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    Clinical Trial Results:
    Allogenic stem cell transplantation in children and adolescents with acute lymphoblastic leukaemia

    Summary
    EudraCT number
    		 2005-005106-23
    Trial protocol
    		 AT   IT  
    Global end of trial date
    31 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Apr 2024
    First version publication date
    12 Apr 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALLSCT06BFMi
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01423500
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    St. Anna Kinderkrebsforschung GmbH
    Sponsor organisation address
    Zimmermannplatz 10, Vienna , Austria, 1090
    Public contact
    Univ.Prof. Dr. Ruth Ladenstein, St. Anna Kinderkrebsforschung GmbH, +43 1 40470 4750, ruth.ladenstein@ccri.at
    Scientific contact
    Univ.Prof. Dr. Christina Peters, St. Anna Kinderkrebsforschung GmbH, +43 1 40410 3100, christina.peters@stanna.at
    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
    21 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    *To evaluate whether HSCT from matched family or unrelated donors (MD) is equivalent to the HSCT from matched sibling donors (MSD) *To evaluate the efficacy of HSCT from mismatched family or unrelated donors (MMD) as compared to HSCT from MSD/MD. *To determine whether therapy has been carried out according to the main HSCT protocol recommendations. The standardisation of the treatment options during HSCT from different donor types aims at the achievement of an optimal comparison of survival after HSCT with survival after chemotherapy only. *To prospectively evaluate and compare the incidence of acute and chronic GvHD after HSCT from MSD, from MD and from MMD.
    Protection of trial subjects
    Detailed supportive care measures have been specified in the trial protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Feb 2007
    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
    Austria: 40
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Czechia: 34
    Country: Number of subjects enrolled
    Denmark: 19
    Country: Number of subjects enrolled
    France: 71
    Country: Number of subjects enrolled
    Israel: 14
    Country: Number of subjects enrolled
    Netherlands: 50
    Country: Number of subjects enrolled
    Poland: 131
    Country: Number of subjects enrolled
    Slovakia: 17
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Turkey: 46
    Worldwide total number of subjects
    450
    EEA total number of subjects
    390
    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)
    19
    Children (2-11 years)
    276
    Adolescents (12-17 years)
    146
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Recruitment in the period from 21.02.2007 until 9 September 2011 in 12 countries.

    Pre-assignment
    Screening details
    		 Principal inclusion criteria: - age at time of initial diagnosis or relapse ≤18 years (until 19th birthday) - indication for hematopoietic stem cell transplantation (HSCT) - complete remission - no pregnancy - no secondary malignancy - no previous HSCT - written consent

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Matched Sibling Donor (MSD)
    Arm description
    		 HSCT with HLA-genotypically identical sibling donor or a 10 out of 10 (high resolution – 4 digits per allel) matched sibling donor if the parental haplotypes are unknown. Assigned Interventions: TBI/VP16 based conditioning regimen for patients older than 24 months - VP16 at a dose of 60mg/kg/d on day -3; Total body irradiation (TBI) at a dose of 2x2Gy/day for 3 days (total 12Gy in 6 fractions) on days -6, -5, -4. Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Etoposid/VP16
    Investigational medicinal product code
    Other name
    Etopophos
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide is administered as a single infusion over 4 hours. The dosage is 60mg/kg BW (maximum 1800mg/m2 BS, absolute dose 3,6 g max. ) or 40mg/kg BW (maximum 1200mg/m2 BS, absolute dose 2,4 g max.) respectively, depending on the conditioning regimen. The infusion is to be performed in accordance with the guidelines of the transplantation centre. VP16 is administered on day -3 in patients with TBI or on day -4 before allogeneic HSCT in those without TBI. If etoposide phosphate is used, the dosage is adapted to the aliquot etoposide according to the recommendations of the pharmaceutical drug description.

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Melphalan is given intravenous once at a dose of 140 mg/m2. Melphalan is chemically instable in solution and should be given as soon as possible (within 1 hour) after being dissolved. It can only be diluted with normal saline and may not come in contact with glucose. Parenteral nutrition containing amino acids has to be stopped 2 hours before administration of Melphalan to prevent competition with cellular uptake of the drug.

    Investigational medicinal product name
    Cyclophosphamid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total dose for Cyclophosphamide is 120 mg/kg BW. It is administered in 2 single doses of 60mg/kg given over 1 hour i.v. on 2 consecutive days (-3 and -2). Between the last BUX application and the infusion of CYCLO an interval of 24 hours is mandatory.

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Busilfex®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BUX is given at weight-adjusted doses. As i.v. Busulfan is registered as orphan drug and because of its more predictable pharmacology and decreased hepatic toxicity by lack of first-pass effect, only i.v. Busulfan is used in this study. BUX is administered in 16 single doses. The BUX infusions are given over 2 hours in six hours distance on 4 consecutive days. Seizure prophylaxis with Phenytoin is started before Busulfan i.v. application, continued for 2 days after the last dose, and then tapered.

    Arm title
    		 Matched Donor (MD)
    Arm description
    		 HSCT with related or unrelated stem cell donors, 10 or 9 out of 10 HLA matches determined by high resolution typing (4 digits per allele) and MMD BM 8/10. Assigned Interventions: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). ATG is given to both age groups at a dose of 20mg/kg/d on days -3, -2, -1. Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Etoposid/VP16
    Investigational medicinal product code
    Other name
    Etopophos
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide is administered as a single infusion over 4 hours. The dosage is 60mg/kg BW (maximum 1800mg/m2 BS, absolute dose 3,6 g max. ) or 40mg/kg BW (maximum 1200mg/m2 BS, absolute dose 2,4 g max.) respectively, depending on the conditioning regimen. The infusion is to be performed in accordance with the guidelines of the transplantation centre. VP16 is administered on day -3 in patients with TBI or on day -4 before allogeneic HSCT in those without TBI. If etoposide phosphate is used, the dosage is adapted to the aliquot etoposide according to the recommendations of the pharmaceutical drug description.

    Investigational medicinal product name
    Melphalan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Melphalan is given intravenous once at a dose of 140 mg/m2. Melphalan is chemically instable in solution and should be given as soon as possible (within 1 hour) after being dissolved. It can only be diluted with normal saline and may not come in contact with glucose. Parenteral nutrition containing amino acids has to be stopped 2 hours before administration of Melphalan to prevent competition with cellular uptake of the drug.

    Investigational medicinal product name
    Cyclophosphamid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total dose for Cyclophosphamide is 120 mg/kg BW. It is administered in 2 single doses of 60mg/kg given over 1 hour i.v. on 2 consecutive days (-3 and -2). Between the last BUX application and the infusion of CYCLO an interval of 24 hours is mandatory.

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Busilfex®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BUX is given at weight-adjusted doses. As i.v. Busulfan is registered as orphan drug and because of its more predictable pharmacology and decreased hepatic toxicity by lack of first-pass effect, only i.v. Busulfan is used in this study. BUX is administered in 16 single doses. The BUX infusions are given over 2 hours in six hours distance on 4 consecutive days. Seizure prophylaxis with Phenytoin is started before Busulfan i.v. application, continued for 2 days after the last dose, and then tapered.

    Investigational medicinal product name
    ATG Fresenius
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    ATG-Fresenius S is an anti-human T-lymphocyte immunoserum which is obtained from rabbits immunised with human T-lymphoblasts of the Jurkat cell-line. ATG-Fresenius S is administered at a dose of 20 mg/kg BW on three consecutive days (day –3 until day –1). The infusion is hypotonic and may only be dissolved with normal saline. Furthermore, Heparin may not be administered as mixed infusion or via the same vascular access, as this can lead to a shift in the pH-value. The infusion may be given over 4 hours, and a premedication with steroids (max. 2mg/kg BW) is recommended. The respective emergency medicines need to be ready for immediate intervention, and frequent checks of the vital parameters are required.

    Arm title
    		 Mismatched Donor (MMD)
    Arm description
    		 Patients with a MMD receive stem cells extracted from bone marrow, cord blood or peripheral blood from a haploidentical donor (parent) or from a non-related donor with a match less or equal to 8/10. Assigned Interventions for patients with a BM 8/10 donor and older than 24 months: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months with a BM 8/10 donor receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). They all receive ATG (20mg/kg/d on day -3,-2,-1). Assigned Interventions for patients with Haploidentical and cord blood HSCT: Fludarabine (30mg/m²/d on day -9 to -5), OKT3 (0,0125-0,1mg/kg on day -9 to 0), ATG fresenius (20mg/kg/d on day -3,-2,-1), Treosulfan (14g/m²/d on day -7 to -5) and Thiotepa (2x5mg/kg/d on day -4).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Etoposid/VP16
    Investigational medicinal product code
    Other name
    Etopophos
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide is administered as a single infusion over 4 hours. The dosage is 60mg/kg BW (maximum 1800mg/m2 BS, absolute dose 3,6 g max. ) or 40mg/kg BW (maximum 1200mg/m2 BS, absolute dose 2,4 g max.) respectively, depending on the conditioning regimen. The infusion is to be performed in accordance with the guidelines of the transplantation centre. VP16 is administered on day -3 in patients with TBI or on day -4 before allogeneic HSCT in those without TBI. If etoposide phosphate is used, the dosage is adapted to the aliquot etoposide according to the recommendations of the pharmaceutical drug description.

    Investigational medicinal product name
    ATG Fresenius
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    ATG-Fresenius S is an anti-human T-lymphocyte immunoserum which is obtained from rabbits immunised with human T-lymphoblasts of the Jurkat cell-line. ATG-Fresenius S is administered at a dose of 20 mg/kg BW on three consecutive days (day –3 until day –1). The infusion is hypotonic and may only be dissolved with normal saline. Furthermore, Heparin may not be administered as mixed infusion or via the same vascular access, as this can lead to a shift in the pH-value. The infusion may be given over 4 hours, and a premedication with steroids (max. 2mg/kg BW) is recommended. The respective emergency medicines need to be ready for immediate intervention, and frequent checks of the vital parameters are required.

    Investigational medicinal product name
    Busulfan
    Investigational medicinal product code
    Other name
    Busilfex®
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BUX is given at weight-adjusted doses. As i.v. Busulfan is registered as orphan drug and because of its more predictable pharmacology and decreased hepatic toxicity by lack of first-pass effect, only i.v. Busulfan is used in this study. BUX is administered in 16 single doses. The BUX infusions are given over 2 hours in six hours distance on 4 consecutive days. Seizure prophylaxis with Phenytoin is started before Busulfan i.v. application, continued for 2 days after the last dose, and then tapered.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients with Mismatched Family Donor (MMFD) HSCT receive Fludarabine i.v. as single dose of 40mg/m2 over 30 minutes at noon for 4 consecutive days. The total dose is 160 mg/m2.

    Investigational medicinal product name
    Treosulfan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treosulfan is an alkylating agents with a half-life of 88 minutes. It is administered at a dose of 14g/m²/d for 3 days (total dose 42g/m²) and for babies < 9kg BW 12g/m²/d for 3 days (total dose 36g/m²). The infusion is given over 1 hour. The solution remains stable at room temperature for 4 days.

    Investigational medicinal product name
    Orthoclone OKT3
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    OKT3 is a murine monoclonal antibody with specific affect against a glycoprotein of the CD-3 complex on human T-lymphocytes. T

    Investigational medicinal product name
    Thiotepa
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Thiopeta is an alkylating agents with cytolytic and radiomimetic effects. It is administered at a dose of 2x5mg/kg for 1 day (total dose 10mg/kg) and for babies < 9 kg BW 2x3,5mg/kg for 1 day (total dose 7mg/kg).

    Investigational medicinal product name
    Cyclophosphamid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Total dose for Cyclophosphamide is 120 mg/kg BW. It is administered in 2 single doses of 60mg/kg given over 1 hour i.v. on 2 consecutive days (-3 and -2). Between the last BUX application and the infusion of CYCLO an interval of 24 hours is mandatory.

    Number of subjects in period 1
    		Matched Sibling Donor (MSD) Matched Donor (MD) Mismatched Donor (MMD)
    Started
    150
    235
    65
    Completed
    150
    235
    65

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study period
    Reporting group description
    		 -

    Reporting group values
    		 Overall study period Total
    Number of subjects
    		 450 450
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 19 19
        Children (2-11 years)
    		 276 276
        Adolescents (>=12 years)
    		 155 155
    Gender categorical
    Units: Subjects
        Female
    		 140 140
        Male
    		 310 310
    Subject analysis sets

    Subject analysis set title
    MSD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MSD (matched sibling donor), having indication for HSCT from MD or MMD

    Subject analysis set title
    MD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MD (matched donor), having indication for HSCT from MD or MMD

    Subject analysis set title
    MMD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MMD (mismatched donor), having indication for HSCT from MMD

    Subject analysis set title
    MSD/MD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MSD or MD (matched sibling donor or matched donor), having indication for HSCT from MMD

    Subject analysis sets values
    		 MSD MD MMD MSD/MD
    Number of subjects
    128
    217
    36
    187
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    4
    11
    1
    7
        Children (2-11 years)
    77
    133
    24
    112
        Adolescents (>=12 years)
    47
    73
    11
    68
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    45
    60
    8
    55
        Male
    83
    157
    28
    132

    End points

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    End points reporting groups
    Reporting group title
    Matched Sibling Donor (MSD)
    Reporting group description
    		 HSCT with HLA-genotypically identical sibling donor or a 10 out of 10 (high resolution – 4 digits per allel) matched sibling donor if the parental haplotypes are unknown. Assigned Interventions: TBI/VP16 based conditioning regimen for patients older than 24 months - VP16 at a dose of 60mg/kg/d on day -3; Total body irradiation (TBI) at a dose of 2x2Gy/day for 3 days (total 12Gy in 6 fractions) on days -6, -5, -4. Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2).

    Reporting group title
    Matched Donor (MD)
    Reporting group description
    		 HSCT with related or unrelated stem cell donors, 10 or 9 out of 10 HLA matches determined by high resolution typing (4 digits per allele) and MMD BM 8/10. Assigned Interventions: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). ATG is given to both age groups at a dose of 20mg/kg/d on days -3, -2, -1. Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2).

    Reporting group title
    Mismatched Donor (MMD)
    Reporting group description
    		 Patients with a MMD receive stem cells extracted from bone marrow, cord blood or peripheral blood from a haploidentical donor (parent) or from a non-related donor with a match less or equal to 8/10. Assigned Interventions for patients with a BM 8/10 donor and older than 24 months: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months with a BM 8/10 donor receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). They all receive ATG (20mg/kg/d on day -3,-2,-1). Assigned Interventions for patients with Haploidentical and cord blood HSCT: Fludarabine (30mg/m²/d on day -9 to -5), OKT3 (0,0125-0,1mg/kg on day -9 to 0), ATG fresenius (20mg/kg/d on day -3,-2,-1), Treosulfan (14g/m²/d on day -7 to -5) and Thiotepa (2x5mg/kg/d on day -4).

    Subject analysis set title
    MSD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MSD (matched sibling donor), having indication for HSCT from MD or MMD

    Subject analysis set title
    MD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MD (matched donor), having indication for HSCT from MD or MMD

    Subject analysis set title
    MMD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MMD (mismatched donor), having indication for HSCT from MMD

    Subject analysis set title
    MSD/MD
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Patients with MSD or MD (matched sibling donor or matched donor), having indication for HSCT from MMD

    Primary: EFS (Event free survival)

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    End point title
    		 EFS (Event free survival)
    End point description
    Event are defined as: leukemic relapse at any site, secondary malignancy, death of any cause.
    End point type
    Primary
    End point timeframe
    Starting point of the analysis: date of HSCT. End point of the analysis is the date of event or the last available follow up date.
    End point values
    		 MSD MD MMD MSD/MD
    Number of subjects analysed
    128
    217
    36
    187
    Units: %
        number (not applicable)
    128
    217
    36
    187
    Statistical analysis title
    		 EFS (study question 1)
    Statistical analysis description
    The null hypothesis was that HSCT from MD was inferior to SCT from MSD. The calculation is done by a one-sided confidence interval for the difference of the Kaplan-Meier estimates of 4-year Event-free Survival (EFS) between both subgroups. Only patients with indication for MD or MMD were included into this analysis.
    Comparison groups
    MSD v MD
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference of KM estimates of 4y-EFS
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.14
    Notes
    [1] - One sided confidence interval of the difference of the Kaplan-Meier (KM) estimates of the 4-years EFS of both subgroups (MSD and MD) is calculated. Hematopoietic stem cell transplantation from a matched donor (MD) is considered non-inferior to that from a matched sibling donor (MSD) if the pEFS of patients from MD does not fall below that of patients from MSD by more than 0.15.
    Statistical analysis title
    		 EFS (study question 2)
    Statistical analysis description
    Kaplan-Meier method was used to estimate EFS, and Log Rank test to compare both subgroups. Null hypothesis: The EFS of patients with MMS does not differ from that of patients with MSD/MD. Only patients with indication for MMD were included into this analysis.
    Comparison groups
    MMD v MSD/MD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 Logrank
    Confidence interval

    Secondary: Occurrence of acute Graft-versus-Host-Disease (GvHD)

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    End point title
    		 Occurrence of acute Graft-versus-Host-Disease (GvHD)
    End point description
    The incidence of acute GvHD equals the proportion of patients with at least one episode of acute GvHD > grade I up to Day+100 after HSCT.
    End point type
    Secondary
    End point timeframe
    The period up to day +100 after HSCT.
    End point values
    		 MSD MD MMD MSD/MD
    Number of subjects analysed
    128
    217
    36
    187
    Units: %
        number (not applicable)
    128
    217
    36
    187
    Statistical analysis title
    		 Comparison of acute GVHD grade > 1 - MSD vs MD
    Comparison groups
    MSD v MD
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.562
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Comparison of acute GVHD grade > 1 - MSD/MD vs MMD
    Comparison groups
    MMD v MSD/MD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.349
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Occurrence of chronic Graft-versus-Host-Disease (GvHD)

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    End point title
    		 Occurrence of chronic Graft-versus-Host-Disease (GvHD)
    End point description
    The incidence of GvHD equals the proportion of patients with at least one episode of chronic GvHD (limited or extended) up to a period of five years after HSCT. These endpoint was estimated using the approach of Prentice and Kalbfleisch, allowing for competing risks, which were death in remission and relapse.
    End point type
    Secondary
    End point timeframe
    Time period between the HSCT and end of 5-year Follow-up.
    End point values
    		 MSD MD MMD MSD/MD
    Number of subjects analysed
    128
    217
    36
    187
    Units: %
        number (not applicable)
    128
    217
    36
    187
    Statistical analysis title
    		 Comparison of chronic GVHD - MSD vs MD
    Comparison groups
    MSD v MD
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Gray
    Confidence interval
    Statistical analysis title
    		 Comparison of chronic GVHD - MSD and MD vs MMD
    Comparison groups
    MMD v MSD/MD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.979
    Method
    		 Gray
    Confidence interval

    Secondary: OS (Overall survival)

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    End point title
    		 OS (Overall survival)
    End point description
    End point type
    Secondary
    End point timeframe
    Starting point of the analysis: date of HSCT. End point is the date of death of any cause or the last available follow up date.
    End point values
    		 MSD MD MMD MSD/MD
    Number of subjects analysed
    128
    217
    36
    187
    Units: %
        number (not applicable)
    128
    217
    36
    187
    Statistical analysis title
    		 (OS study question 1)
    Statistical analysis description
    Kaplan-Meier method was used to estimate OS, and the Log Rank test to compare both subgroups. Only patients with indication for MD and MMD were used for this analysis.
    Comparison groups
    MSD v MD
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.336
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 (OS study question 2)
    Statistical analysis description
    Kaplan-Meier method was used to estimate OS, and the Log Rank test to compare both subgroups. Only patients with indication for MD and MMD were used for this analysis.
    Comparison groups
    MMD v MSD/MD
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Period from start of conditioning until end of 5-year follow-up
    Adverse event reporting additional description
    All adverse events that occur from start of conditioning are reported in the patient’s records and according to national standards on adverse event reporting. Those meeting the definition of a serious adverse event must be reported using the Serious Adverse Event (SAE) Report form.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    MSD (matched sibling donors)
    Reporting group description
    		 -

    Reporting group title
    MD (matched family or unrelated donors)
    Reporting group description
    		 -

    Reporting group title
    MMD (mismatched donors)
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Non-serious adverse events have not been reported explicitly, but rather the maximum grade of toxicity for each of the predefined toxicity categories and time intervals.
    Serious adverse events
    		 MSD (matched sibling donors) MD (matched family or unrelated donors) MMD (mismatched donors)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 150 (7.33%)
    21 / 235 (8.94%)
    6 / 65 (9.23%)
         number of deaths (all causes)
    38
    71
    25
         number of deaths resulting from adverse events
    4
    6
    6
    Cardiac disorders
    Cardiac disorder
         subjects affected / exposed
    2 / 150 (1.33%)
    5 / 235 (2.13%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    2 / 4
    0 / 0
    Nervous system disorders
    Cerebral thrombosis
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 235 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 235 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Encephalopathy
         subjects affected / exposed
    3 / 150 (2.00%)
    0 / 235 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    Nervous system disorder
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 235 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    Psychiatric symptom
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 235 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 150 (2.00%)
    2 / 235 (0.85%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
    Blood and lymphatic system disorders
    Coagulation disorder
         subjects affected / exposed
    1 / 150 (0.67%)
    4 / 235 (1.70%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    3 / 4
    1 / 1
    General disorders and administration site conditions
    Anaphylactic reaction
         subjects affected / exposed
    1 / 150 (0.67%)
    2 / 235 (0.85%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    Skeletal injury
         subjects affected / exposed
    2 / 150 (1.33%)
    0 / 235 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    4 / 150 (2.67%)
    0 / 235 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    3 / 4
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatobiliary disease
         subjects affected / exposed
    7 / 150 (4.67%)
    4 / 235 (1.70%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    4 / 6
    2 / 3
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    1 / 150 (0.67%)
    7 / 235 (2.98%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 7
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    3 / 5
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    ARDS
         subjects affected / exposed
    2 / 150 (1.33%)
    5 / 235 (2.13%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    2 / 2
    5 / 5
    3 / 3
         deaths causally related to treatment / all
    1 / 2
    3 / 4
    3 / 3
    Alveolar hemorrhage
         subjects affected / exposed
    3 / 150 (2.00%)
    0 / 235 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    Engraftment syndrome
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 235 (0.43%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Respiratory thoracic and mediastinal disorders
         subjects affected / exposed
    4 / 150 (2.67%)
    7 / 235 (2.98%)
    3 / 65 (4.62%)
         occurrences causally related to treatment / all
    5 / 5
    10 / 10
    3 / 3
         deaths causally related to treatment / all
    2 / 4
    4 / 7
    3 / 3
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    3 / 150 (2.00%)
    1 / 235 (0.43%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    3 / 3
    0 / 1
    0 / 0
    Renal and urinary disorders
    Acute toxic failure
         subjects affected / exposed
    0 / 150 (0.00%)
    2 / 235 (0.85%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Hemorrhagic cyctitis
         subjects affected / exposed
    1 / 150 (0.67%)
    1 / 235 (0.43%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    Renal and urinary disorder
         subjects affected / exposed
    1 / 150 (0.67%)
    2 / 235 (0.85%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    Endocrine disorders
    Endocrine disorder
         subjects affected / exposed
    1 / 150 (0.67%)
    0 / 235 (0.00%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    4 / 150 (2.67%)
    14 / 235 (5.96%)
    4 / 65 (6.15%)
         occurrences causally related to treatment / all
    5 / 5
    19 / 19
    4 / 4
         deaths causally related to treatment / all
    3 / 4
    8 / 13
    4 / 4
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    		 MSD (matched sibling donors) MD (matched family or unrelated donors) MMD (mismatched donors)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 150 (0.00%)
    0 / 235 (0.00%)
    0 / 65 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2009
    Extension of recruitment for 2 further years; Definition of HSCT options and stem cell source for patients with a MMD donor; Complement and new conditioning schemes for MMD HSCT; Exclusion of TBI based conditioning for MMD HSCT; Definition of GvHD prophylaxis; Correction of study period; Additional consent for patients reaching 18 years of age during participation in a study,

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31319153
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