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

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00910910
• Collaborator: (none)
• Enrollment: 450
• Locations: 165
• Arms: 2
• Actual Duration (Months): 102.8
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and efficacy of lenalidomide as a first line therapy in treating patients with B-cell Chronic Lymphocytic Leukemia. This study will compare the effects (good and bad) of lenalidomide with chlorambucil.

Condition or Disease	Intervention/Treatment	Phase
B-Cell Chronic Lymphocytic Leukemia	Drug: Lenalidomide; Drug: Chlorambucil	Phase 3

Detailed Description

After notification from the US Food and Drug Administration (FDA) on 12 July 2013, Celgene agreed to discontinue the lenalidomide treatment for all patients due to an imbalance in the number of deaths in patients treated with lenalidomide versus patients treated with chlorambucil. No specific causality for this imbalance has been identified to date. Investigators were instructed to immediately discontinue all participants from experimental lenalidomide treatment and inform their patients accordingly. Participants on the Chlorambucil arm may continue up to 12 months (13 cycles) with the last participant completing in March 2014. All randomized participants will continue to be followed for overall survival and secondary primary malignancies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 450 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Randomized, Openlabel, Parallel-Group Study of the Efficacy and Safety of Lenalidomide (Revlimid®) Versus Chlorambucil as First-Line Therapy for Previously Untreated Elderly Patients With B-Cell Chronic Lymphocytic Leukemia (The Origin Trial)
• Actual Study Start Date: Oct 13, 2009
• Actual Primary Completion Date: Mar 31, 2014
• Actual Study Completion Date: May 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 - Lenalidomide 1 - Lenalidomide	Drug: Lenalidomide; For patients with normal renal function (defined as CrCl ≥ 60 mL/min), 5 mg once daily on Days 1 through 28 of the first 28-day cycle, 10 mg once daily on Days 1 through 28 starting at the second cycle, 15 mg once daily starting at the third cycle and for the remainder of the study until PD or unacceptable toxicity, whichever occurs first. For patients with moderate renal impairment (defined as CrCl ≥ 30 to < 60 mL/min), 2.5 mg once daily on Days 1 through 28 of the first 28-day cycle, 5 mg once daily on Days 1 through 28 starting at the second cycle, 7.5 mg once daily starting at the third cycle and for the remainder of the study until PD or unacceptable toxicity, whichever occurs first.; Other Names: Revlimid
Active Comparator: 2- Chlorambucil 2- Chlorambucil	Drug: Chlorambucil; Patients assigned to the chlorambucil arm will receive oral chlorambucil 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).; Other Names: Leukeran

Outcome Measures

Primary Outcome Measures

1. Kaplan-Meier Estimate of Progression Free Survival (PFS) [From first dose of study drug to date of data cut-off of 18 Feb 2013; up to approximately 39 months]

   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

2. Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014 [From randomization to data cut off date of 31 March 2014; median follow up time for all participants was 12.6 months]

   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.

Secondary Outcome Measures

1. Number of Participants With Adverse Events (AEs) [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]

   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

2. Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014 [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]

   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

3. Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines [Up to data cut-off date of 18 Feb 2013; approximately 39 months]

   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

4. Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014 [Up to data cut-off of 31 March 2014; approximately 53 months]

   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

5. Kaplan-Meier Estimate for Duration of Response [Up to data cut-off of 18 Feb 2013; up to approximately 39 months]

   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

6. Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014 [Up to data cut-off of 31 March 2014; up to approximately 53 months]

   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

7. Time to Response [Up to data cut-off of 18 Feb 2013; up to approximately 39 months]

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

8. Time to Response for a Later Cut-off Date of 31 March 2014 [Up to data cut-off of 31 March 2014; up to approximately 53 months]

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

9. Kaplan Meier Estimate of Overall Survival [Up to data cut off of 31 March 2014; median follow-up for all participants was 18.8 months]

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

10. Kaplan Meier Estimate for Overall Survival at the Final Analysis [Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months]

    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.

11. Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument [Day 1 and once every 8 weeks]

    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).

12. Euro Quality of Life Five Dimension (EQ-5D) Questionnaire [Day 1 and once every 8 weeks]

    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.

13. Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment [Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months]

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

Other Outcome Measures

1. Number of Participants Deaths During the Treatment and Survival Follow-Up Phase [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]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Must sign an informed consent form.

2. Age ≥ 65 years

3. Must be able to adhere to the study visit schedule and other protocol requirements.

4. Must have a documented diagnosis of B-cell CLL.

5. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.

6. Must agree to follow pregnancy precautions as required by the protocol.

7. Must agree to receive counseling related to teratogenic and other risks of lenalidomide.

8. Must agree not to donate blood or semen as defined by the protocol

Exclusion Criteria:

1. Prior treatment for B-cell CLL.

2. Any medical condition, that would prevent the subject from signing the informed consent form.

3. Active infections requiring systemic antibiotics.

4. Systemic infection that has not resolved > 2 months prior to initiating lenalidomide

5. Pregnant or lactating females.

6. Participation in any clinical study or having taken any investigational therapy within 28 days.

7. Known presence of alcohol and/or drug abuse.

8. Central nervous system (CNS) involvement.

9. Prior history of malignancies, other than CLL, unless the subject has been free of the disease for ≥3 years. Exceptions include the following:

• Basal cell carcinoma of the skin

• Squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)

1. History of renal failure requiring dialysis.

2. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and/or Hepatitis C Virus (HCV) infection.

3. Prior therapy with lenalidomide.

4. Evidence of TLS at screening

5. Presence of specific hematology and/or chemistry abnormalities

6. Uncontrolled hyperthyroidism or hypothyroidism

7. Venous thromboembolism within one year

8. ≥ Grade-2 neuropathy

9. Uncontrolled autoimmune hemolytic anemia or thrombocytopenia

10. Disease transformation [i.e. Richter's Syndrome (lymphomas) or prolymphocytic leukemia]

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Cancer Associates for Research and Excellence cCARE	Escondido	California	United States	92025
2	Innovative Clinical Research Institute	Whittier	California	United States	90603
3	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
4	Cancer Center of Central Connecticut	Southington	Connecticut	United States	06489
5	University Hematology Oncology Inc.	Centralia	Illinois	United States	62801
6	North Chicago VA Medical Center	North Chicago	Illinois	United States	60064
7	Medical Consultants, PC	Muncie	Indiana	United States	47303
8	Floyd Memorial Cancer Center of Indiana, a division of Floyd Memorial Hospital and Health Services	New Albany	Indiana	United States	47150
9	Purchase Cancer Group	Paducah	Kentucky	United States	42001
10	University of Minnesota	Minneapolis	Minnesota	United States	55455-0392
11	Saint Louis University Cancer Center	Saint Louis	Missouri	United States	63110
12	Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
13	Oncology and Hematology Associates, PA	Denville	New Jersey	United States	07834
14	The Cancer Center, Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
15	Somerset Hematology-Oncology Associates	Somerville	New Jersey	United States	08876
16	Roswell Park Cancer Center	Buffalo	New York	United States	14263
17	New York Medical College	Valhalla	New York	United States	10595
18	Gabrail Cancer Center Research	Canton	Ohio	United States	44718
19	Drexel University, College of Medicine	Philadelphia	Pennsylvania	United States	19102
20	Pottstown Memorial Medical Center	Pottstown	Pennsylvania	United States	19464
21	Berks Hematology-Oncology Associates	West Reading	Pennsylvania	United States	19611
22	Geisinger Health System	Wilkes-Barre	Pennsylvania	United States	18711
23	Charleston Hematology Oncology P.A.	Charleston	South Carolina	United States	29403
24	South Carolina Cancer Specialists	Hilton Head Island	South Carolina	United States	29926
25	Central Texas Veterans Health Care System	Temple	Texas	United States	76504
26	Swedish Tumor Institute	Seattle	Washington	United States	98104
27	Providence St. Mary Regional Cancer Center	Walla Walla	Washington	United States	99362
28	Columbia St Marys Cancer Center	Milwaukee	Wisconsin	United States	53211
29	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
30	IMVS	Adelaide	South Australia	Australia	5000
31	Western Hospital	Footscray	Victoria	Australia	3011
32	Royal Melbourne Hospital	Melbourne	Victoria	Australia	3050
33	Flinders Medical Centre	Bedford Park		Australia	5042
34	St. Vincent Hospital	Fitzroy		Australia	3065
35	Nepean Hospital	Kingswood, NSW		Australia	2751
36	Calvary Mater Hospital	Waratah		Australia	2298
37	Westmead Hospital Australia	Westmead		Australia	NSW2145
38	Universitaetsklinik Innsbruck	Innsbruck		Austria	6020
39	Medical University of Vienna Internalmedicine 1, Hematology	Vienna		Austria	1190
40	Institut Jules Bordet	Brussels		Belgium	1000
41	Hopital Erasme	Brussels		Belgium	1070
42	Hopital de Jolimont	Haine-Saint Paul		Belgium	7100
43	AZ Groeninge	Kortrijk		Belgium	8500
44	UZ Leuven	Leuven		Belgium	3000
45	CHU Mont -Godinne	Yvoir		Belgium	5530
46	Monte Tabor - Hospital Sao Rafael	Salvador	Bahia	Brazil	41253-190
47	BIOCANCER - Centro de Pesquisa e Tratamento do Câncer S/A	Belo Horizonte	Minas Gerais	Brazil	30150-281
48	Hospital de Clínicas de Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90035-903
49	Hospital Nossa Senhora da Conceicao	Porto Alegre	Rio Grande Do Sul	Brazil	91350-200
50	Fundacao Pio XII - Hospital de Cancer de Barretos	Barretos	São Paulo	Brazil	14784-400
51	Hospital Universitario de Brasilia	Brasílía		Brazil	70840-050
52	Hospital Erasto Gaertner	Curitiba		Brazil	81520-060
53	Pro Onco Centro de Tratamento Oncologico	Londrina		Brazil	86050-190
54	Hospital Israelita Albert Einstein	Morumbi		Brazil	05651-901
55	Instituto Estadual Arthur de Siqueira Cavalcanti - HEMORIO	Rio de Janeiro		Brazil	20211-030
56	Instituto Nacional de Cancer - INCA	Rio de Janeiro		Brazil	20230-130
57	Centro de Estudos e Pesquisas de Hematologia e Oncologia da Faculdade de Medicina do ABC	Santo Andre		Brazil	09060-650
58	Instituto de Ensino e Pesquisa Sao Lucas	São Paulo		Brazil	01236-030
59	Fundação Antonio Prudente - AC Camargo Câncer center	São Paulo		Brazil	01509-900
60	MHAT Georgi Stranski PlevenHematology Clinic	Pleven		Bulgaria	5800
61	University hospital Sveti Georgi Hematology Clinic	Plovdiv		Bulgaria	4002
62	Military Medical Academy	Sofia		Bulgaria	1606
63	National Specialized Hospital for Active Treatment of Hematology Diseases	Sofia		Bulgaria	1756
64	University hospital Sveta Marina	Varna		Bulgaria	9010
65	Regional Health Authority B-Saint John Regional Hospital	Saint John	New Brunswick	Canada	E2L 4L2
66	General Hospital, Eastern Health	St John's	Newfoundland and Labrador	Canada	A1B 3V6
67	Hospital Charles LeMoyne	Greenfield Park	Quebec	Canada	J4V2H1
68	Sacre-Couer Hospital	Montreal	Quebec	Canada	H4J 1C5
69	Instituto Oncologico	Renaca		Chile	2540364
70	Instituto Clinico Oncologico del Sur ICOS	Temuco		Chile	4810469
71	Oncomedica S.A.	Monteria		Colombia
72	University Hospital Centre Split	Split		Croatia	21000
73	General Hospital Sveti Duh	Zagreb		Croatia	10000
74	Klinicka bolnica Dubrava Klinika za unutarnje bolesti Odjel za Hematologiju	Zagreb		Croatia	10000
75	University Hospital Centre Zagreb	Zagreb		Croatia	10000
76	University Hospital2.Dep.Intern.Med. Hematology	Hradec Kralove		Czechia	500 05
77	Fakultni nemocnice Ostrava	Ostrava		Czechia	70852
78	Faculty Hospital Kralovske Vinohrady	Prague		Czechia	100 00
79	Rigshospitalet University Hospital	Copenhagen		Denmark	2100
80	Herlev University Hospital Dep of hematology	Harlev		Denmark	2730
81	Roskilde University Hospital	Roskilde		Denmark	4000
82	Bergonie Institut	Bordeaux		France	33076
83	Polyclinique Bordeaux Nord Aquitaine	Bordeaux		France	33300
84	CHRU	Grenoble cedex 09		France	38043
85	CHU Dupuytren	Limoges		France	87042
86	Hopital de l'Archet 1	Nice		France	06200
87	CHU Hautepierre	Strasbourg		France	67098
88	Debreceni Egyetem Orvos- es Egeszsegtudomanyi Centrum	Debrecen		Hungary	4032
89	Kaposi Mor Oktato Korhaz	Kaposvar		Hungary	7400
90	Szegedi TudomanyegyetemII Belgyogyaszati Klinika	Szeged		Hungary	6720
91	Komarom-Esztergom Megye Onkormanyzat Szent Borbala Korhaza	Tatabanya		Hungary
92	Petz Aladar Country Hospital	Vasvari Pal U. 2		Hungary	9023
93	Ha'Emek Medical Center	Afula		Israel	18101
94	Barzilai Medical Center	Ashkelon		Israel	78278
95	Soroka University Medical Center	Beer Sheva		Israel	84101
96	Bnei Zion Medical Center	Haifa		Israel	31048
97	Shaare Zedek Medical Center	Jerusalem		Israel	91031
98	Meir Medical Center	Kfar-Saba		Israel	44281
99	Western Galilee Hospital	Naharia		Israel	22100
100	Rabin Medical Center	Petach Tikva		Israel	49100
101	Kaplan Medical Center	Rehovot		Israel	76100
102	Tel Aviv Sourasky Medical Center Department of Hematology	Tel Aviv		Israel	64239
103	Sheba Medical Center	Tel Hashomer		Israel	52621
104	Azienda Ospedaliera Policlinico di Bari	Bari		Italy	70124
105	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50134
106	IRCSS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena	Milan		Italy	20122
107	Ospedale San Raffaele S.r.l.	Milan		Italy	20132
108	Istituto Europeo di Oncologia - IEO	Milan		Italy	20141
109	Azienda Ospedaliero Universitaria di Modena	Modena		Italy	41100
110	Ospedale Cardarelli	Naples		Italy	80131
111	Universita del Piemonte Orientale	Novara		Italy	28100
112	AOU San Luigi Gonzaga	Orbassano		Italy	10043
113	Universita degli Studi di Padova	Padova		Italy	35128
114	Ospedale S. Chiara	Pisa		Italy	56126
115	Azienda Ospedaliera Ospedale San Carlo	Potenza		Italy	85100
116	Azienda Ospedaliera Universitaria Senese Policlinico Le Scotte	Siena		Italy	53100
117	Ospedale Umberto I	Torrette Di Ancona		Italy	60020
118	Maxima Medisch Centrum	Eindhoven		Netherlands	5631
119	Spaame Ziekenhuis	Hoofddorp		Netherlands	2135
120	Isala Klinieken	Zwolle		Netherlands	8025 AB
121	Christchurch Hospital	Christchurch		New Zealand	8011
122	North Shore University Hospital	Takapuna		New Zealand	1309
123	Uniwersyteckie Centrum Kliniczne	Gdansk		Poland	80-952
124	Wojewodzki Szpital Specjalistczny im. Mikolaja Kopernika	Lodz		Poland	93-510
125	Specjalistyczny Szpital miejski im. Kopernika	Torun		Poland	87-100
126	Klinika Chorob wewnetrznych i Hematologii	Warszawa		Poland	00-909
127	Nowotworww Krwi i Transplantacji Szpiku	Wroclaw		Poland	50-367
128	Hospitais da Universidade de Coimbra	Coimbra		Portugal	3000-075
129	Instituto Portugues Oncologia do Porto Francisco Gentil EPE	Porto		Portugal	4200-072
130	Institutul Clinic Fundeni	Bucharest		Romania	022328
131	Spitalul Clinic Coltea	Bucharest		Romania	030171
132	Spitalul Clinic Judetean de Urgenta Sf Spiridon Iasi	Iasi		Romania	700111
133	Spitalul Clinic Judetean de Urgenta Sibiu	Sibiu		Romania	550245
134	Spitalul Clinic Municipal de Urgenta Timisoara	Timisoara		Romania	300079
135	Archangelsk Regional Clinical Hospital	Arkhangelsk		Russian Federation	163045
136	City Hospital 8	Barnaul		Russian Federation	659010
137	Regional Clinical Hospital 1	Ekaterinburg		Russian Federation	620102
138	Russian Academy of Medical Sciences Institution	Moscow		Russian Federation	115478
139	Moscow GUZ City Clinical Hospital	Moscow		Russian Federation	125284
140	NUZ Central Clinical Hospital	Moscow		Russian Federation	129128
141	GUZ Nizhegorodskaya Regional Clinical Hospital	Nizhniy Novgorod		Russian Federation	603126
142	MUZ City clinical hospital	Novosibirsk		Russian Federation	630051
143	St. Petersburg Research Institute of Hematology and Blood Transfusion	St. Petersburg		Russian Federation	191024
144	GUS Leningrad Regional Clinical Hospital	St. Petersburg		Russian Federation	194291
145	Federal Centre of Heart, Blood and Endocrinology of Rosmed technlologies V.A. Almazov	St. Petersburg		Russian Federation	197341
146	Clinical Center Kragujevac	Kragujevac		Serbia	34000
147	Clinical Center Nis	Nis		Serbia	18000
148	Narodny onkologicky ustav	Bratislava		Slovakia	83101
149	Martinska Fakultna Nemocnica	Martin		Slovakia	03659
150	University Witwatersrand Oncology	Parktown		South Africa	2193
151	Pretoria Academic Hospital	Pretoria		South Africa	0002
152	Mary Potter Oncology Centre	Pretoria		South Africa
153	Hospital Germans Trias I Pujol	Badalona		Spain	08916
154	Hospital Universitario Vall D hebron	Barcelona		Spain	08035
155	Hospital Universitario de la Princesa	Madrid		Spain	28006
156	Hospital Ramon y Cajal	Madrid		Spain	28034
157	Hospital Universitario Puerta de Hierro-Majadahonda	Majadahonda		Spain	28222
158	Hospital General Universitario Morales Messeguer	Murcia		Spain	30008
159	Hospital Universitario de Salamanca	Salamanca		Spain	37007
160	Hospital Donostia	San Sebastian		Spain	20014
161	Hospital Universitario Marques de Valdecilla	Santander		Spain	39008
162	Hospital Universitario La Fe	Valencia		Spain	46009
163	Royal Bournemouth General Hospital	Bournemouth		United Kingdom	BH7 7DW
164	St. Bartholomew's and The Royal London Hospital	London		United Kingdom	EC1A 7BE
165	St George's Healthcare NHS Trust	London		United Kingdom	SW17 0QT

Sponsors and Collaborators

• Celgene

Investigators

• Study Director: Jeffrey Jones, MD, Celgene Corporation

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT00910910
• Other Study ID Numbers: CC-5013-CLL-008; 2008-003079-32
• First Posted: Jun 1, 2009
• Last Update Posted: Jul 9, 2019
• Last Verified: Jun 1, 2019

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lenalidomide; Chlorambucil

Study Results

Participant Flow

Recruitment Details	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
Pre-assignment Detail	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.

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Period Title: Overall Study
STARTED	225	225
Safety Population	224	223
COMPLETED	0	1
NOT COMPLETED	225	224

Baseline Characteristics

Arm/Group Title	Lenalidomide	Chlorambucil	Total
Arm/Group Description	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 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 of all reporting groups
Overall Participants	225	225	450
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.0 (5.72)	73.3 (5.72)	73.1 (5.72)
Sex: Female, Male (Count of Participants)
Female	93 41.3%	83 36.9%	176 39.1%
Male	132 58.7%	142 63.1%	274 60.9%

Outcome Measures

1. Primary Outcome

Title	Kaplan-Meier Estimate of Progression Free Survival (PFS)
Description	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
Time Frame	From first dose of study drug to date of data cut-off of 18 Feb 2013; up to approximately 39 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	212	215
Median (95% Confidence Interval) [months]	30.8	23.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments	Stratification factors: Disease stage (Binet A or Binet B or Rai I or Rai II versus (VS) Binet C or Rai III or Rai IV); Presence of at least one of the co-morbidities Asparate transaminase (AST)/Alanine transaminase (ALT) ≥ 3.0 times Upper Limits of Normal (ULN,) Creatinine clearance ≥ 30 to < 60 mL/min, Yes VS No); Presence of at least one 11q deletion, 17p deletion, unmutated Immunoglobulin Heavy-chain Variable-region (IgVH) or Beta-2 Microglobulin (ß2M )> 4.0 mg/L (Yes versus No VS Unknown)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.323
	Comments
	Method	stratified log rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 90%; 0.88 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

2. Primary Outcome

Title	Kaplan-Meier Estimate of Progression Free Survival (PFS) With a Later Cut-off Date of 14 March 2014
Description	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.
Time Frame	From randomization to data cut off date of 31 March 2014; median follow up time for all participants was 12.6 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	225	225
Median (95% Confidence Interval) [months]	30.8	21.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments	Stratification factors: Disease stage (Binet A or Binet B or Rai I or Rai II versus (VS) Binet C or Rai III or Rai IV); Presence of at least one of the co-morbidities Asparate transaminase (AST)/Alanine transaminase (ALT) ≥ 3.0 times Upper Limits of Normal (ULN,) Creatinine clearance ≥ 30 to < 60 mL/min, Yes VS No); Presence of at least one 11q deletion, 17p deletion, unmutated Immunoglobulin Heavy-chain Variable-region (IgVH) or Beta-2 Microglobulin (ß2M )> 4.0 mg/L (Yes versus No VS Unknown)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.967
	Comments	The p-value is based on a stratified log-rank test
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 90%; 0.76 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

3. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	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
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	211	213
≥ 1 TEAE	202 89.8%	186 82.7%
≥ 1 TEAE related to study drug	183 81.3%	139 61.8%
≥ 1 NCI CTC Grade 3-4 TEAE	173 76.9%	117 52%
Grade 3-4 adverse event related to any study drug	143 63.6%	82 36.4%
≥ 1 NCI CTC Grade 5 TEAE	21 9.3%	9 4%
≥ Grade 5 adverse event related to any study drug	6 2.7%	1 0.4%
≥ 1 Serious TEAE	129 57.3%	76 33.8%
≥ 1 Serious TEAE related to any study drug	95 42.2%	46 20.4%
≥1 TEAE leading to stopping either study drug	61 27.1%	34 15.1%
≥1 Related TEAE leading to stopping either drug	39 17.3%	19 8.4%

4. Secondary Outcome

Title	Number of Participants With Adverse Events With a Later Cut-off Date of 31 March 2014
Description	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
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	224	223
≥ 1 TEAE	216 96%	202 89.8%
≥ 1 TEAE related to study drug	194 86.2%	155 68.9%
≥ 1 NCI CTC Grade 3-4 TEAE	188 83.6%	131 58.2%
Grade 3-4 adverse event related to any study drug	157 69.8%	90 40%
≥ 1 NCI CTC Grade 5 TEAE	21 9.3%	11 4.9%
≥ Grade 5 adverse event related to any study drug	6 2.7%	1 0.4%
≥ 1 Serious TEAE	148 65.8%	90 40%
≥ 1 Serious TEAE related to any study drug	107 47.6%	53 23.6%
≥1 TEAE leading to stopping either study drug	70 31.1%	42 18.7%
≥1 Related TEAE leading to stopping either drug	46 20.4%	23 10.2%

5. Secondary Outcome

Title	Percentage of Participants With the Best Overall Response Based on the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines
Description	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
Time Frame	Up to data cut-off date of 18 Feb 2013; approximately 39 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	212	215
Number [percentage of participants]	51.9 23.1%	62.3 27.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With a Best Overall Response Based on IWCLL Guidelines With a Later Cut-off Date of 31 March 2014
Description	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
Time Frame	Up to data cut-off of 31 March 2014; approximately 53 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	225	225
Number [percentage of participants with response]	60.9 27.1%	70.2 31.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Kaplan-Meier Estimate for Duration of Response
Description	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
Time Frame	Up to data cut-off of 18 Feb 2013; up to approximately 39 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	110	134
Median (95% Confidence Interval) [weeks]	NA	105.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.826
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 90%; 0.58 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups

8. Secondary Outcome

Title	Kaplan-Meier Estimate for Duration of Response With a Later Cut-off Date of 31 March 2014
Description	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
Time Frame	Up to data cut-off of 31 March 2014; up to approximately 53 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	137	158
Median (95% Confidence Interval) [weeks]	NA	87.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.149
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 90%; 0.48 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

9. Secondary Outcome

Title	Time to Response
Description	Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines
Time Frame	Up to data cut-off of 18 Feb 2013; up to approximately 39 months

Outcome Measure Data

Analysis Population Description

ITT participants with an objective response as of 18 February 2013

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	110	134
Median (Full Range) [weeks]	8.6	8.1

10. Secondary Outcome

Title	Time to Response for a Later Cut-off Date of 31 March 2014
Description	Time to response was calculated as the time from randomization to the first nPR, PR, CRi or CR based on IWCLL guidelines
Time Frame	Up to data cut-off of 31 March 2014; up to approximately 53 months

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	137	158
Median (Full Range) [weeks]	10.4	8.1

11. Secondary Outcome

Title	Kaplan Meier Estimate of Overall Survival
Description	Overall Survival is defined as the time between randomization and death from any cause.
Time Frame	Up to data cut off of 31 March 2014; median follow-up for all participants was 18.8 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	225	225
Median (95% Confidence Interval) [Months]	NA	44.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.883
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 90%; 0.73 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups.

12. Secondary Outcome

Title	Kaplan Meier Estimate for Overall Survival at the Final Analysis
Description	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.
Time Frame	Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	225	225
Median (95% Confidence Interval) [Months]	74.3	70.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lenalidomide, Chlorambucil
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.709
	Comments
	Method	stratified log rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 90%; 0.83 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Based on stratified Cox proportional hazards model comparing the hazard functions associated with treatment groups

13. Secondary Outcome

Title	Functional Assessment of Cancer Therapy-General to Create the FACT-Leukemia (FACT-Leu) Quality of Life Instrument
Description	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).
Time Frame	Day 1 and once every 8 weeks

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	0	0

14. Secondary Outcome

Title	Euro Quality of Life Five Dimension (EQ-5D) Questionnaire
Description	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.
Time Frame	Day 1 and once every 8 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	0	0

15. Secondary Outcome

Title	Number of Participants and Types of Subsequent Anti-cancer Therapies Received Post Treatment
Description	Subsequent anti-cancer therapies administered to participants following the discontinuation of study drug (either Lenalidomide or Chlorambucil)
Time Frame	Up to the last patient last visit date of 19 May 2018; median follow-up for all participants was 46.7 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	224	223
Participants receiving additional CLL therapy	125 55.6%	120 53.3%
Participants receiving alkylating agents	107 47.6%	106 47.1%
Participants receiving antineoplastic aents	93 41.3%	86 38.2%
Participants receiving antimetabolites	34 15.1%	24 10.7%
Participants receiving corticosteroids	27 12%	16 7.1%
Participants receiving plant alkaloids	22 9.8%	11 4.9%
Participants receiving cytotoxic antibiotics	10 4.4%	3 1.3%
Participants receiving immunosuppressants	3 1.3%	2 0.9%
Participants receiving therapeutic products	4 1.8%	3 1.3%
Participants receiving other unspecified products	0 0%	2 0.9%
Antihistamine For Systemic Use	1 0.4%	1 0.4%
Drugs for Peptic ulcer and Gastric Reflex	1 0.4%	0 0%
Immunoglobulins	1 0.4%	2 0.9%
Other Analgesics and Antipyretics	1 0.4%	1 0.4%
Specific Antirheumatic Agents	1 0.4%	0 0%
Antiemetics and Antinauseants	0 0%	1 0.4%
Corticosteriods for Systemic Use	0 0%	1 0.4%
Immunostimulants	0 0%	1 0.4%

16. Other Pre-specified Outcome

Title	Number of Participants Deaths During the Treatment and Survival Follow-Up Phase
Description	The number of study participants deaths during the treatment and follow-up phase
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Lenalidomide	Chlorambucil
Arm/Group Description	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 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).
Measure Participants	225	225
Number [Participants]	101 44.9%	95 42.2%

Adverse Events

Time Frame	All AEs were recorded by the Investigator(s) from first dose of study drug to 30 days after the treatment discontinuation visit. The median treatment duration was 263 days for lenalidomide and 362 days for chlorambucil.
Adverse Event Reporting Description	Secondary Primary Malignancies (SPMs) were monitored and reported as SAEs regardless of the treatment arm the participant was is on. SPMs were reported from the time of signing the informed consent up to and including the survival follow-up period. Participants were followed for at least 5 years from the date the last participant was randomized.
Arm/Group Title	Lenalidomide		Chlorambucil
Arm/Group Description	For participants with normal renal function [defined as Creatinine Clearance (CrCL ) ≥ 60 mL/min], 5 mg lenalidomide was administered 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 oral tablets at 0.8 mg/kg on Days 1 and 15 of each 28-day cycle for a total duration of 12 months
All Cause Mortality
	Lenalidomide		Chlorambucil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	100/224 (44.6%)		93/223 (41.7%)
Serious Adverse Events
	Lenalidomide		Chlorambucil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	148/224 (66.1%)		90/223 (40.4%)
Blood and lymphatic system disorders
AGRANULOCYTOSIS	0/224 (0%)		1/223 (0.4%)
ANAEMIA	18/224 (8%)		10/223 (4.5%)
AUTOIMMUNE HAEMOLYTIC ANAEMIA	3/224 (1.3%)		4/223 (1.8%)
FEBRILE NEUTROPENIA	7/224 (3.1%)		3/223 (1.3%)
HAEMOLYTIC ANAEMIA	1/224 (0.4%)		0/223 (0%)
IDIOPATHIC THROMBOCYTOPENIC PURPURA	1/224 (0.4%)		0/223 (0%)
LYMPHOPENIA	0/224 (0%)		1/223 (0.4%)
NEUTROPENIA	54/224 (24.1%)		33/223 (14.8%)
PANCYTOPENIA	0/224 (0%)		1/223 (0.4%)
SPLENIC HAEMORRHAGE	1/224 (0.4%)		0/223 (0%)
THROMBOCYTOPENIA	19/224 (8.5%)		13/223 (5.8%)
Cardiac disorders
ANGINA PECTORIS	1/224 (0.4%)		0/223 (0%)
ATRIAL FIBRILLATION	3/224 (1.3%)		1/223 (0.4%)
ATRIAL FLUTTER	0/224 (0%)		1/223 (0.4%)
ATRIOVENTRICULAR BLOCK COMPLETE	1/224 (0.4%)		0/223 (0%)
ATRIOVENTRICULAR BLOCK FIRST DEGREE	1/224 (0.4%)		0/223 (0%)
BRADYCARDIA	1/224 (0.4%)		0/223 (0%)
CARDIAC ARREST	4/224 (1.8%)		0/223 (0%)
CARDIAC FAILURE	1/224 (0.4%)		1/223 (0.4%)
CARDIAC FAILURE ACUTE	1/224 (0.4%)		0/223 (0%)
CARDIAC FAILURE CONGESTIVE	4/224 (1.8%)		0/223 (0%)
CARDIOPULMONARY FAILURE	3/224 (1.3%)		0/223 (0%)
CONGESTIVE CARDIOMYOPATHY	1/224 (0.4%)		0/223 (0%)
PERICARDIAL EFFUSION	1/224 (0.4%)		0/223 (0%)
SICK SINUS SYNDROME	2/224 (0.9%)		0/223 (0%)
VENTRICULAR TACHYCARDIA	0/224 (0%)		1/223 (0.4%)
CARDIOGENIC SHOCK	1/224 (0.4%)		0/223 (0%)
CORONARY ARTERY DISEASE	1/224 (0.4%)		0/223 (0%)
MYOCARDIAL INFARCTION	3/224 (1.3%)		0/223 (0%)
Eye disorders
DIPLOPIA	0/224 (0%)		1/223 (0.4%)
MACULOPATHY	1/224 (0.4%)		0/223 (0%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	0/224 (0%)		1/223 (0.4%)
ABDOMINAL PAIN	1/224 (0.4%)		2/223 (0.9%)
COLITIS	1/224 (0.4%)		0/223 (0%)
DIARRHOEA	1/224 (0.4%)		0/223 (0%)
FEMORAL HERNIA	1/224 (0.4%)		0/223 (0%)
GASTROINTESTINAL HAEMORRHAGE	0/224 (0%)		2/223 (0.9%)
GASTROOESOPHAGEAL REFLUX DISEASE	0/224 (0%)		1/223 (0.4%)
NAUSEA	1/224 (0.4%)		2/223 (0.9%)
SMALL INTESTINAL OBSTRUCTION	0/224 (0%)		1/223 (0.4%)
VOMITING	0/224 (0%)		3/223 (1.3%)
ABDOMINAL PAIN LOWER	1/224 (0.4%)		0/223 (0%)
General disorders
ASTHENIA	0/224 (0%)		3/223 (1.3%)
FATIGUE	2/224 (0.9%)		2/223 (0.9%)
MULTI-ORGAN FAILURE	3/224 (1.3%)		0/223 (0%)
OEDEMA PERIPHERAL	2/224 (0.9%)		0/223 (0%)
PAIN	0/224 (0%)		1/223 (0.4%)
PYREXIA	10/224 (4.5%)		6/223 (2.7%)
SUDDEN CARDIAC DEATH	0/224 (0%)		1/223 (0.4%)
Hepatobiliary disorders
CHOLECYSTITIS	1/224 (0.4%)		1/223 (0.4%)
CHOLECYSTITIS ACUTE	2/224 (0.9%)		0/223 (0%)
CHOLECYSTITIS CHRONIC	1/224 (0.4%)		0/223 (0%)
CHOLELITHIASIS	0/224 (0%)		2/223 (0.9%)
HEPATIC FUNCTION ABNORMAL	1/224 (0.4%)		0/223 (0%)
HEPATITIS TOXIC	1/224 (0.4%)		0/223 (0%)
Immune system disorders
DRUG HYPERSENSITIVITY	1/224 (0.4%)		0/223 (0%)
Infections and infestations
ANAL ABSCESS	1/224 (0.4%)		0/223 (0%)
ARTHRITIS BACTERIAL	0/224 (0%)		1/223 (0.4%)
ARTHRITIS INFECTIVE	1/224 (0.4%)		0/223 (0%)
BRONCHITIS	2/224 (0.9%)		1/223 (0.4%)
BRONCHITIS BACTERIAL	0/224 (0%)		1/223 (0.4%)
BRONCHOPNEUMONIA	2/224 (0.9%)		1/223 (0.4%)
CELLULITIS	2/224 (0.9%)		3/223 (1.3%)
CELLULITIS STAPHYLOCOCCAL	0/224 (0%)		1/223 (0.4%)
DIARRHOEA INFECTIOUS	1/224 (0.4%)		0/223 (0%)
ENTEROBACTER SEPSIS	0/224 (0%)		1/223 (0.4%)
ERYSIPELAS	1/224 (0.4%)		1/223 (0.4%)
ESCHERICHIA SEPSIS	0/224 (0%)		1/223 (0.4%)
GASTROENTERITIS	0/224 (0%)		1/223 (0.4%)
HERPES ZOSTER	1/224 (0.4%)		0/223 (0%)
LOCALISED INFECTION	0/224 (0%)		1/223 (0.4%)
LOWER RESPIRATORY TRACT INFECTION	3/224 (1.3%)		1/223 (0.4%)
LUNG INFECTION	2/224 (0.9%)		0/223 (0%)
NEUTROPENIC SEPSIS	0/224 (0%)		1/223 (0.4%)
PELVIC INFECTION	1/224 (0.4%)		0/223 (0%)
PNEUMOCOCCAL SEPSIS	1/224 (0.4%)		0/223 (0%)
PNEUMONIA	24/224 (10.7%)		6/223 (2.7%)
PNEUMONIA PNEUMOCOCCAL	1/224 (0.4%)		0/223 (0%)
RESPIRATORY TRACT INFECTION	1/224 (0.4%)		0/223 (0%)
SEPSIS	1/224 (0.4%)		4/223 (1.8%)
SEPSIS SYNDROME	1/224 (0.4%)		0/223 (0%)
STAPHYLOCOCCAL BACTERAEMIA	1/224 (0.4%)		0/223 (0%)
TONSILLITIS	0/224 (0%)		1/223 (0.4%)
URINARY TRACT INFECTION	3/224 (1.3%)		1/223 (0.4%)
CLOSTRIDIUM DIFFICILE COLITIS	1/224 (0.4%)		0/223 (0%)
INFECTION	0/224 (0%)		1/223 (0.4%)
LOBAR PNEUMONIA	2/224 (0.9%)		0/223 (0%)
Injury, poisoning and procedural complications
FALL	1/224 (0.4%)		1/223 (0.4%)
FEMUR FRACTURE	1/224 (0.4%)		0/223 (0%)
HEAD INJURY	1/224 (0.4%)		0/223 (0%)
HIP FRACTURE	1/224 (0.4%)		1/223 (0.4%)
PELVIC FRACTURE	1/224 (0.4%)		0/223 (0%)
POST PROCEDURAL HAEMORRHAGE	1/224 (0.4%)		0/223 (0%)
SPINAL COMPRESSION FRACTURE	2/224 (0.9%)		0/223 (0%)
VASCULAR PSEUDOANEURYSM	1/224 (0.4%)		0/223 (0%)
LUMBAR VERTEBRAL FRACTURE	0/224 (0%)		1/223 (0.4%)
SKULL FRACTURE	0/224 (0%)		1/223 (0.4%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	0/224 (0%)		1/223 (0.4%)
BLOOD BILIRUBIN INCREASED	0/224 (0%)		1/223 (0.4%)
BLOOD UREA INCREASED	1/224 (0.4%)		0/223 (0%)
ASPARTATE AMINOTRANSFERASE INCREASED	0/224 (0%)		1/223 (0.4%)
INTERNATIONAL NORMALISED RATIO INCREASED	1/224 (0.4%)		0/223 (0%)
Metabolism and nutrition disorders
DEHYDRATION	2/224 (0.9%)		3/223 (1.3%)
DIABETES MELLITUS	0/224 (0%)		2/223 (0.9%)
GOUT	1/224 (0.4%)		0/223 (0%)
HYPERCALCAEMIA	1/224 (0.4%)		1/223 (0.4%)
HYPERGLYCAEMIA	1/224 (0.4%)		1/223 (0.4%)
HYPOCALCAEMIA	1/224 (0.4%)		0/223 (0%)
HYPOGLYCAEMIA	1/224 (0.4%)		0/223 (0%)
HYPONATRAEMIA	2/224 (0.9%)		3/223 (1.3%)
TUMOUR LYSIS SYNDROME	2/224 (0.9%)		0/223 (0%)
Musculoskeletal and connective tissue disorders
ARTHROPATHY	1/224 (0.4%)		0/223 (0%)
BACK PAIN	2/224 (0.9%)		0/223 (0%)
INTERVERTEBRAL DISC PROTRUSION	1/224 (0.4%)		0/223 (0%)
MUSCULAR WEAKNESS	1/224 (0.4%)		0/223 (0%)
SPINAL OSTEOARTHRITIS	1/224 (0.4%)		0/223 (0%)
FLANK PAIN	0/224 (0%)		1/223 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA PANCREAS	1/224 (0.4%)		0/223 (0%)
BASAL CELL CARCINOMA	5/224 (2.2%)		8/223 (3.6%)
BASOSQUAMOUS CARCINOMA OF SKIN	1/224 (0.4%)		1/223 (0.4%)
BOWEN'S DISEASE	0/224 (0%)		1/223 (0.4%)
BREAST CANCER	1/224 (0.4%)		0/223 (0%)
CHRONIC LYMPHOCYTIC LEUKAEMIA	0/224 (0%)		1/223 (0.4%)
COLON ADENOMA	1/224 (0.4%)		0/223 (0%)
HEPATIC CANCER	0/224 (0%)		1/223 (0.4%)
HODGKIN'S DISEASE	1/224 (0.4%)		0/223 (0%)
LUNG NEOPLASM MALIGNANT	1/224 (0.4%)		0/223 (0%)
LUNG SQUAMOUS CELL CARCINOMA STAGE II	1/224 (0.4%)		0/223 (0%)
MALIGNANT MELANOMA	1/224 (0.4%)		0/223 (0%)
METASTASES TO LIVER	1/224 (0.4%)		1/223 (0.4%)
METASTATIC MALIGNANT MELANOMA	0/224 (0%)		1/223 (0.4%)
RICHTER'S SYNDROME	0/224 (0%)		1/223 (0.4%)
SKIN CANCER	1/224 (0.4%)		1/223 (0.4%)
SQUAMOUS CELL CARCINOMA	1/224 (0.4%)		0/223 (0%)
SQUAMOUS CELL CARCINOMA OF SKIN	2/224 (0.9%)		7/223 (3.1%)
SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY	0/224 (0%)		1/223 (0.4%)
TUMOUR FLARE	8/224 (3.6%)		0/223 (0%)
Nervous system disorders
CEREBRAL HAEMORRHAGE	0/224 (0%)		1/223 (0.4%)
CEREBRAL INFARCTION	1/224 (0.4%)		0/223 (0%)
CEREBRAL ISCHAEMIA	0/224 (0%)		1/223 (0.4%)
CEREBROVASCULAR ACCIDENT	0/224 (0%)		1/223 (0.4%)
CONVULSION	0/224 (0%)		1/223 (0.4%)
HAEMORRHAGE INTRACRANIAL	1/224 (0.4%)		0/223 (0%)
HEMIPARESIS	0/224 (0%)		1/223 (0.4%)
ISCHAEMIC STROKE	0/224 (0%)		1/223 (0.4%)
SCIATICA	0/224 (0%)		1/223 (0.4%)
SIMPLE PARTIAL SEIZURES	0/224 (0%)		1/223 (0.4%)
SYNCOPE	3/224 (1.3%)		0/223 (0%)
TRANSIENT ISCHAEMIC ATTACK	3/224 (1.3%)		0/223 (0%)
Psychiatric disorders
DEPRESSION	1/224 (0.4%)		0/223 (0%)
Renal and urinary disorders
RENAL COLIC	1/224 (0.4%)		0/223 (0%)
RENAL FAILURE	2/224 (0.9%)		0/223 (0%)
RENAL FAILURE ACUTE	3/224 (1.3%)		0/223 (0%)
URINARY RETENTION	1/224 (0.4%)		0/223 (0%)
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA	0/224 (0%)		1/223 (0.4%)
ACUTE RESPIRATORY FAILURE	1/224 (0.4%)		1/223 (0.4%)
BRONCHIECTASIS	0/224 (0%)		1/223 (0.4%)
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	2/224 (0.9%)		1/223 (0.4%)
DYSPNOEA	3/224 (1.3%)		1/223 (0.4%)
LUNG INFILTRATION	0/224 (0%)		1/223 (0.4%)
PLEURAL EFFUSION	1/224 (0.4%)		1/223 (0.4%)
PULMONARY ALVEOLAR HAEMORRHAGE	1/224 (0.4%)		0/223 (0%)
PULMONARY EMBOLISM	4/224 (1.8%)		1/223 (0.4%)
PULMONARY HYPERTENSION	1/224 (0.4%)		0/223 (0%)
RESPIRATORY FAILURE	2/224 (0.9%)		0/223 (0%)
SINUS CONGESTION	1/224 (0.4%)		0/223 (0%)
Skin and subcutaneous tissue disorders
BLISTER	0/224 (0%)		1/223 (0.4%)
DRUG ERUPTION	1/224 (0.4%)		0/223 (0%)
EXFOLIATIVE RASH	2/224 (0.9%)		0/223 (0%)
RASH	4/224 (1.8%)		1/223 (0.4%)
RASH GENERALISED	1/224 (0.4%)		0/223 (0%)
RASH MACULO-PAPULAR	0/224 (0%)		1/223 (0.4%)
STEVENS-JOHNSON SYNDROME	0/224 (0%)		1/223 (0.4%)
URTICARIA	1/224 (0.4%)		0/223 (0%)
Vascular disorders
DEEP VEIN THROMBOSIS	3/224 (1.3%)		1/223 (0.4%)
HYPERTENSIVE CRISIS	0/224 (0%)		1/223 (0.4%)
LERICHE SYNDROME	1/224 (0.4%)		0/223 (0%)
PERIPHERAL ARTERY ANEURYSM	1/224 (0.4%)		0/223 (0%)
SHOCK	1/224 (0.4%)		0/223 (0%)
THROMBOPHLEBITIS SUPERFICIAL	1/224 (0.4%)		0/223 (0%)
VENOUS THROMBOSIS LIMB	1/224 (0.4%)		0/223 (0%)
Other (Not Including Serious) Adverse Events
	Lenalidomide		Chlorambucil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	204/224 (91.1%)		184/223 (82.5%)
Blood and lymphatic system disorders
NEUTROPENIA	126/224 (56.3%)		74/223 (33.2%)
ANAEMIA	69/224 (30.8%)		46/223 (20.6%)
THROMBOCYTOPENIA	72/224 (32.1%)		50/223 (22.4%)
Gastrointestinal disorders
VOMITING	11/224 (4.9%)		28/223 (12.6%)
ABDOMINAL PAIN	30/224 (13.4%)		10/223 (4.5%)
CONSTIPATION	28/224 (12.5%)		17/223 (7.6%)
DIARRHOEA	66/224 (29.5%)		32/223 (14.3%)
NAUSEA	33/224 (14.7%)		63/223 (28.3%)
General disorders
ASTHENIA	19/224 (8.5%)		10/223 (4.5%)
PYREXIA	37/224 (16.5%)		18/223 (8.1%)
FATIGUE	66/224 (29.5%)		53/223 (23.8%)
OEDEMA PERIPHERAL	43/224 (19.2%)		16/223 (7.2%)
Infections and infestations
NASOPHARYNGITIS	12/224 (5.4%)		3/223 (1.3%)
PNEUMONIA	13/224 (5.8%)		1/223 (0.4%)
BRONCHITIS	16/224 (7.1%)		4/223 (1.8%)
INFLUENZA	13/224 (5.8%)		2/223 (0.9%)
UPPER RESPIRATORY TRACT INFECTION	16/224 (7.1%)		11/223 (4.9%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	14/224 (6.3%)		7/223 (3.1%)
ASPARTATE AMINOTRANSFERASE INCREASED	14/224 (6.3%)		7/223 (3.1%)
BLOOD CREATININE INCREASED	22/224 (9.8%)		7/223 (3.1%)
WEIGHT DECREASED	34/224 (15.2%)		23/223 (10.3%)
Metabolism and nutrition disorders
DECREASED APPETITE	30/224 (13.4%)		13/223 (5.8%)
HYPERKALAEMIA	12/224 (5.4%)		4/223 (1.8%)
Musculoskeletal and connective tissue disorders
PAIN IN EXTREMITY	16/224 (7.1%)		4/223 (1.8%)
ARTHRALGIA	15/224 (6.7%)		12/223 (5.4%)
BACK PAIN	28/224 (12.5%)		18/223 (8.1%)
MUSCLE SPASMS	15/224 (6.7%)		5/223 (2.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
TUMOUR FLARE	85/224 (37.9%)		11/223 (4.9%)
Nervous system disorders
DIZZINESS	16/224 (7.1%)		12/223 (5.4%)
HEADACHE	16/224 (7.1%)		11/223 (4.9%)
Psychiatric disorders
INSOMNIA	14/224 (6.3%)		11/223 (4.9%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	21/224 (9.4%)		12/223 (5.4%)
COUGH	38/224 (17%)		21/223 (9.4%)
Skin and subcutaneous tissue disorders
NIGHT SWEATS	24/224 (10.7%)		14/223 (6.3%)
PRURITUS	18/224 (8%)		7/223 (3.1%)
RASH	41/224 (18.3%)		19/223 (8.5%)

Limitations/Caveats

After notification by the US Food and Drug Administration on 12Jul2013, Celgene agreed to stop lenalidomide due to an imbalance in the number of deaths on the lenalidomide arm versus the chlorambucil arm; no causality for the imbalance was identified

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.