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    Clinical Trial Results:
    Efficacy of alternating immunochemotherapy consisting of R-CHOP + R-HAD versus R-CHOP alone, followed by maintenance therapy consisting of additional lenalidomide with rituximab versus rituximab alone for older patients with mantle cell lymphoma

    Summary
    EudraCT number
    		 2012-002542-20
    Trial protocol
    		 FR   BE   DE   NL   PT   ES   PL  
    Global end of trial date
    30 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2026
    First version publication date
    18 Feb 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MCL-R2 Elderly
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01865110
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LYSARC
    Sponsor organisation address
    CH Lyon Sud – Bat 2D, PIERRE-BENITE Cedex, France, 69495
    Public contact
    Christine STEPHAN, LYSARC, mclr2@lysarc.org
    Scientific contact
    Vincent Ribrag, LYSA, vincent.ribrag@gustaveroussy.fr
    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
    30 Jan 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to evaluate whether the addition of lenalidomide to standard rituximab-maintenance improves progression free survival (PFS) compared to standard rituximab maintenance after response to induction chemotherapy in older patients with mantle cell lymphoma not suitable for autologous stem cell transplantation
    Protection of trial subjects
    Therapies considered necessary for the subject’s well-being may be administered at the discretion of the Investigator. Growth factors during induction treatment (e.g. G-CSF, GM-CSF, erythropoietin, etc.) may be prescribed by the Investigator for rescue from severe hematologic events and should be used in accordance with the American Society of Clinical Oncology’s (ASCO) guidelines or the European Society for Medical Oncology (ESMO) guidelines
    Background therapy
    		 Induction treatment with RCHOP followed by R-maintenance
    Evidence for comparator
    		 The European MCL network presented a randomized phase III study including a high number of patients (560 elderly patients). Two induction therapies were compared, 8 cycles of R-CHOP and 6 cycles of R-FC. A second randomization compared rituximab maintenance given every other month to IFN maintenance. Maintenance therapy was continued until progression or recurrence of the lymphoma{Kluin-Nelemans HC, Hoster E, Hermine O et al. Treatment of older patients with mantle cell lymphoma. N Engl J Med. 2012;367(6):520-31}. Out of 560 patients, 532 could be analyzed according to intention-to-treat for response, whereas 485 were fully evaluable. Median age was 70 yrs. Although complete remission rates were similar after R-FC vs R-CHOP (40% vs 34%, p=0.10), progressive disease was more frequent during R-FC (14% vs 5%). Four-year overall survival was significantly inferior after R-FC (47% vs 62%; p=0.005) with more patients dying in first remission (10% vs 4%). In 274 of 316 patients randomized for maintenance, rituximab almost doubled the remission duration compared with interferon-alfa (at 4-yr 58% vs 29% in remission; hazard ratio 0.55, 95% CI 0.36-0.87; p=0.0109). Rituximab maintenance significantly improved 4-year overall survival up to 87% vs. 63% on interferon-alfa (p=0.0051) in patients responding to R-CHOP. This study strongly suggests that 8 cycles of R-CHOP followed by rituximab maintenance could now represent a real standard therapy in elderly patients {6}. Still, the percentage of patients obtaining an initial CR is low. Patients who show early progression do not respond upon salvage therapy and die early. These data ask for further improvement of induction therapy. Furthermore, no plateau in remission duration has been observed, suggesting that maintenance with rituximab is not sufficient.
    Actual start date of recruitment
    04 Nov 2013
    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
    Netherlands: 75
    Country: Number of subjects enrolled
    Portugal: 8
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Belgium: 24
    Country: Number of subjects enrolled
    France: 412
    Country: Number of subjects enrolled
    Germany: 74
    Country: Number of subjects enrolled
    Poland: 10
    Worldwide total number of subjects
    620
    EEA total number of subjects
    620
    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)
    37
    From 65 to 84 years
    578
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 First patients was randomized in the trial in France on 04/11/2013, in Germany on 11/05/2015, in Belgium on 29/09/2015, in Portugal and the Netherlands on 14/12/2015, in Spain on 13/09/2016 and in Poland on 22/05/2018. Last patient was randomized for induction part on 05/12/2019 and for maintenance part on 21/08/2020.

    Pre-assignment
    Screening details
    		 Previously untreated participants with biopsy-proven mantle cell lymphoma according to WHO classification could be enrolled. From 03/11/2013 to 03/05/2014, patients could be randomized directly for maintenance treatment if they received 8 RCHOP before registration in the trial. 636 patients were screened and 623 randomizedin the trial.

    Period 1
    Period 1 title
    Induction
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 R-CHOP
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 at Day 1, compound of standard CHOP chemotherapy, 8 cycles of 21-day cycle

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 at D1 before starting CHOP

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 at Day 1, compound of standard CHOP chemotherapy, 8 cycles of 21-day cycle

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m2 (2mg cap) at Day 1, compound of standard CHOP chemotherapy, 8 cycles of 21-day cycle

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/day at Day 1 to day 5, compound of standard CHOP chemotherapy, 8 cycles of 21-day cycle

    Arm title
    		 R-CHOP/R-HAD
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Aracytine
    Pharmaceutical forms
    Solution for injection, Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m2 at day 1 (twice every 12 to 24 hours), 3 cycles of 28-day cycle for R-HAD alternating with R-CHOP

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    375 mg/m2 at day 1 (and 4 only during the first 2 cycles of RHAD)

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    20 mg/day at day 1 to 4 of RHAD cycles The administration route for dexamethasone will be used according to the marketing authorization available in each country for the dose used in the protocol (i.e. oral administration is allowed only in countries where this formulation has a marketing authorization)

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    750 mg/m2 at Day 1, compound of standard CHOP chemotherapy, 3 cycles of 21-day cycle alternating with R-HAD

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 mg/m2 at Day 1, compound of standard CHOP chemotherapy, 3 cycles of 21-day cycle alternating with R-HAD

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    1.4 mg/m2 (2mg cap) at Day 1, compound of standard CHOP chemotherapy, 3 cycles of 21-day cycle alternating with R-HAD

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/day at Day 1 to day 5, compound of standard CHOP chemotherapy, 3 cycles of 21-day cycle alternating with R-HAD

    Number of subjects in period 1
    		R-CHOP R-CHOP/R-HAD
    Started
    312
    308
    Completed
    259
    281
    Not completed
    53
    27
         Consent withdrawn by subject
    2
    2
         progression
    13
    16
         Death
    6
    2
         concurrent illness
    2
    -
         Other
    9
    2
         Insufficient response
    9
    2
         Toxicity of study treatment
    7
    2
         Protocol deviation
    5
    1
    Period 2
    Period 2 title
    Maintenance
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 R Arm
    Arm description
    		 Rituximab
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fixed dose of 1400 mg administered subcutaneousely

    Arm title
    		 R2 Arm
    Arm description
    		 Rituximab + Lenalidomide
    Arm type
    		 Experimental

    Investigational medicinal product name
    rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fixed dose of 1400 mg administered subcutaneousely

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    lenalidomide 15 mg daily on days 2 to 22 every 4 weeks. starting dose reduced to 10 mg in case of moderate renal insufficiency

    Number of subjects in period 2 [1]
    		R Arm R2 Arm
    Started
    248
    247
    Completed
    147
    154
    Not completed
    101
    93
         Consent withdrawn by subject
    2
    4
         progression
    78
    42
         concurrent illness
    5
    11
         Death
    2
    2
         Other
    4
    11
         Toxicity of study treatment
    5
    19
         Protocol deviation
    5
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Regarding the second randomization, only patients who had a confirmed or unconfirmed complete response were eligible for randomization

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R-CHOP
    Reporting group description
    		 -

    Reporting group title
    R-CHOP/R-HAD
    Reporting group description
    		 -

    Reporting group values
    		 R-CHOP R-CHOP/R-HAD Total
    Number of subjects
    		 312 308 620
    Age categorical
    Three categorises have been defined
    Units: Subjects
        Adults (18-64 years)
    		 19 18 37
        From 65-84 years
    		 290 288 578
        85 years and over
    		 3 2 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.6 ( 5.22 ) 71.7 ( 4.77 ) -
    Gender categorical
    Units: Subjects
        Female
    		 91 86 177
        Male
    		 221 222 443
    Ann arbor stage
    Units: Subjects
        stage I
    		 0 2 2
        stage II
    		 12 15 27
        stage III
    		 15 16 31
        stage IV
    		 284 275 559
        Missing
    		 1 0 1
    ECOG Performance status
    Units: Subjects
        0-1
    		 287 282 569
        >1
    		 23 26 49
        Missing
    		 2 0 2
    LDH > upper limit
    Units: Subjects
        No
    		 181 174 355
        Yes
    		 127 131 258
        Missing
    		 4 3 7
    MIPI risk group at baseline
    Units: Subjects
        Low risk (<5.7)
    		 21 18 39
        Intermediate risk (>=5.7 & <6.2)
    		 137 134 271
        High risk (>=6.2)
    		 149 153 302
        Missing
    		 5 3 8
    Weight
    weight collected in kg
    Units: kg
        arithmetic mean (standard deviation)
    		 77.1 ( 15.13 ) 76.3 ( 14.93 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 170.3 ( 8.52 ) 170.7 ( 8.84 ) -
    Hemoglobin
    Units: g/dl
        arithmetic mean (standard deviation)
    		 12.6 ( 1.91 ) 12.2 ( 2.08 ) -
    Leukocytes
    Units: G/L
        arithmetic mean (standard deviation)
    		 21.1 ( 55.14 ) 17.3 ( 39.75 ) -
    Neutrophils
    Units: G/L
        arithmetic mean (standard deviation)
    		 4.9 ( 3.53 ) 4.5 ( 2.32 ) -
    Lymphocytes
    Units: G/L
        arithmetic mean (standard deviation)
    		 8.2 ( 27.3 ) 9.0 ( 36.0 ) -
    Lymphoma cells (%)
    Units: percentage
        arithmetic mean (standard deviation)
    		 13 ( 26.28 ) 14.2 ( 24.63 ) -
    Platelets
    Units: G/L
        arithmetic mean (standard deviation)
    		 198.4 ( 94.1 ) 189.3 ( 98.01 ) -

    End points

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    End points reporting groups
    Reporting group title
    R-CHOP
    Reporting group description
    		 -

    Reporting group title
    R-CHOP/R-HAD
    Reporting group description
    		 -
    Reporting group title
    R Arm
    Reporting group description
    		 Rituximab

    Reporting group title
    R2 Arm
    Reporting group description
    		 Rituximab + Lenalidomide

    Primary: Progression-Free Survival for maintenance randomisation (PFSm)

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    End point title
    		 Progression-Free Survival for maintenance randomisation (PFSm)
    End point description
    PFS at 2 years
    End point type
    Primary
    End point timeframe
    From the date of maintenance randomization to the date of first documented disease progression, relapse or death from any cause, whichever occurs first or last contact if no event occurs
    End point values
    		 R Arm R2 Arm
    Number of subjects analysed
    248
    247
    Units: percentage
        number (confidence interval 95%)
    62.3 (55.9 to 68.0)
    77.0 (71.2 to 81.8)
    Attachments
    		 Primary analysis -PFS curves
    Statistical analysis title
    		 PFSm superiority analysis
    Comparison groups
    R Arm v R2 Arm
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.784
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.635
         upper limit
    		 0.967

    Secondary: Overall Survival since maintenance randomisation (OSm)

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    End point title
    		 Overall Survival since maintenance randomisation (OSm)
    End point description
    End point type
    Secondary
    End point timeframe
    From maintenance randomisation to death/last visit
    End point values
    		 R Arm R2 Arm
    Number of subjects analysed
    248
    247
    Units: percent
        number (confidence interval 95%)
    85.3 (80.2 to 89.2)
    87.7 (82.9 to 91.2)
    Attachments
    		 secondary endpoint -OS curves
    Statistical analysis title
    		 Overall survival
    Statistical analysis description
    Overall survival from maintenance randomisation - Maintenance ITT set
    Comparison groups
    R Arm v R2 Arm
    Number of subjects included in analysis
    495
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.766
         upper limit
    		 1.359

    Secondary: Overall Survival since induction randomisation (OSi)

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    End point title
    		 Overall Survival since induction randomisation (OSi)
    End point description
    End point type
    Secondary
    End point timeframe
    From the date of induction randomisation randomization to the date of first documented disease progression, relapse or death from any cause, whichever occurs first
    End point values
    		 R-CHOP R-CHOP/R-HAD
    Number of subjects analysed
    312
    308
    Units: percent
        number (confidence interval 95%)
    83.0 (78.3 to 86.8)
    83.2 (78.4 to 86.9)
    Attachments
    		 key secondary analysis -OS curves
    Statistical analysis title
    		 OS since induction randomisation
    Comparison groups
    R-CHOP/R-HAD v R-CHOP
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.932
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.733
         upper limit
    		 1.185

    Secondary: Complete Response rate (CR/CRu)

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    End point title
    		 Complete Response rate (CR/CRu)
    End point description
    End point type
    Secondary
    End point timeframe
    End of induction
    End point values
    		 R-CHOP R-CHOP/R-HAD
    Number of subjects analysed
    290
    300
    Units: percentage
        arithmetic mean (confidence interval 95%)
    41 (35.32 to 56.94)
    41.3 (35.7 to 47.14)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Patients randomized to receive rituximab and lenalidomide received up to twenty six cycles of lenalidomide 15 mg daily on days 2 to 22 every 4 weeks and up to thirteen injections of rituximab 1400 mg on day 1 every 8 weeks.
    Adverse event reporting additional description
    Evaluated for AEs at each visit with the NCI CTCAE v4.0 used as a guide for the grading of severity.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    R Arm
    Reporting group description
    		 -

    Reporting group title
    R2 Arm
    Reporting group description
    		 -

    Serious adverse events
    		 R Arm R2 Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    77 / 250 (30.80%)
    101 / 238 (42.44%)
         number of deaths (all causes)
    91
    93
         number of deaths resulting from adverse events
    1
    4
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED
         subjects affected / exposed
    42 / 250 (16.80%)
    48 / 238 (20.17%)
         occurrences causally related to treatment / all
    3 / 57
    48 / 86
         deaths causally related to treatment / all
    0 / 2
    4 / 11
    Vascular disorders
    VASCULAR DISORDERS
         subjects affected / exposed
    6 / 250 (2.40%)
    6 / 238 (2.52%)
         occurrences causally related to treatment / all
    0 / 6
    3 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Surgical and medical procedures
    SURGICAL AND MEDICAL PROCEDURES
         subjects affected / exposed
    2 / 250 (0.80%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
         subjects affected / exposed
    1 / 250 (0.40%)
    4 / 238 (1.68%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    IMMUNE SYSTEM DISORDER
         subjects affected / exposed
    1 / 250 (0.40%)
    1 / 238 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
         subjects affected / exposed
    3 / 250 (1.20%)
    9 / 238 (3.78%)
         occurrences causally related to treatment / all
    0 / 5
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    PSYCHIATRIC DISORDERS
         subjects affected / exposed
    2 / 250 (0.80%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    investigations
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    INJURY, POISONING AND PROCEDURAL COMPLICATIONS
         subjects affected / exposed
    6 / 250 (2.40%)
    5 / 238 (2.10%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC DISORDERS
         subjects affected / exposed
    10 / 250 (4.00%)
    14 / 238 (5.88%)
         occurrences causally related to treatment / all
    1 / 11
    7 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    NERVOUS SYSTEM DISORDERS
         subjects affected / exposed
    3 / 250 (1.20%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    BLOOD AND LYMPHATIC SYSTEM DISORDERS
         subjects affected / exposed
    2 / 250 (0.80%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    EAR AND LABYRINTH DISORDERS
         subjects affected / exposed
    1 / 250 (0.40%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    EYE DISORDERS
         subjects affected / exposed
    2 / 250 (0.80%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    GASTROINTESTINAL DISORDERS
         subjects affected / exposed
    2 / 250 (0.80%)
    7 / 238 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATOBILIARY DISORDERS
         subjects affected / exposed
    3 / 250 (1.20%)
    0 / 238 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS
         subjects affected / exposed
    0 / 250 (0.00%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL AND URINARY DISORDERS
         subjects affected / exposed
    0 / 250 (0.00%)
    2 / 238 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
         subjects affected / exposed
    3 / 250 (1.20%)
    6 / 238 (2.52%)
         occurrences causally related to treatment / all
    0 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    INFECTIONS AND INFESTATIONS
         subjects affected / exposed
    10 / 250 (4.00%)
    38 / 238 (15.97%)
         occurrences causally related to treatment / all
    4 / 11
    17 / 46
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Metabolism and nutrition disorders
    METABOLISM AND NUTRITION DISORDERS
         subjects affected / exposed
    1 / 250 (0.40%)
    3 / 238 (1.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 R Arm R2 Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    150 / 250 (60.00%)
    216 / 238 (90.76%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)
         subjects affected / exposed
    42 / 250 (16.80%)
    48 / 238 (20.17%)
         occurrences all number
    57
    87
    Surgical and medical procedures
    SURGICAL AND MEDICAL PROCEDURES
         subjects affected / exposed
    2 / 250 (0.80%)
    2 / 238 (0.84%)
         occurrences all number
    2
    4
    General disorders and administration site conditions
    VASCULAR DISORDERS
         subjects affected / exposed
    11 / 250 (4.40%)
    11 / 238 (4.62%)
         occurrences all number
    11
    11
    GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
         subjects affected / exposed
    2 / 250 (0.80%)
    26 / 238 (10.92%)
         occurrences all number
    2
    29
    Immune system disorders
    IMMUNE SYSTEM DISORDER
         subjects affected / exposed
    1 / 250 (0.40%)
    2 / 238 (0.84%)
         occurrences all number
    1
    2
    Reproductive system and breast disorders
    REPRODUCTIVE SYSTEM AND BREAST DISORDERS
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 238 (0.42%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
         subjects affected / exposed
    8 / 250 (3.20%)
    17 / 238 (7.14%)
         occurrences all number
    10
    18
    Psychiatric disorders
    PSYCHIATRIC DISORDERS
         subjects affected / exposed
    2 / 250 (0.80%)
    0 / 238 (0.00%)
         occurrences all number
    2
    0
    Investigations
    investigations
         subjects affected / exposed
    3 / 250 (1.20%)
    5 / 238 (2.10%)
         occurrences all number
    3
    5
    Injury, poisoning and procedural complications
    INJURY, POISONING AND PROCEDURAL COMPLICATIONS
         subjects affected / exposed
    6 / 250 (2.40%)
    6 / 238 (2.52%)
         occurrences all number
    6
    6
    Cardiac disorders
    CARDIAC DISORDERS
         subjects affected / exposed
    14 / 250 (5.60%)
    20 / 238 (8.40%)
         occurrences all number
    15
    28
    Nervous system disorders
    NERVOUS SYSTEM DISORDERS
         subjects affected / exposed
    8 / 250 (3.20%)
    23 / 238 (9.66%)
         occurrences all number
    8
    25
    Blood and lymphatic system disorders
    BLOOD AND LYMPHATIC SYSTEM DISORDERS
         subjects affected / exposed
    70 / 250 (28.00%)
    144 / 238 (60.50%)
         occurrences all number
    121
    520
    Ear and labyrinth disorders
    EAR AND LABYRINTH DISORDERS
         subjects affected / exposed
    2 / 250 (0.80%)
    5 / 238 (2.10%)
         occurrences all number
    2
    5
    Eye disorders
    EYE DISORDERS
         subjects affected / exposed
    4 / 250 (1.60%)
    2 / 238 (0.84%)
         occurrences all number
    4
    3
    Gastrointestinal disorders
    GASTROINTESTINAL DISORDERS
         subjects affected / exposed
    3 / 250 (1.20%)
    25 / 238 (10.50%)
         occurrences all number
    3
    28
    Hepatobiliary disorders
    HEPATOBILIARY DISORDERS
         subjects affected / exposed
    3 / 250 (1.20%)
    2 / 238 (0.84%)
         occurrences all number
    4
    3
    Skin and subcutaneous tissue disorders
    SKIN AND SUBCUTANEOUS TISSUE DISORDERS
         subjects affected / exposed
    0 / 250 (0.00%)
    30 / 238 (12.61%)
         occurrences all number
    0
    37
    Endocrine disorders
    ENDOCRIN DISORDER
         subjects affected / exposed
    0 / 250 (0.00%)
    1 / 238 (0.42%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
         subjects affected / exposed
    4 / 250 (1.60%)
    14 / 238 (5.88%)
         occurrences all number
    4
    16
    Infections and infestations
    INFECTIONS AND INFESTATIONS
         subjects affected / exposed
    60 / 250 (24.00%)
    105 / 238 (44.12%)
         occurrences all number
    100
    183
    Metabolism and nutrition disorders
    METABOLISM AND NUTRITION DISORDERS
         subjects affected / exposed
    4 / 250 (1.60%)
    5 / 238 (2.10%)
         occurrences all number
    4
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2013
    Addition of AE collection of grade >=3 during induction treatment and updates on blood/bone marrow samples collected
    17 Mar 2014
    Maintenance treatment: use of rituximab SC instead IV Addition of an exclusion criterion in case of cardiac insufficiency (left ventricular ejection fraction < 50%) on ultrasound Modification of patient stratification rules for maintenance part
    14 Oct 2015
    Postponing of the schedule of interim analysis and IDMC review data meeting originally planned after 25 patients had received 6 months of lenalidomide maintenance treatment or no later than 1 year after the first patient was randomized to maintenance treatment, due to a delay in enrollments: will be conducted after 6 months of maintenance treatment for the 25 patients, in order to ensure a minimum number of patients in the analysis and enhance its robustness. Update to the patient and investigator information documents regarding the risks of lenalidomide to the fetus and contraception recommendations (PPP: Pregnancy Prevention Plan).
    05 Jul 2019
    Update to storage conditions for subcutaneous rituximab according to the Investigator's Brochure Update to dose reduction measures for lenalidomide Additional safety measures for adverse events such as hepatitis B virus reactivation following recent publications in patients treated with immunochemotherapy, Additional safety measures regarding adverse events such as DRESS syndrome and hypo/hyperthyroidism in accordance with the Investigator's Brochure for lenalidomide Clarifications on the maintenance phase: Clarifications on the duration of reporting adverse events
    08 Sep 2020
    Addendum 1 aims to describe the measures taken to adapt the protocol during the pandemic period: postponement of a cycle, possibility of dispensing two cycles of lenalidomide, exceptional authorization to conduct visits by telephone or video to limit travel and patients' exposure to COVID-19; authorization of teleconsultations, authorization to postpone scans; and, if urgent, authorization to use a local imaging center.
    13 Mar 2023
    Reduction of the follow-up period by 5 months: end of patient follow-up on January 30, 2025

    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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