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    Clinical Trial Results:
    Nonmyeloablative Conditioning with Pre- and Post-Transplant Rituximab followed by Related or Unrelated Donor Hematopoietic Cell Transplantation for Patients with Advanced Chronic Lymphocytic Leukemia: A Multi-Center Trial

    Summary
    EudraCT number
    		 2009-015968-34
    Trial protocol
    		 DK  
    Global end of trial date
    28 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jun 2022
    First version publication date
    04 Jun 2022
    Other versions
    Summary report(s)
    		 Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience

    Trial information

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    Trial identification
    Sponsor protocol code
    FHCRC1840
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fred Hutchinson Cancer Research Center
    Sponsor organisation address
    1100 Fairview Ave. N., Seattle, United States,
    Public contact
    Kim Drever , Fred Hutchinson Cancer Research Center, 1 (206) 667-6825, kdrever@fredhutch.org
    Scientific contact
    Mohamed Sorror, MD MSc , Fred Hutchinson Cancer Research Center, 1 (206) 667-2765, msorror@fredhutch.org
    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
    02 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine whether nonmyeloablative conditioning using rituximab and allogeneic HCT improves survival at 18 months for patients with fludarabine-refractory, FCR-failed, or del 17p CLL over that of historical controls
    Protection of trial subjects
    Patient were followed closely in very specialized department of bone marrow transplant.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 100 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 55
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    66
    EEA total number of subjects
    11
    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)
    54
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients and donors are screened using the protocol's inclusion/exclusion criteria and, if accepted, randomized to an arm by data management.

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

    Arms
    Arm title
    		 Treatment
    Arm description
    		 Patients receive a conditioning regimen comprising fludarabine IV on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38. Patients undergo single fraction low-dose TBI on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive rituximab IV on days 10, 24, and 38. Patients receive an immunosuppressive regimen comprising cyclosporine PO BID on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or TID on days 0-40 followed by a taper to day 96 (unrelated recipients). Allogeneic Hematopoietic Stem Cell Transplantation: Undergo HSCT Cyclosporine: Given PO Fludarabine Phosphate: Given IV Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation:
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    2-F-ara-AMP, Beneflur, SH T 586
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients receive 30 mg/m^2 fludarabine administered over 30 minutes on Days -4, -3, and -2.

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    Cellcept, MMF
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    MMF will be given based on adjusted body weight, at 15 mg/kg PO, 4-6 hours after HCT is complete. For related recipients MMF to be given at 15 mg/kg PO Q12 hrs, continue to day +27, then stop abruptly. For unrelated recipients MMF to be given at 15 mg/kg PO Q8 hrs, continue to day +40, then start to taper to day +96.

    Investigational medicinal product name
    Cyclosporine
    Investigational medicinal product code
    Other name
    CSP
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Commence CSP on Day –3 at 5.0 mg/kg PO Q12 hrs, continue to day +56 for related and day +100 for unrelated recipients, then taper to day +180. CSP should be routinely taken at 9:00 a.m. and 9:00 p.m.

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Rituxan
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients will receive rituximab intravenously at a dose of 375 mg/m2 at three time points after stem cell transplantation. These time points are set up at days 10, 24, and 38. However, if there are clinical reasons that prohibit giving Rituximab at one of these specified time points the dose can be delayed to a maximum of 5 days. Following doses should be attempted to be given at the scheduled time points. If doses need to be delayed more than 5 days from the specified time points, then patient should only get the next scheduled dose Day 38+ dose can be delayed up to 100 days after HCT.

    Number of subjects in period 1
    		Treatment
    Started
    66
    Completed
    66

    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
    		 66 66
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 54 54
        From 65-84 years
    		 12 12
    Age continuous
    Units: years
        median (full range (min-max))
    		 59.6 (35.2 to 74.1) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 49 49

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 Patients receive a conditioning regimen comprising fludarabine IV on days -4 to -2 and rituximab IV on days -3, 10, 24, and 38. Patients undergo single fraction low-dose TBI on day 0. After completion of TBI, patients undergo allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive rituximab IV on days 10, 24, and 38. Patients receive an immunosuppressive regimen comprising cyclosporine PO BID on days -3 to 56 followed by a taper to day 180 (related recipients) or on days -3 to 100 followed by a taper to day 180 (unrelated recipients). Patients also receive mycophenolate mofetil PO BID on days 0-27 (related recipients) or TID on days 0-40 followed by a taper to day 96 (unrelated recipients). Allogeneic Hematopoietic Stem Cell Transplantation: Undergo HSCT Cyclosporine: Given PO Fludarabine Phosphate: Given IV Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation:

    Subject analysis set title
    Patients with FCgammaRIIIa receptor
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants with polymorphisms of the FCgammaRIIIa receptor.

    Subject analysis set title
    Patients without FCgammaRIIIa receptor
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants without polymorphisms of the FCgammaRIIIa receptor.

    Subject analysis set title
    Day 60 Rituxan testing group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The population of participants who had Rituxan Concentration testing performed at Day 60 post-transplant.

    Subject analysis set title
    Day 84 Rituxan testing group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The population of participants who had Rituxan Concentration testing performed at Day 84 post-transplant.

    Subject analysis set title
    Day 180 Rituxan testing group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The population of participants who had Rituxan Concentration testing performed at Day 180 post-transplant.

    Subject analysis set title
    1 Year Rituxan testing group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The population of participants who had Rituxan Concentration testing performed at 1 Year post-transplant.

    Subject analysis set title
    Arm 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All accrued subjects. This is a single-arm study and this analysis set was created as a workaround for the primary endpoint's statistical analysis.

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Estimated probability of overall survival at 3 years post-transplant.
    End point type
    Primary
    End point timeframe
    3 years post-transplant
    End point values
    		 Treatment Arm 1
    Number of subjects analysed
    52 [1]
    52 [2]
    Units: Subjects
    34
    34
    Notes
    [1] - 14 enrolled subjects did not receive rituximab and not evaluated for outcome measure.
    [2] - 14 enrolled subjects did not receive rituximab and not evaluated for outcome measure.
    Statistical analysis title
    		 Kaplan-Meier point estimate of overall survival
    Statistical analysis description
    Kaplan-Meier point estimate of overall survival at 3 years among all patients on trial
    Comparison groups
    Treatment v Arm 1
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Kaplan-Meier estimate
    Point estimate
    53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 38
         upper limit
    		 67
    Notes
    [3] - Point estimate of 3-year overall survival

    Secondary: Rate of relapse/progression

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    End point title
    		 Rate of relapse/progression
    End point description
    Cumulative incidence estimate of relapse/progression at 3 years post-transplant. Relapse/Progression criteria for CLL Progressive disease: ≥1 of: Physical exam/imaging studies ≥50% increase or new, circulating lymphocytes by morphology and/or flow cytometry ≥50% increase, and lymph node biopsy w/ Richter's transformation. Relapsed disease: Criteria of progression occurring 6 months after achievement of complete or partial remission
    End point type
    Secondary
    End point timeframe
    3 years post-transplant
    End point values
    		 Treatment
    Number of subjects analysed
    52 [4]
    Units: Subjects
    1
    Notes
    [4] - 14 enrolled subjects did not receive rituximab and not evaluated for outcome measure.
    No statistical analyses for this end point

    Secondary: Incidences of Grade II-III / III-IV acute GVHD / chronic GVHD

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    End point title
    		 Incidences of Grade II-III / III-IV acute GVHD / chronic GVHD
    End point description
    Number of participants who developed grade II-III acute GVHD. Number of participants who developed grade III-IV acute GVHD. Number of participants who developed chronic extensive GVHD. Acute GVHD grading: Grade I +1 to +2 skin rash, No gut or liver involvement Grade II +1 to +3 skin rash, +1 gastrointestinal involvement and/or +1 liver involvement Grade III +2 to +4 gastrointestinal involvement and/or +2 to +4 liver involvement with or without a rash Grade IV Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death Chronic GVHD grading: The diagnosis of chronic GVHD requires at least one manifestation that is distinctive for chronic GVHD as opposed to acute GVHD. In all cases, infection and others causes must be ruled out in the differential diagnosis of chronic GVHD.
    End point type
    Secondary
    End point timeframe
    One year post-transplant
    End point values
    		 Treatment
    Number of subjects analysed
    52 [5]
    Units: Subjects
        Grade II-III acute GVHD
    33
        Grade III-IV acute GVHD
    12
        Chronic extensive GVHD
    27
    Notes
    [5] - 14 enrolled subjects did not receive rituximab and not evaluated for outcome measure.
    No statistical analyses for this end point

    Secondary: Number of Participants With Regimen-related Toxicity and Infections

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    End point title
    		 Number of Participants With Regimen-related Toxicity and Infections
    End point description
    Number of Participants With Regimen-related Toxicity and Infections, reported using the adapted National Cancer Institute Common Toxicity Criteria.
    End point type
    Secondary
    End point timeframe
    100 days post-transplant
    End point values
    		 Treatment
    Number of subjects analysed
    52 [6]
    Units: Subjects
    46
    Notes
    [6] - 14 enrolled subjects did not receive rituximab and not evaluated for outcome measure.
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-related Mortality

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    End point title
    		 Number of Participants With Treatment-related Mortality
    End point description
    Number of subjects expired without disease progression/relapse.
    End point type
    Secondary
    End point timeframe
    One year post-transplant
    End point values
    		 Treatment
    Number of subjects analysed
    52 [7]
    Units: Subjects
    14
    Notes
    [7] - 14 enrolled subjects did not receive rituximab and not evaluated for outcome measure.
    No statistical analyses for this end point

    Secondary: Rituxan Concentration

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    End point title
    		 Rituxan Concentration
    End point description
    Median rituxan level at days 60, 84, 180, and 1 year.
    End point type
    Secondary
    End point timeframe
    Days 60, 84, 180, and 1 year.
    End point values
    		 Day 60 Rituxan testing group Day 84 Rituxan testing group Day 180 Rituxan testing group 1 Year Rituxan testing group
    Number of subjects analysed
    27
    28
    15
    6
    Units: Rituxan level
        median (full range (min-max))
    109 (0.2 to 480.5)
    51 (0.1 to 369)
    1.3 (0 to 103.6)
    0.03 (0 to 0.6)
    No statistical analyses for this end point

    Secondary: Number of Patients Achieving Complete Response and Partial Response (Overall Response Rate)

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    End point title
    		 Number of Patients Achieving Complete Response and Partial Response (Overall Response Rate)
    End point description
    Complete Remission (CR): Imaging studies (Xray, CT, MRI) (nodes, liver, and spleen): Normal Peripheral blood by flow cytometry: No clonal lymphocytes Bone marrow by morphology: No nodules; or if present, nodules are free from CLL cells by immunohistochemistry Duration: ≥2 months CR with minimal residual disease Peripheral blood or bone marrow by flow cytometry: >0 - <1 CLL cells/1000 leukocytes (0.1%) Partial Remission (PR): Both criteria: Absolute lymphocyte count in peripheral blood: ≥50% decrease Physical exam/Imaging studies (nodes, liver, and/or spleen): ≥50% decrease Duration: ≥2 months
    End point type
    Secondary
    End point timeframe
    One year post-transplant
    End point values
    		 Treatment
    Number of subjects analysed
    52 [8]
    Units: Subjects
    35
    Notes
    [8] - 14 enrolled subjects did not receive rituximab and not evaluated for outcome measure.
    No statistical analyses for this end point

    Secondary: Donor and Host Polymorphisms of the FCgammaRIIIa Receptor and CD32 and Their Impact on Disease Response and Relapse

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    End point title
    		 Donor and Host Polymorphisms of the FCgammaRIIIa Receptor and CD32 and Their Impact on Disease Response and Relapse
    End point description
    Number of participants without progressive disease and surviving at one year. Participants with FCgammaRIIIa receptor vs participants without FCgammaRIIIa receptor.
    End point type
    Secondary
    End point timeframe
    One year post-transplant
    End point values
    		 Patients with FCgammaRIIIa receptor Patients without FCgammaRIIIa receptor
    Number of subjects analysed
    2
    30
    Units: Subjects
        Surviving patients
    2
    21
        Progression free
    2
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs: Conditioning through Day 100 SAEs: Conditioning through Day 200
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Adapted CTC
    Dictionary version
    2.0
    Reporting groups
    Reporting group title
    Rituxan group
    Reporting group description
    		 -

    Serious adverse events
    		 Rituxan group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 52 (7.69%)
         number of deaths (all causes)
    33
         number of deaths resulting from adverse events
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Grade 4 GVHD
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Rituxan group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 52 (42.31%)
    Investigations
    Weight gain
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Blood bilirubin increased
         subjects affected / exposed
    7 / 52 (13.46%)
         occurrences all number
    7
    Creatinine increased
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Cardiac disorders
    Heart Failure
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Left ventricular systolic dysfunction
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Chest pain - cardiac
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Atrial fibrillation
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    3
    Nervous system disorders
    Syncope
         subjects affected / exposed
    3 / 52 (5.77%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    4 / 52 (7.69%)
         occurrences all number
    7
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Colitis
         subjects affected / exposed
    1 / 52 (1.92%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    4 / 52 (7.69%)
         occurrences all number
    4

    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
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