Trial Outcomes & Findings for Study Of The Effectiveness & Safety Of Lenalidomide Versus Chlorambucil As First Line Therapy For Elderly Patients With B-Cell CLL (The ORIGIN Trial) (NCT NCT00910910)

Last Updated: 2019-07-09

Results Overview

Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

450 participants

Primary outcome timeframe

From first dose of study drug to date of data cut-off of 18 Feb 2013; up to approximately 39 months

Results posted on

2019-07-09

Participant Flow

118 sites randomized participants in Austria, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, Columbia, Croatia, Czech Republic, Denmark, Hungary, Israel, Italy, the Netherlands, New Zealand, Poland, Portugal, Romania, Russia, South Africa, Slovakia, Spain, Serbia, the United Kingdom, and the United States of America

Participants were randomized 1:1 to lenalidomide or chlorambucil and stratified by disease stage, presence of pre-defined co-morbidities and presence of at least one of the following poor prognostic factors: 11q deletion, 17 p deletion, unmutated IgVH and B2M\>4.0 mg/dL.

Participant milestones

Participant milestones
Measure	Lenalidomide For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Overall Study STARTED	225	225
Overall Study Safety Population	224	223
Overall Study COMPLETED	0	1
Overall Study NOT COMPLETED	225	224

Reasons for withdrawal

Reasons for withdrawal
Measure	Lenalidomide For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Overall Study Adverse Event	63	35
Overall Study PD without histologic change	27	23
Overall Study PD with histologic change	0	2
Overall Study Withdrawal by Subject	7	5
Overall Study Lost to Follow-up	2	2
Overall Study Death	9	3
Overall Study Protocol Violation	2	2
Overall Study Completed 13 cycles of treatment	0	118
Overall Study Other	114	32
Overall Study Untreated before cycle 1	1	2

Baseline Characteristics

Study Of The Effectiveness & Safety Of Lenalidomide Versus Chlorambucil As First Line Therapy For Elderly Patients With B-Cell CLL (The ORIGIN Trial)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lenalidomide n=225 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=225 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).	Total n=450 Participants Total of all reporting groups
Age, Continuous	73.0 years STANDARD_DEVIATION 5.72 • n=5 Participants	73.3 years STANDARD_DEVIATION 5.72 • n=7 Participants	73.1 years STANDARD_DEVIATION 5.72 • n=5 Participants
Sex: Female, Male Female	93 Participants n=5 Participants	83 Participants n=7 Participants	176 Participants n=5 Participants
Sex: Female, Male Male	132 Participants n=5 Participants	142 Participants n=7 Participants	274 Participants n=5 Participants

PRIMARY outcome

Timeframe: From first dose of study drug to date of data cut-off of 18 Feb 2013; up to approximately 39 months

Population: This is a smaller population used in this analysis (earlier cut-off date) prior to the last participant enrolled in the study. The ITT population was defined as all participants who were randomized, independent of whether they received study treatment or not.

Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression

Outcome measures

Outcome measures
Measure	Lenalidomide n=212 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=215 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Kaplan-Meier Estimate of Progression Free Survival (PFS)	30.8 months Interval 18.7 to Not Applicable = The upper boundary of confidence interval (CI) is not estimable because of censored participants.	23.0 months Interval 19.3 to 29.2

PRIMARY outcome

Timeframe: From randomization to data cut off date of 31 March 2014; median follow up time for all participants was 12.6 months

Population: The Intent-to-Treat (ITT) population was defined as all participants who were randomized, independent of whether they received study treatment or not.

Progression-free survival was defined as the time from randomization to the first documented progression confirmed per investigator's assessment or death due to any cause on study, whichever occurred first. Progressive disease included lymphadenopathy, an appearance of any new lesion such as enlarged lymph nodes (\> 1.5 cm), splenomegaly, hepatomegaly or other organ infiltrates, an increase by 50% or more in greatest determined diameter of any previous site or an increase by 50% or more in the sum of the product of diameters of multiple nodes. The progression date was assigned to the earliest time when any progression was observed without prior missing assessments. If withdrawal of consent or lost to follow-up occurred before documented progression or death, then these observations were censored at the date when the last complete tumor assessments determined a lack of progression.

Outcome measures

Outcome measures
Measure	Lenalidomide n=225 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=225 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014	30.8 months Interval 18.7 to NA = The upper boundary of CI is not estimable because of censored participants.	21.4 months Interval 19.3 to 25.1

SECONDARY outcome

Timeframe: From randomization up to data cut-off of 18 Feb 2013; Up to approximately 39 months; maximum duration of exposure for Lenalidomide was 1086 days and 406 days for Chlorambucil

Population: This is a smaller population used in this analysis (earlier cut-off date) prior to the last participant enrolled in the study. The safety population was defined as all randomized participants who received at least 1 dose of the study treatment (either lenalidomide or chlorambucil) as of the data cut off date of 18 Feb 2013

AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild - transient or mild discomfort; no medical intervention required; Grade 2 = Moderate - mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death

Outcome measures

Outcome measures
Measure	Lenalidomide n=211 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=213 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Number of Participants With Adverse Events (AEs) ≥ 1 TEAE	202 participants	186 participants
Number of Participants With Adverse Events (AEs) ≥ 1 TEAE related to study drug	183 participants	139 participants
Number of Participants With Adverse Events (AEs) ≥ 1 NCI CTC Grade 3-4 TEAE	173 participants	117 participants
Number of Participants With Adverse Events (AEs) Grade 3-4 adverse event related to any study drug	143 participants	82 participants
Number of Participants With Adverse Events (AEs) ≥ 1 NCI CTC Grade 5 TEAE	21 participants	9 participants
Number of Participants With Adverse Events (AEs) ≥ Grade 5 adverse event related to any study drug	6 participants	1 participants
Number of Participants With Adverse Events (AEs) ≥ 1 Serious TEAE	129 participants	76 participants
Number of Participants With Adverse Events (AEs) ≥ 1 Serious TEAE related to any study drug	95 participants	46 participants
Number of Participants With Adverse Events (AEs) ≥1 TEAE leading to stopping either study drug	61 participants	34 participants
Number of Participants With Adverse Events (AEs) ≥1 Related TEAE leading to stopping either drug	39 participants	19 participants

SECONDARY outcome

Timeframe: From randomization to the data cut-off date of 31 March 2014; Up to 53 months; maximum duration of exposure for Lenalidomide was 1140 days and 406 days for Chlorambucil

Population: The safety population was defined as all randomized participants who received at least 1 dose of the study treatment (either lenalidomide or chlorambucil).

Outcome measures

Outcome measures
Measure	Lenalidomide n=224 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=223 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥ 1 TEAE	216 participants	202 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥ 1 TEAE related to study drug	194 participants	155 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥ 1 NCI CTC Grade 3-4 TEAE	188 participants	131 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 Grade 3-4 adverse event related to any study drug	157 participants	90 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥ 1 NCI CTC Grade 5 TEAE	21 participants	11 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥ Grade 5 adverse event related to any study drug	6 participants	1 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥ 1 Serious TEAE	148 participants	90 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥ 1 Serious TEAE related to any study drug	107 participants	53 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥1 TEAE leading to stopping either study drug	70 participants	42 participants
Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 ≥1 Related TEAE leading to stopping either drug	46 participants	23 participants

SECONDARY outcome

Timeframe: Up to data cut-off date of 18 Feb 2013; approximately 39 months

Population: This is a smaller population used in this analysis (earlier cut-off date) prior to the last participant enrolled in the study. The Intent-to-Treat (ITT) population was defined as all participants who were randomized, independent of whether they received study treatment or not.

A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): * No lymphadenopathy * No hepatomegaly or splenomegaly * Absence of constitutional symptoms * Polymorphonuclear leukocytes ≥ 1500/ul * No circulating clonal B-lymphocytes * Platelets \> 100,000/ul * Hemoglobin \> 11.0 g/dl * Normocellular \<30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response (nPR): • CR with the presence of residual clonal nodules. Partial Response (PR) requires: * ≥ 50% decrease in peripheral blood lymphocyte count * ≥ 50% reduction in lymphadenopathy * ≥ 50% reduction in size of liver and/or spleen * 1 or more of the following: * Polymorphonuclear leukocytes ≥ 1500/ul * Platelets \>100,000/ul

Outcome measures

Outcome measures
Measure	Lenalidomide n=212 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=215 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines	51.9 percentage of participants	62.3 percentage of participants

SECONDARY outcome

Timeframe: Up to data cut-off of 31 March 2014; approximately 53 months

Population: The Intent-to-Treat population was defined as all participants who were randomized, independent of whether they received study treatment or not

A best overall response rate is a CR, CRi, nPR or PR and is defined as: Complete Remission (CR): * No lymphadenopathy * No hepatomegaly or splenomegaly * Absence of constitutional symptoms * Polymorphonuclear leukocytes ≥ 1500/ul * No circulating clonal B-lymphocytes * Platelets \> 100,000/ul * Hemoglobin \> 11.0 g/dl * Normocellular \<30% lymphocytes, no B-lymphoid nodules; Incomplete Clinical Response (CRi): • CR without bone marrow biopsy confirmation. Nodular Partial Response: • CR with the presence of residual clonal nodules. Partial Response requires: * ≥ 50% decrease in peripheral blood lymphocyte count * ≥ 50% reduction in lymphadenopathy * ≥ 50% reduction in size of liver and/or spleen * 1 or more of the following: * Polymorphonuclear leukocytes ≥ 1500/ul * Platelets \>100,000/ul

Outcome measures

Outcome measures
Measure	Lenalidomide n=225 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=225 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014	60.9 percentage of participants with response	70.2 percentage of participants with response

SECONDARY outcome

Timeframe: Up to data cut-off of 18 Feb 2013; up to approximately 39 months

Population: Intent to Treat population with an objective response as of 18 Feb 2013; includes responders

Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) participants who had not progressed at the time of analysis; 2) participants who had withdrawn consent or were lost to follow-up prior to documentation of progression

Outcome measures

Outcome measures
Measure	Lenalidomide n=110 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=134 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Kaplan-Meier Estimate for Duration of Response	NA weeks Interval 131.1 to NA = The median and upper limit of the CI not estimable due to insufficient number of participants with events.	105.3 weeks Interval 77.4 to 123.7

SECONDARY outcome

Timeframe: Up to data cut-off of 31 March 2014; up to approximately 53 months

Population: Intent to Treat population with an objective response as of 31 March 2014; includes responders.

Duration of response was defined as the time from first nPR, PR, CRi, or CR to PD. Duration of response was censored at the last date that the patient was known to be progression-free for: 1) patients who had not progressed at the time of analysis; 2) patients who had withdrawn consent or were lost to follow-up prior to documentation of progression

Outcome measures

Outcome measures
Measure	Lenalidomide n=137 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=158 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014	NA weeks Interval 149.4 to NA due to large number of censored observations.	87.1 weeks Interval 77.1 to 108.7

SECONDARY outcome

Timeframe: Up to data cut-off of 18 Feb 2013; up to approximately 39 months

Population: ITT participants with an objective response as of 18 February 2013

Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines

Outcome measures

Outcome measures
Measure	Lenalidomide n=110 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=134 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Time to Response	8.6 weeks Interval 3.7 to 104.3	8.1 weeks Interval 3.7 to 52.7

SECONDARY outcome

Timeframe: Up to data cut-off of 31 March 2014; up to approximately 53 months

Population: ITT participants who had not progressed at the time of analysis; or those who had withdrawn consent or were lost to follow-up prior to documentation of progression.

Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines

Outcome measures

Outcome measures
Measure	Lenalidomide n=137 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=158 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Time to Response for a Later Cut-off Date of 31 March 2014	10.4 weeks Interval 3.7 to 136.1	8.1 weeks Interval 3.7 to 68.7

SECONDARY outcome

Timeframe: Up to data cut off of 31 March 2014; median follow-up for all participants was 18.8 months

Population: The Intent-to-Treat (ITT) population was defined as all participants who were randomized, independent of whether they received study treatment or not.

Overall Survival is defined as the time between randomization and death from any cause.

Outcome measures

Outcome measures
Measure	Lenalidomide n=225 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=225 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Kaplan Meier Estimate of Overall Survival	NA Months The median had not been reached and CI not estimable because of small number of events. .	44.0 Months Interval 37.3 to Upper level CI not estimable because of small number of events

SECONDARY outcome

Timeframe: Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months

Population: The ITT population was defined as all participants who were randomized, independent of whether they received study treatment.

Overall Survival is defined as the time between randomization and death from any cause. Overall survival was censored at the last date that the subject was known to be alive for participants who were alive as of the data cutoff date and for participants who were lost to follow-up before death was documented.

Outcome measures

Outcome measures
Measure	Lenalidomide n=225 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=225 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Kaplan Meier Estimate for Overall Survival at the Final Analysis	74.3 Months Interval 58.5 to 84.4	70.5 Months Interval 57.1 to Upper CI not estimable because of censored observations.

SECONDARY outcome

Timeframe: Day 1 and once every 8 weeks

Population: No data were collected for the FACT-Leu QOL assessment. Analysis was not conducted due to the discontinuation of the lenalidomide arm.

The FACT-Leu scale is a valid, reliable, and efficient measure of leukemia-specific health-related quality of life for acute and chronic disease. The FACT-Leu is described as including 27 items that assess 17 physical symptoms (fevers, bleeding, general pain, stomach pain, chills, night sweats, bruising, lymph node swelling, weakness, tiredness, weight loss, appetite, shortness of breath, functional ability, diarrhea, concentration, and mouth sores) and 10 emotional/social concerns (frustration with activity limitation, discouraged by illness, future planning, uncertainty, worry about illness, emotional lability, isolation, infertility concern, family worry, and worry about infections).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1 and once every 8 weeks

Population: No data were collected for the EQ-5D QOL assessment. The EQ-5D analysis was not conducted due to the discontinuation of the lenalidomide arm.

The standardized extended version of EQ-5D was designed for the collection of health state values using a visual analogue scale (VAS) rating scale - a vertical 20 cm visual analogue scale with the end points labeled best imaginable health state at the top and worst imaginable health state at the bottom having numeric values of 100 and 0 respectively. The participant is asked to indicate his/her health state by ticking (or placing a cross) in the box against the most appropriate statement in each of the 5 dimensions.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months

Population: The safety population was defined as all randomized participants who received at least 1 dose of the study treatment (either lenalidomide or chlorambucil).

Subsequent anti-cancer therapies administered to participants following the discontinuation of study drug (either Lenalidomide or Chlorambucil)

Outcome measures

Outcome measures
Measure	Lenalidomide n=224 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=223 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving additional CLL therapy	125 participants	120 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving alkylating agents	107 participants	106 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving antineoplastic aents	93 participants	86 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving antimetabolites	34 participants	24 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving corticosteroids	27 participants	16 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving plant alkaloids	22 participants	11 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving cytotoxic antibiotics	10 participants	3 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving immunosuppressants	3 participants	2 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving therapeutic products	4 participants	3 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Participants receiving other unspecified products	0 participants	2 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Antihistamine For Systemic Use	1 participants	1 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Drugs for Peptic ulcer and Gastric Reflex	1 participants	0 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Immunoglobulins	1 participants	2 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Other Analgesics and Antipyretics	1 participants	1 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Specific Antirheumatic Agents	1 participants	0 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Antiemetics and Antinauseants	0 participants	1 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Corticosteriods for Systemic Use	0 participants	1 participants
Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment Immunostimulants	0 participants	1 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From the first dose of study drug up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months

Population: ITT population includes all participants who were randomized, independent of whether they received study treatment or not

The number of study participants deaths during the treatment and follow-up phase

Outcome measures

Outcome measures
Measure	Lenalidomide n=225 Participants For participants with normal renal function \[defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min\], 5 mg lenalidomide by mouth (PO) once daily (QD) on Days 1 through 28 of the first 28-day cycle, 10 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 15 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until progressive disease (PD) or unacceptable toxicity, whichever occurred first. For participants with moderate renal impairment (defined as CrCL ≥ 30 to \< 60 mL/min), 2.5 mg lenalidomide PO QD on Days 1 through 28 of the first 28-day cycle, 5 mg lenalidomide PO QD on Days 1 through 28 starting at cycle 2, 7.5 mg lenalidomide PO QD starting at cycle 3 and for the remainder of the study until PD or unacceptable toxicity, whichever occurred first.	Chlorambucil n=225 Participants Chlorambucil oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months (approximately 13 cycles).
Number of Participants Deaths During the Treatment and Survival Follow-Up Phase	101 Participants	95 Participants

Adverse Events

Lenalidomide

Serious events: 148 serious events

Other events: 204 other events

Deaths: 100 deaths

Chlorambucil

Serious events: 90 serious events

Other events: 184 other events

Deaths: 93 deaths

Serious adverse events

Other adverse events

Additional Information

Anne McClain, Senior Manager of Clinical Trial Disclosure

Celgene Corporation

Phone: 888-260-1599

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Results from a center cannot be submitted for publication before results of multicenter study are published unless it is more than 12 months since study completion. Investigator can publish if manuscript is submitted to Celgene 60 days prior to submission. If Celgene decides publication would hinder drug development, Investigator must delay submission for up to 90 days. Investigator must delete confidential information before submission or defer publication to permit patent applications.
Publication restrictions are in place

Restriction type: OTHER