37
        Intermediate
    160 160
        Poor
    112 112
        Missing
    25 25
        Not tested
    1 1
    HLA matching
    Units: Subjects
        8/8
    346 346
    HCT-comorbidity index
    The HCT-CI was developed to identify comorbidities relevant to transplant and act as a tool for risk assessment and before allogeneic hematopoietic stem cell transplantation. Patients with no comorbidities are assigned a score of zero. Arrhythmia, cardiac, bowel, diabetes, cerebrovascular, psychological, mild chronic hepatitis, obesity, infection are assigned a score of 1. Rheumatoid arthritis, peptic ulcer, renal moderate/severe, pulmonary moderate, are assigned a score of 2. Solid tumor, heart valve disease, pulmonary sever, hepatic moderate/severe are assigned a score of 3.
    Units: Subjects
        Zero
    123 123
        1-2
    129 129
        3 or greater
    75 75
        Not applicable
    19 19
    Pre-transplant CMV status
    Pre-Transplant CMV Status is assessed in transplanted patients.
    Units: Subjects
        Positive
    156 156
        Negative
    171 171
        Not applicable
    19 19
    Donor CMV Status
    Measure Analysis Population Description: Donor CMV Status is assessed in transplanted patients.
    Units: Subjects
        Negative
    199 199
        Positive
    127 127
        Unknown
    1 1
        Not applicable
    19 19
    Stem cell source
    Measure Analysis Population Description: Stem cell source is assessed in transplanted patients.
    Units: Subjects
        Peripheral Blodd
    121 121
        Bone Marrow
    206 206
        Not applicable
    19 19
    Time from diagnosis to transplantation
    Units: month
        median (full range (min-max))
    5.0 (1.6 to 231.3) -

    End points

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    End points reporting groups
    Reporting group title
    CD34 Selection Arm
    Reporting group description
    Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products.

    Reporting group title
    Post-Transplant Cyclophosphamide
    Reporting group description
    Unmanipulated Bone Marrow Graft with Cyclophosphamide

    Reporting group title
    Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Reporting group description
    Unmanipulated bone marrow graft with Tacrolimus(Cyclopsorin)/Methotrexate GVHD prophylaxis. Tacrolimus(Cyclosporin) will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant. Cyclosporine may be substituted for tacrolimus in germany or if the patient is intolerant of tacrolimus or per institutional practice.

    Primary: Chronic GVHD-free, Relapse-free Survival (CRFS) Probability

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    End point title
    Chronic GVHD-free, Relapse-free Survival (CRFS) Probability
    End point description
    The primary endpoint of the trial is Chronic GVHD/Relapse-Free Survival (CRFS), treated as a time to event variable. An event for this time to event outcome is defined as moderate to severe chronic GVHD, disease relapse, or death by any cause. Participant will be censored if lost to follow up prior to 2 years. Time is from randomization to the event of moderate to severe chronic GVHD, disease relapse, death, last follow up, or 2 years, whichever comes first. The primary analysis is performed using the intent-to-treat principle (ITT) so that all randomized patients are included in the analysis. All randomized patients are analyzed for this endpoint.
    End point type
    Primary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    114
    114
    118
    Units: percentage of participants
    number (confidence interval 95%)
        1 year Post Randomization
    60.2 (50.3 to 68.7)
    60.3 (50.5 to 68.7)
    52.6 (43.1 to 61.3)
        2 years Post Randomization
    50.6 (40.8 to 59.6)
    48.1 (38.5 to 57.1)
    41 (32 to 49.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between CD34 select graft vs. Tac/MTX Control. The data in primary outcome table provides point estimates at specific time points (1 year and 2 years post randomization). The statistics in this session provides comparisons between different arms for the entire period of the study.
    Comparison groups
    Tacrolimus(Cyclosporin)/Methotrexate Control Arm v CD34 Selection Arm
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2368 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.805
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.562
         upper limit
    1.154
    Notes
    [1] - The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between Post-Transplant Cyclophosphamide vs. Tac/MTX Control. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
    Comparison groups
    Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4134 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.864
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.609
         upper limit
    1.228
    Notes
    [2] - The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between CD34 select graft vs. Post-Transplant Cyclophosphamide. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7166 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.933
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.643
         upper limit
    1.355
    Notes
    [3] - The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The null hypothesis is that there is no difference of the CRFS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.386 [4]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [4] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 5
    Statistical analysis description
    Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and disease risk (Low/Intermediate vs. High) for CRFS.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.461 [5]
    Method
    Cox proportional hazards regression
    Confidence interval
    Notes
    [5] - A Bonferroni adjusted significance level of 0.05/3=0.0167 is used for each of three interaction tests to account for multiple testing.
    Statistical analysis title
    Statistical Analysis 6
    Statistical analysis description
    Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and Age (<=50 vs. >50) for CRFS.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.115 [6]
    Method
    Cox proportional hazards regression
    Confidence interval
    Notes
    [6] - Cox proportional hazards regression
    Statistical analysis title
    Statistical Analysis 7
    Statistical analysis description
    Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and Disease (AML vs. ALL vs. MDS) for CRFS.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.227 [7]
    Method
    Cox proportional hazards regression
    Confidence interval
    Notes
    [7] - A Bonferroni adjusted significance level of 0.05/3=0.0167 is used for each of three interaction tests to account for multiple testing.

    Secondary: Percentage of Participants With Overall Survival (OS)

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    End point title
    Percentage of Participants With Overall Survival (OS)
    End point description
    OS is a key secondary endpoint, with explicit control of the type I error rate through a gatekeeper approach. Formal significance testing of OS between a CNI-free strategy and the control will be conducted if the corresponding CRFS comparison is significant. This OS comparison will be done using a Bonferroni adjusted significance level of 0.05/3 to account for three potential CNI-free comparisons to the control. Otherwise, survival analyses will be considered exploratory. Death from any cause is considered as event for this endpoint. Participant is censored if lost to follow up.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    114
    114
    118
    Units: percentage of subjects
    number (confidence interval 95%)
        1 year post-randomization
    75.7 (66.4 to 82.8)
    84.6 (76.4 to 90.1)
    84.2 (76.1 to 89.7)
        2 year post-randomization
    60.1 (50.1 to 68.8)
    76.2 (67.1 to 83.1)
    76.1 (67.2 to 83.0)
        1 year post-transplantation
    74.8 (65.2 to 82.1)
    83.4 (74.9 to 89.2)
    83.3 (75.0 to 89.0)
        2 year post-transplantation
    61.6 (51.4 to 70.3)
    76.7 (67.5 to 83.6)
    74.2 (65.0 to 81.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of the OS hazard ratio between CD34 select graft vs. Tac/MTX Control.
    Comparison groups
    CD34 Selection Arm v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0197 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.744
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.086
         upper limit
    2.8
    Notes
    [8] - The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no difference of the OS hazard ratio between Post-Transplant Cyclophosphamide vs. Tac/MTX Control.
    Comparison groups
    Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9525 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.016
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.599
         upper limit
    1.724
    Notes
    [9] - The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The null hypothesis is that there is no difference of the OS hazard ratio between CD34 select graft vs. Post-Transplant Cyclophosphamide.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0185 [10]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.774
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.093
         upper limit
    2.877
    Notes
    [10] - The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The null hypothesis is that there is no difference of the OS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.026 [11]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [11] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Percentage of Participants With Relapse-free Survival

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    End point title
    Percentage of Participants With Relapse-free Survival
    End point description
    The events for this endpoint RFS are death and relapse of the underlying malignancy. The analyses of this endpoint use the transplanted populations and time is from transplant to the event of disease relapse or death, or last follow up, whichever comes first. The analyses of this endpoint will use the transplanted population.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
    number (confidence interval 95%)
        1 year post-transplantation
    64.1 (54.0 to 72.5)
    78.8 (69.9 to 85.4)
    70.1 (60.8 to 77.6)
        2 years post-transplantation
    57.1 (46.9 to 66.0)
    70.3 (60.7 to 78.0)
    66.5 (56.9 to 74.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Relapse-Free Survival between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.029 [12]
    Method
    Logrank
    Confidence interval
    Notes
    [12] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no difference of the RFS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.145 [13]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [13] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Percentage of Participants With Treatment-related Mortality

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    End point title
    Percentage of Participants With Treatment-related Mortality
    End point description
    The events for this endpoint TRM are deaths prior to relapse of the underlying malignancy. The analyses of this endpoint will use the transplanted populations, and time will be from transplant to the first of disease relapse, death, or last follow up. TRM are evaluated using the cumulative incidence function. Deaths without relapse are the events for this endpoint and relapse is a competing risk for this endpoint. The analyses of this endpoint will use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
    number (confidence interval 95%)
        1 year post-transplantation
    16.5 (10.1 to 24.3)
    12.0 (6.7 to 18.9)
    7.0 (3.2 to 12.7)
        2 years post-transplantation
    21.5 (14.1 to 30.0)
    15.7 (9.6 to 23.2)
    7.9 (3.9 to 13.8)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Transplant-Related Mortality between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02 [14]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [14] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no difference of the TRM hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.04 [15]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [15] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Participants With Immunosuppression-free Survival

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    End point title
    Participants With Immunosuppression-free Survival
    End point description
    Patients who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post HSCT are considered successes for this endpoint. Immune suppression is defined as any systemic agents used to control or suppress GVHD. The analyses of this endpoint will use the transplanted populations. Two participant of CD34 Selected Graft arm and one participants of Post-Transplant Cyclophosphamide arm were lost to follow-up while alive and not relapsed, and they are considered as not evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    1 year
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    102
    108
    114
    Units: participants
    59
    73
    66
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of immunosuppression-free survival at 1-year post-transplant between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2389 [16]
    Method
    Chi-squared
    Confidence interval
    Notes
    [16] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no agreement between CRFS and immunosuppression-free survival at 1-year post-transplant.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Cohen's Kappa
    Confidence interval

    Secondary: Percentage of Participants With Disease Relapse

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    End point title
    Percentage of Participants With Disease Relapse
    End point description
    Relapse is defined by either morphological evidence of acute leukemia or MDS consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not by biopsy. The event is defined as increase in size of prior sites of disease or evidence of new sites of disease, documented or not by biopsy. Relapse is adjudicated by ERC. Disease relapse is analyzed using cumulative incidence function with death as a competing risk. The analyses of this endpoint use the transplanted populations, and the time will be measured from transplant to the earliest of death, relapse/progression, or last follow up. The analyses of this endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
    number (confidence interval 95%)
        1 year post transplantation
    19.4 (12.4 to 27.6)
    9.2 (4.7 to 15.6)
    22.9 (15.6 to 31.0)
        2 years post transplantation
    21.4 (14.0 to 29.8)
    13.9 (8.1 to 21.2)
    25.6 (17.9 to 33.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Disease Relapse between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.076 [17]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [17] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no difference of the Disease Relapse hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.106 [18]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [18] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Percentage of Participants With Neutrophil Engraftment

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    End point title
    Percentage of Participants With Neutrophil Engraftment
    End point description
    Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 500/mm^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
        number (confidence interval 95%)
    97.1 (90.5 to 99.1)
    91.7 (84.4 to 95.7)
    96.5 (90.3 to 98.8)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Neutrophil Engraftment post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0764 [19]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [19] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Percentage of Participants With Platelet Recovery

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    End point title
    Percentage of Participants With Platelet Recovery
    End point description
    Platelet recovery is defined as the first day of a sustained platelet count >20,000/mm^3 with no platelet transfusion in the preceding seven days. The first day of sustained platelet count above this threshold will be designated the day of platelet engraftment. The competing event is death without platelet recovery. The analyses of the endpoint use the transplanted populations. Three transplanted participants (one from the CD34 arm and two from the PTCy arm) are missing platelet data and are not included in the analyses.
    End point type
    Secondary
    End point timeframe
    Day 60
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    103
    107
    114
    Units: percentage of participants
        number (confidence interval 95%)
    94.2 (86.9 to 97.5)
    91.6 (84.2 to 95.6)
    98.2 (93.4 to 99.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Platelet recovery post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001 [20]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [20] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Participants With Primary Graft Failure

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    End point title
    Participants With Primary Graft Failure
    End point description
    Primary graft failure is defined as no neutrophil recovery to > 500 cells/µL by Day 28 post HSCT. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: Participants
    3
    9
    4
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Secondary Graft Failure

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    End point title
    Percentage of Participants With Secondary Graft Failure
    End point description
    Secondary graft failure will be assessed according to neutrophil count after initial hematologic recovery. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy, but cannot be explained by disease relapse or medications. Secondary graft failure will be analyzed using cumulative incidence function with death as a competing risk. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
        number (confidence interval 95%)
    2.9 (0.8 to 7.5)
    0 (0 to 0)
    0.9 (0.1 to 4.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Secondary graft failure post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1478
    Method
    Gray's test for cumulative Incidence
    Confidence interval

    Secondary: Percentage of Participants With Acute GVHD

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    End point title
    Percentage of Participants With Acute GVHD
    End point description
    Cumulative incidences of grade II-IV and III-IV acute GVHD were determined. Death prior to acute GVHD is treated as the competing risk. Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Staging for skin: Stage 1. <25% rash; 2. 25-50%; 3. >50%; 4. generalized erythroderma with bullae. Staging for GI: Stage 1. Diarrhea>500ml/d or persistent nausea; 2. >1000ml/d; 3. >1500ml/d; 4. Large volume diarrhea and severe abdominal pain +- ileus. Staging for Liver: Stage 1. bilirubin 2-3mg/dl; 2. bilirubin 3-6 mg/dl; 3. bilirubin 6-15 mg/dl; 4. bilirubin>15mg/dl. Grade 4 is the worst outcome. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    Day 100
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
    number (confidence interval 95%)
        Grade II-IV acute GvHD
    16.3 (9.9 to 24.1)
    37.6 (28.5 to 46.6)
    29.8 (21.7 to 38.4)
        Grade III-IV acute GvHD
    2.9 (0.8 to 7.5)
    10.1 (5.3 to 16.6)
    3.5 (1.1 to 8.1)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of grade II-IV acute GVHD post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0026 [21]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [21] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no difference of grade III-IV acute GVHD post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0369 [22]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [22] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    The null hypothesis is that there is no difference of the grade II-IV acute GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [23]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [23] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 4
    Statistical analysis description
    The null hypothesis is that there is no difference of the grade III-IV acute GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.046 [24]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [24] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Participants With Maximum Acute GVHD

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    End point title
    Participants With Maximum Acute GVHD
    End point description
    Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Max acute GVHD by Day 100 was computed. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    Day 100
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: participants
        Grade 0, No aGvHD
    72
    45
    55
        Grade I
    15
    23
    25
        Grade II
    14
    30
    30
        Grade III
    3
    9
    4
        Grade IV
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Chronic GVHD

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    End point title
    Percentage of Participants With Chronic GVHD
    End point description
    The cumulative incidence of chronic GVHD will be determined. Death prior to acute GVHD is treated as the competing risk. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
    number (confidence interval 95%)
        1 year post transplantation
    16.4 (9.8 to 24.5)
    33.0 (24.0 to 42.3)
    31.1 (22.5 to 40.1)
        2 years post transplantation
    18.5 (11.5 to 26.8)
    37.0 (27.6 to 46.4)
    40.0 (30.5 to 49.3)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of chronic GVHD post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0024 [25]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [25] - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no difference of the chronic GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005 [26]
    Method
    Regression, Cox
    Confidence interval
    Notes
    [26] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Percentage of Participants With Chronic GVHD-free Survival

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    End point title
    Percentage of Participants With Chronic GVHD-free Survival
    End point description
    The event for this endpoint includes moderate to severe chronic GVHD according to NIH consensus criteria global score, or death by any cause. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: percentage of participants
    number (confidence interval 95%)
        1 year post-transplantation
    71.0 (61.4 to 78.6)
    67.4 (57.8 to 75.3)
    65.8 (56.3 to 73.7)
        2 years post-transplantation
    55.4 (45.3 to 64.3)
    54.2 (44.4 to 63.0)
    47.1 (37.7 to 56.0)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Chronic GVHD-free Survival post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.229 [27]
    Method
    Logrank
    Confidence interval
    Notes
    [27] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Participants With Grade ≥ 3 Toxicity

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    End point title
    Participants With Grade ≥ 3 Toxicity
    End point description
    All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention arm. The number of unique patients is counted. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: participants
        Any Grade 3-5 Stem Cell Infusional Toxicities
    6
    4
    17
        Grades 3-5 Oral mucositis
    39
    51
    63
        Grades 3-5 Cystitis noninfective
    4
    11
    2
        Grades 3-5 Acute kidney injury
    12
    13
    15
        Grades 3-5 Chronic kidney disease
    4
    4
    3
        Grade 3-5 Hemorrhage
    12
    9
    4
        Grades 3-5 Hypotension
    19
    15
    11
        Grades 3-5 Hypertension
    20
    21
    30
        Grades 3-5 Cardiac arrhythmia
    9
    6
    8
        Grades 3-5 Levt ventricular systolic dysfunction
    5
    2
    8
        Grades 3-5 Somnolence
    7
    4
    4
        Grades 3-5 Seizure
    6
    0
    2
        Grades 3-5 Thrombotic thrombocytopenic purpura
    1
    2
    4
        Grades 3-5 Capillary leak syndrome
    1
    0
    1
        Grades 3-5 Hypoxia
    32
    22
    14
        Grades 3-5 Dyspnea
    23
    15
    12
        Grades 3-4 ALT
    10
    26
    18
        Grades 3-4 AST
    11
    27
    19
        Grades 3-4 Billirubin
    8
    14
    7
        Grades 3-4 Alkaline Phosphatase
    11
    12
    6
        Received dialysis
    5
    2
    6
        Abnormal liver function
    12
    14
    24
        SOS/VOD
    0
    2
    1
        IPS
    2
    2
    3
        Toxicities Within Day 100
    68
    82
    81
        Toxicities Day 100 to 1 year
    26
    33
    41
        Toxicities 1 year to 2 years
    23
    18
    24
        Overall NCI CTCAE Grade 3-5 Toxicities
    80
    88
    100
    No statistical analyses for this end point

    Secondary: Participants Infected Post Transplant

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    End point title
    Participants Infected Post Transplant
    End point description
    All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: participants
        Patients with Grades 2-3 infections
    72
    66
    50
        Patients with Grade 3 infections
    31
    23
    16
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis is that there is no difference of Grades II-III infection post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006 [28]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [28] - Superiority - Statistical significance was determined using a pre-specified threshold of 0.05.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    The null hypothesis is that there is no difference of Grades III infection post-transplantation between the treatment groups.
    Comparison groups
    CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0145 [29]
    Method
    Gray's test for cumulative Incidence
    Confidence interval
    Notes
    [29] - Statistical significance was determined using a pre-specified threshold of 0.05.

    Secondary: Incidence of Infections

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    End point title
    Incidence of Infections
    End point description
    All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm. The analyses of the endpoint use the transplanted populations.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: Events
    157
    161
    123
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HQL) - Medical Outcomes Study Short Form 36 (SF36)

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    End point title
    Health-Related Quality of Life (HQL) - Medical Outcomes Study Short Form 36 (SF36)
    End point description
    HQL will be measured post-transplant using patient-reported survey SF36. The SF36 is a 36 item general assessment of health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, Mental Health Index. Each domain is positively scored, indicating that higher scores are associated with positive outcome. The total score ranges from 0 to 100. This scale is being used in this protocol as a generic measure of quality of life. To facilitate comparison of results with published norms, the Physical Component Summary and Mental Component Summary are used as the outcome measures in summarizing the SF36 data. These summary scores are derived by multiplying the z-score for each scale by its respective physical or mental factor score coefficient and summing the products. Resulting scores are then transformed into Tscores (mean=50; standard deviation=10). The SF36 takes 6 minutes to complete.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 100, Day 180, 1 year, 2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: Score on a Scale
    arithmetic mean (standard error)
        STANDARDIZED MENTAL COMPONENT SCALE at Baseline
    48 ± 1.0
    46 ± 1.2
    48 ± 1.1
        STANDARDIZED MENTAL COMPONENT SCALE at Day 100
    48 ± 1.0
    48 ± 1.1
    48 ± 1.0
        STANDARDIZED MENTAL COMPONENT SCALE at Day 180
    50 ± 1.1
    50 ± 1.1
    49 ± 0.9
        STANDARDIZED MENTAL COMPONENT SCALE at 1 year
    50 ± 1.2
    52 ± 1.1
    49 ± 1.2
        STANDARDIZED MENTAL COMPONENT SCALE at 2 years
    50 ± 1.5
    50 ± 1.5
    51 ± 1.1
        STANDARDIZED PHYSICAL COMPONENT SCALE at Baseline
    42 ± 1.0
    44 ± 1.0
    41 ± 1.2
        STANDARDIZED PHYSICAL COMPONENT SCALE at Day 100
    40 ± 1.1
    41 ± 1.1
    40 ± 1.0
        STANDARDIZED PHYSICAL COMPONENT SCALE at Day 180
    43 ± 1.1
    44 ± 1.2
    44 ± 0.9
        STANDARDIZED PHYSICAL COMPONENT SCALE at 1 year
    46 ± 1.2
    47 ± 1.2
    44 ± 1.1
        STANDARDIZED PHYSICAL COMPONENT SCALE at 2 years
    46 ± 1.4
    47 ± 1.2
    47 ± 1.3
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HQL) - Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT)

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    End point title
    Health-Related Quality of Life (HQL) - Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT)
    End point description
    The FACT-BMT is a 37 item scale comprised of a general core questionnaire, the FACT-G with a possible range of 0-108 points, that evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer, and a specific module, BMT Concerns, that addresses disease and treatment-related questions specific to bone marrow transplant. The FACT-G consists of four subscales developed and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Wellbeing, and Functional Well-being. Each subscale is positively scored, with higher scores indicating better functioning. The FACT-BMT Trial Outcome Index, comprised of the physical well-being scale, the functional well-being scale and the BMT specific items, will be used as the outcome measure in summarizing the FACT-BMT data. The FACT-BMT takes 6 minutes to complete. The final score for FACT-BMT ranges from 0 to 196. Higher scores for the scales and subscales indicate better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 100, Day 180, 1 year, 2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: Score on a scale
    arithmetic mean (standard error)
        FACT-G Total at Baseline
    81 ± 1.6
    79 ± 1.4
    80 ± 1.9
        FACT-G Total at Day 100
    79 ± 1.7
    80 ± 1.5
    79 ± 1.6
        FACT-G Total at Day 180
    80 ± 1.9
    83 ± 1.7
    82 ± 1.6
        FACT-G Total at 1 Year
    84 ± 2.1
    86 ± 2.0
    84 ± 1.7
        FACT-G Total at 2 Years
    87 ± 2.5
    86 ± 2.1
    84 ± 2.1
        FACT-BMT Trial Outcome Index at Baseline
    67 ± 1.6
    67 ± 1.3
    65 ± 1.8
        FACT-BMT Trial Outcome Index at Day 100
    63 ± 1.9
    66 ± 1.5
    63 ± 1.6
        FACT-BMT Trial Outcome Index at Day 180
    67 ± 1.8
    69 ± 1.8
    67 ± 1.5
        FACT-BMT Trial Outcome Index at 1 Year
    73 ± 1.9
    72 ± 2.0
    69 ± 1.7
        FACT-BMT Trial Outcome Index at 2 Years
    73 ± 2.3
    73 ± 2.1
    71 ± 2.0
        FACT-BMT Total at Baseline
    109 ± 2.1
    108 ± 1.8
    108 ± 2.4
        FACT-BMT Total at Day 100
    106 ± 2.4
    108 ± 2.0
    105 ± 2.2
        FACT-BMT Total at Day 180
    108 ± 2.5
    112 ± 2.3
    110 ± 2.1
        FACT-BMT Total at 1 Year
    114 ± 2.8
    116 ± 2.6
    113 ± 2.2
        FACT-BMT Total at 2 Years
    117 ± 3.4
    115 ± 2.8
    113 ± 2.7
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HQL) - MDASI

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    End point title
    Health-Related Quality of Life (HQL) - MDASI
    End point description
    HQL will be measured post-transplant using patient-reported survey MD Anderson Symptom Inventory (MDASI). The MDASI is a 19 item instrument that captures 13 symptoms (0="not present" to 10="as bad as you can imagine") and 6 items measuring interference with life from 0 ("did not interfere") to 10 ("interfered completely"). MDASI Tool questions are negatively scored - higher levels indicate more severe symptoms and levels of interference. Codelist for each question is from 0 to 10. Scoring is taking the mean of items, so the range is 0-10. Lower scores for the scales indicate better quality of life. It provides two summary scales: symptoms and interference. The MDASI takes less than 5 minutes to complete.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 100, Day 180, 1 year, 2 years
    End point values
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    104
    109
    114
    Units: Score on a scale
    arithmetic mean (standard error)
        Symptoms Score at Baseline
    2 ± 0.2
    2 ± 0.2
    2 ± 0.2
        Symptoms Score at Day 100
    2 ± 0.2
    2 ± 0.1
    2 ± .02
        Symptoms Score at Day 180
    2 ± 0.2
    2 ± 0.2
    2 ± 0.2
        Symptoms Score at 1 Year
    2 ± 0.2
    1 ± 0.2
    2 ± 0.2
        Symptoms Score at 2 Years
    1 ± 0.2
    2 ± 0.2
    2 ± 0.2
        Interference Score at Baseline
    2 ± 0.2
    2 ± 0.2
    3 ± 0.2
        Interference Score at Day 100
    2 ± 0.2
    2 ± 0.2
    2 ± 0.2
        Interference Score at Day 180
    2 ± 0.3
    2 ± 0.3
    2 ± 0.2
        Interference Score at 1 Year
    2 ± 0.3
    2 ± .03
    2 ± 0.3
        Interference Score at 2 Years
    1 ± 0.3
    2 ± 0.3
    2 ± 0.3
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HQL) - PedsQL

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    End point title
    Health-Related Quality of Life (HQL) - PedsQL [30]
    End point description
    HQL will be measured post-transplant using patient-reported survey PedsQL. The PedsQL™ Stem Cell Transplant Module is a 46-item instrument that measures health-related quality of life in children and adolescents undergoing hematopoietic stem cell transplant and is developmentally appropriate for self-report in ages 8 through 18 years. The score ranges from 0 to 100 with higher scores associated with positive outcome.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 100, Day 180, 1 year, 2 years
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only 2 trial subjects were pediatrics, both randomized to Tacrolimus/Methotrexate Control arm.
    End point values
    Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Number of subjects analysed
    2
    Units: Score on a scale
    arithmetic mean (standard error)
        Pediatric Quality of Life Score at Baseline
    80.18 ± 14.94
        Pediatric Quality of Life Score at Day 100
    69.82 ± 2.75
        Pediatric Quality of Life Score at Day 180
    72.56 ± 3.05
        Pediatric Quality of Life Score at 1 Year
    78.05 ± 4.27
        Pediatric Quality of Life Score at 2 Years
    53.66 ± 21.34
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting and monitoring were conducted throughout the study, up to 2 years.
    Adverse event reporting additional description
    Adverse event (AE) reporting was conducted according to the BMT CTN's manual of operating procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals and re
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    CD34 Selection Arm
    Reporting group description
    Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products.

    Reporting group title
    Post-Transplant Cyclophosphamide
    Reporting group description
    Unmanipulated Bone Marrow Graft with Cyclophosphamide

    Reporting group title
    Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Reporting group description
    Unmanipulated bone marrow graft with Tacrolimus(Cyclopsorin)/Methotrexate GVHD prophylaxis. Tacrolimus(Cyclosporin) will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant. Cyclosporine may be substituted for tacrolimus in germany or if the patient is intolerant of tacrolimus or per institutional practice.

    Serious adverse events
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 114 (7.89%)
    7 / 114 (6.14%)
    7 / 118 (5.93%)
         number of deaths (all causes)
    42
    27
    30
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEW MALIGNANCY-RECTAL ADENOCARCINOM
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    SUPERIOR VENA CAVA SYNDROME
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    FETAL DEATH
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    NON CARDIAC CHEST PAIN
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUDDEN CARDIAC ARREST
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    DEATH
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    EDEMA
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    DISSEMINATED ADENOVIRUS INFECTION
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 114 (1.75%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    DELIRIUM
         subjects affected / exposed
    2 / 114 (1.75%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    GRADE 3 UNEXPECTED WEIGHT LOSS
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sudden cardiac death
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    WORSENING EYESIGHT DUE TO CATARACT
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    COLONIC PERFORATION
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RETROPERITONEAL BLEED
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    SEPSIS
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HOSPITAL ADMISSION FOR INFECTION
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    CD34 Selection Arm Post-Transplant Cyclophosphamide Tacrolimus(Cyclosporin)/Methotrexate Control Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 114 (2.63%)
    1 / 114 (0.88%)
    2 / 118 (1.69%)
    Investigations
    PLATELET COUNT DECREASE
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences all number
    1
    0
    0
    ELEVATED FERRITIN
         subjects affected / exposed
    0 / 114 (0.00%)
    1 / 114 (0.88%)
    0 / 118 (0.00%)
         occurrences all number
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    FOLLICULAR LYMPHOMA
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 114 (0.00%)
    0 / 114 (0.00%)
    1 / 118 (0.85%)
         occurrences all number
    0
    0
    1
    Product issues
    ELEVATED ENDOTOXIN LEVEL
         subjects affected / exposed
    1 / 114 (0.88%)
    0 / 114 (0.00%)
    0 / 118 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2015
    The major changes to the protocol include the addition of a requirement for informed consent from donors of patients randomized to the CD34 selection arm (the protocol document only includes the informed consent for related donors, while the NMDP will have purview over consenting the unrelated donors); a modification to the way that chemotherapy doses are calculated; exclusion of modifications to the conditioning regimens in Arms A and B and of modifications to MTX regimens; addition of information regarding data submission and adverse event reporting; addition of information about ethics and regulatory requirements and procedures; addition of risks for rATG and risk language for lymphoproliferative syndrome as well as Mesna.
    21 Jul 2016
    Major changes to the Protocol include: 1. Inclusion criteria for patients with CMML were added as follows: “Patients with CMML must have a WBC count ≤ 10,000 cells/μL and < 5% blasts in the marrow.” 2. FLT3 and other tyrosine kinase inhibitors for post-transplant maintenance and for prevention of disease relapse are now allowed. 3. The fourth dose of Mesna may now be infused 8-9 hours after the completion of cyclophosphamide. 4. Toxoplasmosis NAAT for patients on the CD34+ arm considered at risk for infection/reactivation has been replaced with placing such patients on prophylactic agents. 5. The window from randomization to initiation of conditioning has been removed. 6. After randomization of MDS patients, the bone marrow assessment must be repeated if it did not occur within 6 weeks prior to the initiation of the transplant conditioning regimen. Patient Informed Consent: 1. Weekly monitoring of toxoplasmosis until Day 100 then at each clinical assessment until Day 180 was removed from §Health Evaluations After the Transplant, as for NAAT for toxoplasmosis were removed from the protocol. 2. The volume of optional blood samples to be collected after transplant was corrected from 80mL to 86mL as required by Table 1 of Appendix C, Laboratory Procedures. Donor Informed Consent: 1. Language was updated to limit confusion with regards to charges for the cell manipulation procedure. The selection procedure will be paid for, for this study. 2. Clarification was provided to explain that the investigational device that is part of the cell selection system that will be used to remove T cells from your stem cell donation, called stem cell manipulation, prior to transplantation. 3. The costs section was updated to reflect that the patient will need to pay for the cell selection procedure and that the donor will not be charged for the selection procedure.
    22 Aug 2017
    Major changes to the Protocol include: Clarification of the definition of “leukemia in complete morphologic CR with or without hematologic recovery”. Added Inclusion Criteria statement: “Patients with > 5% blasts due to a regenerating marrow must contact the protocol chairs for review.”. Clarification for sites to declare planned post-transplant maintenance therapy prior to randomization. Addition of new Exclusion Criterion: “If it is known prior to enrollment that the hematopoietic stem cell product will need to be cryopreserved, the patient should not be enrolled.”. Addition of extra day of rest in the conditioning regimens of any treatment arm when delivery of the patient’s graft is delayed. Addition of cryopreservation language. Addition of new secondary endpoint “graft failure.” Primary graft failure defined as “no neutrophil recovery to > 500 cells/μL by Day 28 post HSCT.” Secondary graft failure defined as “initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts < 500 cells/μL for > 3 days, unresponsive to growth factor therapy, but cannot be explained by disease relapse or medications.” Clarification of systemic steroid usage to “if clinically indicated”. Loosened the requirement of the pre-transplant bone marrow aspirate for MDS patients prior to randomization. The protocol still requires that it must be repeated if not within 6 weeks prior to the initiation of the transplant conditioning regimen. Addition of Adverse Device Effect Reporting requirement. Patient Informed Consent: A new “Risks and Toxicities Related to GVHD Prophylaxis” from Investigator’s Brochure v8.0 was added to the patient informed consent. A new complication from the Investigator’s Brochure v8.0 “PTLD can be fatal” was added to the “Lymphoproliferative Syndrome-other Complication section. Donor Informed Consent: New information from the Investigator’s Brochure v8.0 was added to the protocol and donor informed consent on effectiveness of the device.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    SPONSOR=NHLBI; COLLABORATORS=BMT-CTN, NCI;INVESTIGATORS=Study Director:Mary Horowitz, MD, CIBMTR

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/34855460
    http://www.ncbi.nlm.nih.gov/pubmed/33811823
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