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    Clinical Trial Results:
    Prophylactic infusion of CD4 positive donor lymphocytes early after T-cell depleted stem cell transplantation

    Summary
    EudraCT number
    		 2008-001447-19
    Trial protocol
    		 NL  
    Global end of trial date
    01 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Nov 2021
    First version publication date
    30 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LUMCCD4PROTOCOL
    Additional study identifiers
    ISRCTN number
    		 ISRCTN51398568
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Leids Universitair Medisch Centrum, department of hematology
    Sponsor organisation address
    Albinusdreef 2, Leiden, Netherlands, 2333ZA
    Public contact
    Dr. P van Balen, LUMC, department of hematology, 0031 715262267, P.van_Balen@lumc.nl
    Scientific contact
    Dr. P van Balen, LUMC, department of hematology, 0031 715262267, P.van_Balen@lumc.nl
    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
    10 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether CD4+ lymphocytes infusion given three months after T-cell depleted allogeneic SCT improves immunological recovery (number of circulating CD4+ lymphocytes) with an incidence of GvHD requiring systemic treatment not exceeding 30% of the patients.
    Protection of trial subjects
    Patients are closely monitored in our outpatient clinic on a regular basis. A structured anamnesis was performed, as well as physical anamnesis and laboratory results. Furthermore bone marrow examination was performed (morphology, flow cytometry, bone marrow chimerism) at regular intervals ( after transplantation: 3 months, 4.5 months, 6 months, 9 months, 12 months). (local lab, physical exam and structured anamnesis).
    Background therapy
    		 All patients after alloSCT are monitored and treated according to local guidelines with regards to immunosuppressive treatment, antibiotic treatment.
    Evidence for comparator
    		 At the time of initiation of this study all patients were eligible for prophylactic DLI 6 months after alloSCT. To assess whether prophylactic CD4 DLI 3 months after alloSCT would be benificial in addition to unmodified DLI at 6 months, we compared patients in the control group (treated according to standard protocol and eligible for prophylactic unmodified DLI 6 months after alloSCT) to the experimental arm with prophylactic CD4 DLI at 3 months (the expirimental arm was also eligible to receive unmodified prophylactic DLI at 6 months.
    Actual start date of recruitment
    04 Jan 2008
    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
    Netherlands: 66
    Worldwide total number of subjects
    66
    EEA total number of subjects
    66
    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)
    0
    Adults (18-64 years)
    56
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All adult patients treated with 10/10 HLA matched alemtuzumab based T-cell depleted stem cell transplantation from a related donor in the Leiden University medical center are eligible for inclusion. Patients were recruited between and 4 January 2008 and 1 May 2020 in the departement of hematology.

    Pre-assignment
    Screening details
    		 Inclusion criteria: concomitant disease, WHO performance status of 0-2, Life expectancy longer than 3 months and providing informed consent. Exclusion criteria: progressive disease, severe GVHD, systemic immunosuppressive treatment, pregnancy, positive HIV test

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Patients were randomized to receive either CD4 DLI or no treatment at 3 months after alloSCT. All patients were eligible to receive unmodified DLI at 6 months. Both patient and doctor were aware of randomization arm.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CD4+ donor lymfocyten infusion
    Arm description
    		 Infusion of 1 x 10^6 CD4+ T-cells/kg 3 months after alloSCT
    Arm type
    		 Experimental

    Investigational medicinal product name
    CD4 positive lymphocytes
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    1x 10^6 CD4+ T cells/kg infused once at 3 months after alloSCT

    Arm title
    		 Control
    Arm description
    		 No intervention 3 months. Patients are eligible to receive unmodified DLI 6 months after alloSCT according to standard LUMc protocol
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		CD4+ donor lymfocyten infusion Control
    Started
    33
    33
    Completed
    29
    31
    Not completed
    4
    2
         Adverse event, serious fatal
    4
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CD4+ donor lymfocyten infusion
    Reporting group description
    		 Infusion of 1 x 10^6 CD4+ T-cells/kg 3 months after alloSCT

    Reporting group title
    Control
    Reporting group description
    		 No intervention 3 months. Patients are eligible to receive unmodified DLI 6 months after alloSCT according to standard LUMc protocol

    Reporting group values
    		 CD4+ donor lymfocyten infusion Control Total
    Number of subjects
    		 33 33 66
    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 (inter-quartile range (Q1-Q3))
    		 60.5 (57.4 to 64.4) 59.1 (50.2 to 61.7) -
    Gender categorical
    Units: Subjects
        Female
    		 10 14 24
        Male
    		 23 19 42
    Conditioning
    Conditioning regime for transplantation. Myeloablative conditioning consists of cyclophosphamide and TBI, while non-myeloablative conditioning consists of Fludarabine and Busulfan
    Units: Subjects
        Myeloablative
    		 8 6 14
        Non-myeloablative
    		 25 27 52
    HCT comorbidity score
    HCT comorbidity score before transplantation
    Units: Subjects
        0-2
    		 28 28 56
        3-7
    		 5 5 10
    Hematologic disease
    Hematologic disease for which a allogeneic stem cell transplantation was performed
    Units: Subjects
        CML
    		 1 2 3
        MPN
    		 1 2 3
        MDS/MPN overlap
    		 3 1 4
        MDS
    		 3 0 3
        AML
    		 14 15 29
        Multiple myeloma
    		 5 6 11
        Mature B-cell lymphoma
    		 3 5 8
        ALL/LBL
    		 2 2 4
        Leukemia with mixed phenotype
    		 1 0 1
    CD4+ T-cell count at randomization
    CD4+ T-cell count measured with flow cytometry at randomization. In patients who did receive CD4+ DLI, T-cell counts were measured before infusion.
    Units: cells/microlitre
        median (inter-quartile range (Q1-Q3))
    		 113 (69 to 233) 112 (64 to 198) -

    End points

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    End points reporting groups
    Reporting group title
    CD4+ donor lymfocyten infusion
    Reporting group description
    		 Infusion of 1 x 10^6 CD4+ T-cells/kg 3 months after alloSCT

    Reporting group title
    Control
    Reporting group description
    		 No intervention 3 months. Patients are eligible to receive unmodified DLI 6 months after alloSCT according to standard LUMc protocol

    Primary: CD4+ T-cell counts 6 months after alloSCT

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    End point title
    		 CD4+ T-cell counts 6 months after alloSCT
    End point description
    End point type
    Primary
    End point timeframe
    The primary endpoint (CD4+ T-cell counts) is measured 3 months after randomization (6 months after alloSCT).
    End point values
    		 CD4+ donor lymfocyten infusion Control
    Number of subjects analysed
    29 [1]
    32
    Units: cells/microlitre
        median (inter-quartile range (Q1-Q3))
    155 (102 to 211)
    178 (132.5 to 223.2)
    Notes
    [1] - 4 patients did not survive until 3 months after alloSCT
    Statistical analysis title
    		 CD4+ T-cell counts at 3 months
    Statistical analysis description
    Mann Whitney U test between CD4+ T-cell counts the two treatment arms at 3 months after inclusion
    Comparison groups
    Control v CD4+ donor lymfocyten infusion
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2917
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: severe GvHD

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    End point title
    		 severe GvHD
    End point description
    Cumulative incidence of GvHD requiring immunosuppressive treatment. We used a competing risk analysis with relapse, unmodified DLI and death as competing events.
    End point type
    Primary
    End point timeframe
    3 months after randomization
    End point values
    		 CD4+ donor lymfocyten infusion Control
    Number of subjects analysed
    33
    33
    Units: Cumulative incidence
    9
    9
    Attachments
    		 Untitled (Filename: competing events at 3 months.png)
    Untitled (Filename: GvHD.png)
    Statistical analysis title
    		 Cumulative incidence
    Statistical analysis description
    Comparing cumulative incidence of developing GvHD requiring immunosuppressive treatment with log-rank test.
    Comparison groups
    CD4+ donor lymfocyten infusion v Control
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8
    Method
    		 Logrank
    Confidence interval

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Probability of overall survival after randomization in intention to treat analysis
    End point type
    Secondary
    End point timeframe
    up to 5 years after randomization
    End point values
    		 CD4+ donor lymfocyten infusion Control
    Number of subjects analysed
    33
    33
    Units: Overall survival
    44
    52
    Attachments
    		 Untitled (Filename: Overall survival.png)
    Statistical analysis title
    		 Overall Survival
    Statistical analysis description
    Overall survival between two treatment arms
    Comparison groups
    CD4+ donor lymfocyten infusion v Control
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5
    Method
    		 Logrank
    Confidence interval

    Secondary: Relapse

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    End point title
    		 Relapse
    End point description
    Relapse requiring systemic treatment during follow-up. Competing risk analysis with death as a competing event
    End point type
    Secondary
    End point timeframe
    up to 5 years after randomization
    End point values
    		 CD4+ donor lymfocyten infusion Control
    Number of subjects analysed
    33
    33
    Units: Cumulative incidence
    39
    36
    Attachments
    		 Untitled (Filename: relapse.png)
    Statistical analysis title
    		 Relapse
    Statistical analysis description
    Comparing relapse between two treatment arms
    Comparison groups
    CD4+ donor lymfocyten infusion v Control
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5
    Method
    		 Logrank
    Confidence interval

    Secondary: Any sign of GvHD

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    End point title
    		 Any sign of GvHD
    End point description
    Cumulative incidence of any signs of GvHD. Patients did not need to receive immunosuppressive. We used a competing risk analysis with relapse, unmodified DLI and death as competing events.
    End point type
    Secondary
    End point timeframe
    3 months after randomization
    End point values
    		 CD4+ donor lymfocyten infusion Control
    Number of subjects analysed
    33
    33
    Units: Cumulative incidence
    24
    27
    Attachments
    		 Untitled (Filename: anyGvHD.png)
    Statistical analysis title
    		 Cumulative incidence
    Comparison groups
    CD4+ donor lymfocyten infusion v Control
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Between randomization and 6 months after alloSCT
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    CD4+ donor lymfocyten infusion
    Reporting group description
    		 All adverse events from randomization until 6 months after alloSCT Serious adverse events: severe GvHD, relapse, death, infections requiring hospitalization

    Reporting group title
    Controle
    Reporting group description
    		 -

    Serious adverse events
    		 CD4+ donor lymfocyten infusion Controle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 33 (30.30%)
    9 / 33 (27.27%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    4
    1
    Blood and lymphatic system disorders
    GVHD
    Additional description: Graft versus host disease between randomization and 6 months.
         subjects affected / exposed
    4 / 33 (12.12%)
    3 / 33 (9.09%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Relapse
    Additional description: Relapse between 3 and 6 months. Fatality numbers reported until6 months after alloSCT
         subjects affected / exposed
    5 / 33 (15.15%)
    6 / 33 (18.18%)
         occurrences causally related to treatment / all
    5 / 5
    6 / 6
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    Immune system disorders
    Autoimmunity
    Additional description: Autoimmunity between randomization and 6 months after alloSCT requiring IST
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
    Additional description: Any infection requiring hospitalization between randomization and 6 months after alloSCT
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 33 (12.12%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CD4+ donor lymfocyten infusion Controle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 33 (18.18%)
    2 / 33 (6.06%)
    Blood and lymphatic system disorders
    GvHD without IST
    Additional description: Patients that did develop signs of GvHD, but did not need systemic immunosuppressive treatment for it.
         subjects affected / exposed
    5 / 33 (15.15%)
    1 / 33 (3.03%)
         occurrences all number
    5
    1
    Immune system disorders
    autoimmuity without immune suppression
    Additional description: Any sign of autoimmunity, not requiring immunosuppressive treatment
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1

    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.
    Since all patients were eligible to receive unmodified DLI at 6 months, the reported outcomes and all AE/SAE are reported until 6 months; afterwards the adverse events are probably related to the unmodified DLI. These results are not reported here.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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