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    Clinical Trial Results:
    Elimination of the preleukemic clone in children with Down syndrome and transient myeloproloferative disorder (TMD) to prevent AML - Model of leukemia prevention

    Summary
    EudraCT number
    		 2006-002962-20
    Trial protocol
    		 DE   NL  
    Global end of trial date
    08 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jan 2025
    First version publication date
    19 Jan 2025
    Other versions
    Summary report(s)
    		 Summary

    Trial information

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    Trial identification
    Sponsor protocol code
    TMD01/2007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hannover Medical School
    Sponsor organisation address
    Carl-Neuberg-Str. 1, Hannover, Germany, 30625
    Public contact
    Zentrum für Klinische Studien, MHH, Hannover Medical School, EudraCT@mh-hannover.de
    Scientific contact
    Zentrum für Klinische Studien, MHH, Hannover Medical School, EudraCT@mh-hannover.de
    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
    03 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Feb 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that monitoring of the GATA1s positive preleukemic clone in TMD and elimination of the clone with cytarabine can reduce the risk of DS-AMKL
    Protection of trial subjects
    The clinical trial was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with the standards of International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). A continuous risk assessment was performed during the study.
    Background therapy
    		 Monitoring of GATA1s positive preleukemic clones and low-dose cytaribine treatment in children with persisiting GATA1s clone according to a defined treatment algorithm. 43 patients were treated with Cytarabine, 27 received one cozrse, 10 two courses and six three courses of chemotheapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 224
    Country: Number of subjects enrolled
    Netherlands: 26
    Worldwide total number of subjects
    250
    EEA total number of subjects
    250
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    97
    Infants and toddlers (28 days-23 months)
    153
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment to the study based on the diagnosis of transient leukemia within the first 4 weeks after birth, in-time initiation of the study site and the informed consent of the parents/guardians. Potentially in all 69 children’s hospitals with a department of pediatric hematology/oncology participating in the AML-BMF Studies (GER/NL).

    Pre-assignment
    Screening details
    		 Eligibility will be determined based upon the inclusion and exclusion criteria

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TMD study population
    Arm description
    		 All children with trisomy 21 in Germany and the Netherlands that showed > 5% myeloid blasts or with detection of a GATA1-mutation (exon 1, 2, or 3) in the peripheral blood and/or bone marrow within the first 3 months of life were eligible for inclusion in the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    cytarabin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion, Injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Cytarabin 1,5mg/kgKG i.v./s.c. on day 1,2,3,4,5,6,7 (=one course) maximum treatment of three courses with blood count controls on day 0 or 1, day 4 and day 10 (including blood count,GOT and GST, creatinine) cytostatic therapy indicated in following patients: a)clinical symptoms due to TMD or "hepatopathy) b) MRD ≤10-3MRD after 8 weeks c) MRD: IP≤10-2 or qPCR≤10-3 after treatment

    Arm title
    		 Control Group
    Arm description
    		 The historical control group is a previously reported cohort of patients that were reported to the Acute Myeloid Leukemia Berlin-Frankfurt-Münster (AML-BFM) study group between 01 January 1993 and 31 December 2006 using similar criteria for in- and exclusion.
    Arm type
    		 historical control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		TMD study population Control Group
    Started
    104
    146
    Completed
    101
    146
    Not completed
    3
    0
         Lost to follow-up
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TMD study population
    Reporting group description
    		 All children with trisomy 21 in Germany and the Netherlands that showed > 5% myeloid blasts or with detection of a GATA1-mutation (exon 1, 2, or 3) in the peripheral blood and/or bone marrow within the first 3 months of life were eligible for inclusion in the study.

    Reporting group title
    Control Group
    Reporting group description
    		 The historical control group is a previously reported cohort of patients that were reported to the Acute Myeloid Leukemia Berlin-Frankfurt-Münster (AML-BFM) study group between 01 January 1993 and 31 December 2006 using similar criteria for in- and exclusion.

    Reporting group values
    		 TMD study population Control Group Total
    Number of subjects
    		 104 146 250
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 104 146 250
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: weeks
        median (full range (min-max))
    		 37 (28 to 43) 37 (30 to 41) -
    Gender categorical
    Units: Subjects
        Female
    		 44 66 110
        Male
    		 60 80 140

    End points

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    End points reporting groups
    Reporting group title
    TMD study population
    Reporting group description
    		 All children with trisomy 21 in Germany and the Netherlands that showed > 5% myeloid blasts or with detection of a GATA1-mutation (exon 1, 2, or 3) in the peripheral blood and/or bone marrow within the first 3 months of life were eligible for inclusion in the study.

    Reporting group title
    Control Group
    Reporting group description
    		 The historical control group is a previously reported cohort of patients that were reported to the Acute Myeloid Leukemia Berlin-Frankfurt-Münster (AML-BFM) study group between 01 January 1993 and 31 December 2006 using similar criteria for in- and exclusion.

    Primary: Incidence of acute megakaryoblastic leukemia

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    End point title
    		 Incidence of acute megakaryoblastic leukemia
    End point description
    The primary end point of the study was the cumulative incidence (CI) of ML-DS (constructed by the method of Kalbfleisch and Prentice) 3 years after diagnosis of TMD (3y-CI ML-DS). The null hypothesis (no difference from the historical control or higher rate in the study cohort) was tested using the 1-sided 95% confidence interval of the difference. In addition, Gray’s test was used for comparisons.16 The secondary end point of the study was the MRD level (independent of prior treatment) at week 12.
    End point type
    Primary
    End point timeframe
    Outcome was assessed at 10 different time points: week 0, 4 to 8, 8, and 12, as well as month 6, 9, 12, 18, 24 and 36 after diagnosis.
    End point values
    		 TMD study population Control Group
    Number of subjects analysed
    101
    146
    Units: percent
        arithmetic mean (confidence interval 95%)
    19.9 (16.4 to 23.4)
    19.7 (15.4 to 24.0)
    Statistical analysis title
    		 Control versus TMD
    Statistical analysis description
    Historical Control versus TMD, three-years cumulative incidence of AMKL
    Comparison groups
    TMD study population v Control Group
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.62
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -8.9
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04
    Notes
    [1] - Efficacy: Main target criterion is the proportion of patients who survive the TMD and develop AMKL within 3 years after diagnosis. The null hypothesis (no difference to the historical control group, AMKL-rate 22%) has been tested with a one-sided 95% confidence interval for the difference of the 3-years cumulative incidence of AMKL.

    Secondary: MRD level at week 12

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    End point title
    		 MRD level at week 12 [2]
    End point description
    The secondary end point of the study was the MRD level at week 12 irrespective of prior intervention. (GATA1s negativity (sensitivity 10-4) at week 12)
    End point type
    Secondary
    End point timeframe
    12 week
    Notes
    [2] - 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: The endpoint MRD level at week 12 was evaluated exclusively in the TMD study population in the current trial.
    End point values
    		 TMD study population
    Number of subjects analysed
    63
    Units: GATA1s negativity
    number (not applicable)
        MRD negative
    50
        MRD positive
    13
    No statistical analyses for this end point

    Other pre-specified: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    three years period
    End point values
    		 TMD study population Control Group
    Number of subjects analysed
    104
    146
    Units: percent
        number (confidence interval 95%)
    90 (87 to 93)
    85 (82 to 88)
    Statistical analysis title
    		 Control versus TMD, overall survival
    Comparison groups
    TMD study population v Control Group
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.16
    Method
    		 Logrank
    Confidence interval
    Notes
    [3] - The Kaplan-Meier method was used to estimate survival rates.17 The 2-sided logrank test was used to compare differences between different groups. Standard errors were obtained using Greenwoods formula.

    Other pre-specified: Eventfree survival

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    End point title
    		 Eventfree survival
    End point description
    End point type
    Other pre-specified
    End point timeframe
    three years
    End point values
    		 TMD study population Control Group
    Number of subjects analysed
    104
    146
    Units: percent
        number (confidence interval 95%)
    72 (68 to 76)
    63 (59 to 67)
    Statistical analysis title
    		 Control versus TMD, eventfree survival
    Statistical analysis description
    The Kaplan-Meier method was used to estimate survival rates. The 2-sided logrank test was used to compare differences between different groups.
    Comparison groups
    TMD study population v Control Group
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.17
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the entire study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTC
    Dictionary version
    2.0
    Reporting groups
    Reporting group title
    TMD study population
    Reporting group description
    		 -

    Serious adverse events
    		 TMD study population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 104 (0.00%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 TMD study population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    47 / 104 (45.19%)
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    44 / 104 (42.31%)
         occurrences all number
    44
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    44 / 104 (42.31%)
         occurrences all number
    44
    Cardiac function
         subjects affected / exposed
    27 / 104 (25.96%)
         occurrences all number
    27
    Echokardio: LV-SF
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences all number
    1
    Nervous system disorders
    Central Neurotoxicity
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences all number
    1
    Peripheral Neurotoxicity
         subjects affected / exposed
    39 / 104 (37.50%)
         occurrences all number
    39
    General disorders and administration site conditions
    General condition
         subjects affected / exposed
    45 / 104 (43.27%)
         occurrences all number
    45
    Blood and lymphatic system disorders
    Bilirubin
         subjects affected / exposed
    46 / 104 (44.23%)
         occurrences all number
    46
    Immune system disorders
    Fever
         subjects affected / exposed
    45 / 104 (43.27%)
         occurrences all number
    45
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    41 / 104 (39.42%)
         occurrences all number
    41
    Vomiting
         subjects affected / exposed
    46 / 104 (44.23%)
         occurrences all number
    46
    Stomatitis
         subjects affected / exposed
    46 / 104 (44.23%)
         occurrences all number
    46
    Diarrhae
         subjects affected / exposed
    46 / 104 (44.23%)
         occurrences all number
    46
    Hepatobiliary disorders
    SGOT/SPOT
         subjects affected / exposed
    46 / 104 (44.23%)
         occurrences all number
    46
    Respiratory, thoracic and mediastinal disorders
    Lung problems
         subjects affected / exposed
    42 / 104 (40.38%)
         occurrences all number
    42
    Skin and subcutaneous tissue disorders
    Skin changes
         subjects affected / exposed
    45 / 104 (43.27%)
         occurrences all number
    45
    Renal and urinary disorders
    Creatinine
         subjects affected / exposed
    47 / 104 (45.19%)
         occurrences all number
    47
    Infections and infestations
    Infection
         subjects affected / exposed
    45 / 104 (43.27%)
         occurrences all number
    45

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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/29959152
    http://www.ncbi.nlm.nih.gov/pubmed/18182574
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