Lenalidomide Safety/Efficacy in Myelodysplastic Syndromes (MDS) Associated With a Deletion (Del)(5q) Cytogenetic Abnormality

• Sponsor: Celgene (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00065156
• Collaborator: (none)
• Enrollment: 148
• Locations: 32
• Arm: 1
• Actual Duration (Months): 62
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is a multicenter, single-arm, open-label study of oral lenalidomide monotherapy administered to red blood cell (RBC) transfusion-dependent subjects with low- or intermediate-1-risk Myelodysplastic Syndromes (MDS) associated with a del (5q31-33) cytogenetic abnormality. Screening procedures will take place within 28 days of the first day of lenalidomide treatment. Subjects will receive lenalidomide in 28-day cycles for up to 6 cycles, or until bone marrow disease progression or progression/relapse following erythroid hematologic improvement is documented. Study visits will occur every cycle (every 28 days) and laboratory monitoring to assess hematological parameters will occur every 14 days. Safety and efficacy assessments to be performed during the study are outlined in the Schedule of Study Assessments.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes	Drug: lenalidomide	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 148 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Single-arm, Open-label Study of the Efficacy and Safety of Lenalidomide Monotherapy in Red Blood Cell Transfusion-dependent Subjects With Myelodysplastic Syndromes Associated With a Del(5q) Cytogenetic Abnormality.
• Actual Study Start Date: Jun 1, 2003
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lenalidomide

Drug: lenalidomide; 10 mg orally once daily for 21 days out of a 28-day cycle (syncopated); subsequently amended (Amendment 1, dated 27 August 2003) to employ a continuous dosage regimen in which 10 mg was taken once daily for 28 day cycles (continuous). Subjects who initially began a syncopated regimen and who did not experience a dose-limiting adverse event were allowed to switch to the continuous regimen.; Other Names: CC-5013

Outcome Measures

Primary Outcome Measures

1. Participants Who Achieved Red Blood Cell (RBC) -Transfusion Independence [Up to 2 years]

   Number of participants who achieved RBC-transfusion independence, which was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive "rolling" 56 days during the treatment period (eg, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin.

Secondary Outcome Measures

1. Participants With Adverse Experiences [Up to 2 Years]

   Counts of study participants who had adverse events (AEs) during the study. A participant with multiple occurrences of an adverse event within a category is counted only once in that category. Adverse events were evaluated by the investigator. The National Cancer Institute (NCI)'s Common Toxicity Criteria for AEs (NCI CTC) was used to grade AE severity. Severity grade 3= severe and undesirable AE. Severity grade 4= life-threatening or disabling AE.

2. Participants With a >= 50% Decrease From Baseline in Red Blood Cell (RBC) Transfusion Requirements Over Any Consecutive 56 Days During Study [Baseline (Day -54 to Day 0), During study (Day 1 up to 2 years)]

   A participant was categorized as having a transfusion reduction response if there was a ≥ 50% decrease from pretreatment transfusion requirements (before the start of the study mediation) compared to any consecutive 56 days during the study (i.e. post treatment).

3. Time to Transfusion Independence [up to 2 years]

   Transfusion independence was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive "rolling" 56 days during the treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin. Time to transfusion independence was defined as the day of the first dose of study drug to the first day of the first 56-day RBC transfusion-free period.

4. Participants Who Relapsed or Maintained Their Transfusion Independence After Achieving Transfusion Independence During the Study [up to 2 years]

   Transfusion independence was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive "rolling" 56 days during the treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin. Participants who relapsed required a transfusion after the period of transfusion independence. Participants who maintained transfusion independence did not require a transfusion during the remainder of the study.

5. Kaplan Meier Estimate for Duration of Transfusion Independence Response [up to 2 years]

   Duration of response is measured from the first of the consecutive 56 days during which the participant was free of RBC transfusions to the date of the first RBC transfusion after this period. Duration of response was censored at the date of last visit for participants who maintained transfusion independence.

6. Change in Hemoglobin Concentration From Baseline to Maximum Value During Response Period for Responders [Baseline (Day -54 to Day 0), During study (Day 1 up to 2 years)]

   The change from baseline in hemoglobin for participants who became RBC-transfusion independent. The maximum hemoglobin value obtained during the response period is used in the calculation of change from baseline.

7. Participant Counts of Cytogenetic Response [up to 2 years]

   Participants deemed evaluable by the central cytogenetic review had their cytogenetic response categorized as major or minor. A major cytogenetic response was defined as ≥ 20 metaphases recorded at baseline, and at least 1 post baseline evaluation with ≥ 20 metaphases analyzed with no abnormal metaphases observed. A minor cytogenetic response was defined as ≥ 20 metaphases analyzed at baseline, and at least 1 post baseline evaluation with ≥ 20 metaphases analyzed with a ≥ 50% reduction in the proportion of hematopoietic cells with cytogenetic abnormalities compared with baseline.

8. Participant Counts of Platelet Response [up to 2 years]

   Major platelet response: participants with a minimum pretreatment platelet of <100,000/mm^3 in all values within 56 days of start of treatment, an absolute increase of ≥30,000/mm^3 sustained for ≥56 consecutive days. In platelet transfusion-dependent participants, a major response was stabilization of platelet counts and platelet transfusion independence. Minor platelet response: participants with a minimum pretreatment platelet of <100,000/mm^3, a ≥ 50% increase in platelet count with a net increase >10,000/mm^3 for a consecutive 56-day period in the absence of platelet transfusions.

9. Participant Counts of Absolute Neutrophil Count (ANC) Response [up to 2 years]

   Major neutrophil response: participants with a minimum pretreatment ANC concentration of < 1500/mm^3 in all values obtained within 56 days of start of treatment, a ≥ 100% increase or an absolute increase of ≥ 500/mm^3, whichever was greater (at least to be ≥ 500/mm^3), sustained for 56 consecutive days. Minor neutrophil response: participants with a minimum pretreatment ANC concentration of < 1500/mm^3, an increase in ANC concentration of ≥ 100% sustained for 56 consecutive days.

10. Participants With Complete or Partial Bone Marrow Improvement [up to 2 years]

    Bone marrow aspirates were assessed by a central reviewer. A complete bone marrow improvement required a baseline French-American-British (FAB) classification (see Baseline Characteristics) of refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML) and a during study assessment of no MDS. A partial bone marrow improvement reflected an improved FAB classification compared to baseline (e.g. RARS to RA) but evidence of MDS continued to exist.

11. Participants With Bone Marrow Progression [up to 2 years]

    Bone marrow aspirate was assessed by a central reviewer. Progression is represented in two categories according to changes from baseline in French-American-British (FAB) classification (see Baseline Characteristics): Baseline classification of refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) to a during treatment (plus 30 days) classification of refractory anemia with excess blasts (RAEB). Any baseline FAB classification to a during treatment (plus 30 days) classification of acute myeloid leukemia (AML).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must understand and voluntarily sign an informed consent form

• Age 18 years or older at the time of signing the informed consent

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

• Diagnosis of low or intermediate-1-risk International Prognostic Scoring System (IPSS) Myelodysplastic Syndromes (MDS) without an abnormality of chromosome 5 involving a deletion between bands q31 and q33.

• Red blood cell (RBC) transfusion-dependent anemia defined as having received greater than or equal to 2 units of RBCs within 8 weeks of the first day of study drug treatment.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1 or 2.

• Women of childbearing potential (WCBP) must have a negative serum or urine pregnancy test within 7 days of starting study drug.

• Sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on study drug.

• WCBP must agree to have pregnancy tests every 4 weeks while on study drug.

Exclusion Criteria:

• Pregnant or lactating females

• Prior therapy with lenalidomide.

• An abnormality of chromosome 5 involving a deletion between bands q31 and q33.

• Lab Abnormality: Absolute neutrophil count (ANC) <500 cell/mm^{3 (0.5*10}9/L)

• Lab Abnormality: Platelet count <50,000/mm^{3 (50*10}9/L)

• Lab Abnormality: Serum creatinine >2.5 mg/dL (221 mmol/L)

• Lab Abnormality: Serum total bilirubin >2.0 mg/dL (34 mmol/L)

• Prior greater than or equal to grade 3 National Cancer Institute (NCI) Common Toxicity Criteria (CTC) allergic reaction/hypersensitivity to thalidomide.

• Clinically significant anemia due to factors such as iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding

• If a marrow aspirate is not evaluable for storage iron, transferrin saturation must be

20% and serum ferritin not less than 50 ng/mL

• Use of hematopoietic growth factors within 7 days of the first day of study drug treatment.

• Prior greater than or equal to grade 3 NCI CTC rash or any desquamation (blistering) while taking thalidomide.

• Chronic use (>2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to >10 mg/day of prednisone) within 28 days of the first day of study drug treatment.

• Use of experimental or standard drugs (i.e. chemotherapeutic, immunosuppressive, and cytoprotective agents) for the treatment of MDS within 28 days of the first day of study drug treatment.

• Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for greater than or equal to 3 years.

• Use of any other experimental therapy within 28 days of the first day of study drug treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Cancer Center	Scottsdale	Arizona	United States	85258
2	Mayo Clinic	Scottsdale	Arizona	United States	85259
3	Arizona Cancer Center	Tucson	Arizona	United States	85724-5024
4	Desert Hematology & Oncology Medical Group	Rancho Mirage	California	United States	92270
5	Stanford University Medical Center	Stanford	California	United States	94305-5750
6	Mayo Clinic	Jacksonville	Florida	United States	32224
7	Cancer & Blood Disease Center	Lecanto	Florida	United States	34461
8	University of Miami Sylvester Comp Cancer Center	Miami	Florida	United States	33136
9	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612-9497
10	Northwest Georgia Oncology - Wellstar Cancer Research	Marietta	Georgia	United States	30060
11	Rush-Presbyterian- St. Luke's Medical Center	Chicago	Illinois	United States	60612
12	University of Chicago Medical Center	Chicago	Illinois	United States	60637-1470
13	Midwest Cancer Research Group	Skokie	Illinois	United States	60077
14	Johns Hopkins Oncology Center	Baltimore	Maryland	United States	21287-8963
15	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115-6084
16	Wayne State University School of Medicine	Detroit	Michigan	United States	48201-2097
17	Mayo Clinic	Rochester	Minnesota	United States	55905
18	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7680
19	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
20	New York Hospital-Cornell	New York	New York	United States	10021-0034
21	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021-6007
22	Mt. Sinai Medical Center	New York	New York	United States	10029
23	University of Rochester- James P. Wilmot Cancer Center	Rochester	New York	United States	14642
24	Wake Forest University School of Medicine	Winston-Salem	North Carolina	United States	27157-1082
25	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
26	Oregon Health & Science University	Portland	Oregon	United States	97201
27	Kaiser Permanente Northwest Region	Portland	Oregon	United States	97227
28	Western Pennsylvania Cancer Institute	Pittsburgh	Pennsylvania	United States	15224
29	MD Anderson Cancer Center	Houston	Texas	United States	77030
30	Swedish Cancer Institute	Seattle	Washington	United States	98104
31	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-4417
32	St. Johannes Hospital	Duisburg		Germany

Sponsors and Collaborators

• Celgene

Investigators

• Principal Investigator: Alan F List, MD, H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

• Prebet T, Cluzeau T, Park S, Sekeres MA, Germing U, Ades L, Platzbecker U, Gotze K, Vey N, Oliva E, Sugrue MM, Bally C, Kelaidi C, Al Ali N, Fenaux P, Gore SD, Komrokji R. Outcome of patients treated for myelodysplastic syndromes with 5q deletion after failure of lenalidomide therapy. Oncotarget. 2017 Jun 14;8(47):81926-81935. doi: 10.18632/oncotarget.18477. eCollection 2017 Oct 10.
• Sekeres MA, Maciejewski JP, Giagounidis AA, Wride K, Knight R, Raza A, List AF. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2008 Dec 20;26(36):5943-9. doi: 10.1200/JCO.2007.15.5770. Epub 2008 Nov 17.

• Responsible Party: Celgene
• ClinicalTrials.gov Identifier: NCT00065156
• Other Study ID Numbers: CC-5013-MDS-003; NCT00074126
• First Posted: Jul 18, 2003
• Last Update Posted: Nov 19, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Celgene: MDS; CC-5013; Revlimid; Celgene
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Chromosome Disorders; Syndrome; Chromosome Aberrations; Lenalidomide

Study Results

Participant Flow

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Period Title: Overall Study
STARTED	148
Modified Intent to Treat Population	94
COMPLETED	24
NOT COMPLETED	124

Baseline Characteristics

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Overall Participants	148
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.0 (10.50)
Age, Customized (participants) [Number]
<= 65 years	48 32.4%
>65 years	100 67.6%
Sex: Female, Male (Count of Participants)
Female	97 65.5%
Male	51 34.5%
Race/Ethnicity, Customized (participants) [Number]
White	143 96.6%
Hispanic	3 2%
Asian/Pacific Islander	2 1.4%
Region of Enrollment (participants) [Number]
United States	112 75.7%
Germany	36 24.3%
Duration of Myelodysplastic Syndrome (MDS) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.4 (3.29)
Participants with 5q(-) (31-33) Chromosomal Abnormality (participants) [Number]
Number [participants]	148 100%
International Prognostic Scoring System (IPSS) Score (participants) [Number]
Low (0)	49 33.1%
Intermediate-1 (0.5 to 1.0)	69 46.6%
Intermediate-2 (1.5 to 2.0)	7 4.7%
High (>=2.5)	2 1.4%
Missing (unable to assign)	21 14.2%
French-American-British (FAB) Classification (participants) [Number]
Refractory anemia (RA)	78 52.7%
Refractory anemia with ringed sideroblasts (RARS)	16 10.8%
Refractory anemia with excess blasts (RAEB)	30 20.3%
Chronic myelomonocytic leukemia (CMML)	3 2%
Acute leukemia	1 0.7%
Unable to classify	20 13.5%
Cytogenetic Complexity (participants) [Number]
Isolated 5q	110 74.3%
Intermediate (5q + 1 abnormality)	25 16.9%
Complex	12 8.1%
Unknown	1 0.7%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0	59 39.9%
1	75 50.7%
2	14 9.5%
3 - 5	0 0%

Outcome Measures

1. Primary Outcome

Title	Participants Who Achieved Red Blood Cell (RBC) -Transfusion Independence
Description	Number of participants who achieved RBC-transfusion independence, which was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive "rolling" 56 days during the treatment period (eg, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat (MITT) diagnosis of low- or int-1-risk MDS associated with a del(5q) cytogenetic abnormality based on central hematologic and cytogenetic reviewers confirmation received ≥2 transfusions in each of the 8-week periods during the 16 week pre-treatment period received ≥1 dose of study drug

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	94
Number [participants]	59 39.9%

2. Secondary Outcome

Title	Participants With Adverse Experiences
Description	Counts of study participants who had adverse events (AEs) during the study. A participant with multiple occurrences of an adverse event within a category is counted only once in that category. Adverse events were evaluated by the investigator. The National Cancer Institute (NCI)'s Common Toxicity Criteria for AEs (NCI CTC) was used to grade AE severity. Severity grade 3= severe and undesirable AE. Severity grade 4= life-threatening or disabling AE.
Time Frame	Up to 2 Years

Outcome Measure Data

Analysis Population Description

Safety population included all participants who received at least one dose of study drug.

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	148
At least one AE	148 100%
At least one AE related to study drug	143 96.6%
At least one NCI CTC grade 3-4 AE	140 94.6%
At least one NCI CTC grade 3-4 AE related to drug	131 88.5%
At least one serious AE	89 60.1%
At least one serious AE related to study drug	40 27%
AE leading to dose reduction or interruption	131 88.5%
AE leading to discontinuation of study drug	47 31.8%

3. Secondary Outcome

Title	Participants With a >= 50% Decrease From Baseline in Red Blood Cell (RBC) Transfusion Requirements Over Any Consecutive 56 Days During Study
Description	A participant was categorized as having a transfusion reduction response if there was a ≥ 50% decrease from pretreatment transfusion requirements (before the start of the study mediation) compared to any consecutive 56 days during the study (i.e. post treatment).
Time Frame	Baseline (Day -54 to Day 0), During study (Day 1 up to 2 years)

Outcome Measure Data

Analysis Population Description

Modified Intent to Treat (MITT) diagnosis of low- or int-1-risk MDS associated with a del(5q) cytogenetic abnormality based on central hematologic and cytogenetic reviewers confirmation received ≥2 transfusions in each of the 8-week periods during the 16 week pre-treatment period received ≥1 dose of study drug

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	94
Number [participant]	70

4. Secondary Outcome

Title	Time to Transfusion Independence
Description	Transfusion independence was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive "rolling" 56 days during the treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin. Time to transfusion independence was defined as the day of the first dose of study drug to the first day of the first 56-day RBC transfusion-free period.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Modified intent to treat population who achieved transfusion independence

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	59
Mean (Standard Deviation) [weeks]	6.2 (6.89)

5. Secondary Outcome

Title	Participants Who Relapsed or Maintained Their Transfusion Independence After Achieving Transfusion Independence During the Study
Description	Transfusion independence was defined as the absence of an intravenous infusion of any RBC transfusion during any consecutive "rolling" 56 days during the treatment period (e.g., Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.), and accompanied by at least a 1 g/dL increase from screening/baseline in hemoglobin. Participants who relapsed required a transfusion after the period of transfusion independence. Participants who maintained transfusion independence did not require a transfusion during the remainder of the study.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Modified intent to treat population who achieved transfusion independence

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	59
Relapsed (had a transfusion after response)	35 23.6%
Maintained transfusion independence	24 16.2%

6. Secondary Outcome

Title	Kaplan Meier Estimate for Duration of Transfusion Independence Response
Description	Duration of response is measured from the first of the consecutive 56 days during which the participant was free of RBC transfusions to the date of the first RBC transfusion after this period. Duration of response was censored at the date of last visit for participants who maintained transfusion independence.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Modified intent to treat population who achieved transfusion independence

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	59
Median (95% Confidence Interval) [weeks]	97.0

7. Secondary Outcome

Title	Change in Hemoglobin Concentration From Baseline to Maximum Value During Response Period for Responders
Description	The change from baseline in hemoglobin for participants who became RBC-transfusion independent. The maximum hemoglobin value obtained during the response period is used in the calculation of change from baseline.
Time Frame	Baseline (Day -54 to Day 0), During study (Day 1 up to 2 years)

Outcome Measure Data

Analysis Population Description

Modified intent to treat population who achieved transfusion independence

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	59
Mean (Standard Deviation) [g/dL]	6.1 (1.92)

8. Secondary Outcome

Title	Participant Counts of Cytogenetic Response
Description	Participants deemed evaluable by the central cytogenetic review had their cytogenetic response categorized as major or minor. A major cytogenetic response was defined as ≥ 20 metaphases recorded at baseline, and at least 1 post baseline evaluation with ≥ 20 metaphases analyzed with no abnormal metaphases observed. A minor cytogenetic response was defined as ≥ 20 metaphases analyzed at baseline, and at least 1 post baseline evaluation with ≥ 20 metaphases analyzed with a ≥ 50% reduction in the proportion of hematopoietic cells with cytogenetic abnormalities compared with baseline.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Evaluable participants from the modified intent to treat population. Evaluable participants had ≥ 20 metaphases analyzed at baseline during the 56-day period immediately preceding the first day of study drug intake and ≥ 20 metaphases analyzed at least once at postbaseline visits.

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	52
Major	18 12.2%
Minor	20 13.5%
None	14 9.5%

9. Secondary Outcome

Title	Participant Counts of Platelet Response
Description	Major platelet response: participants with a minimum pretreatment platelet of <100,000/mm^3 in all values within 56 days of start of treatment, an absolute increase of ≥30,000/mm^3 sustained for ≥56 consecutive days. In platelet transfusion-dependent participants, a major response was stabilization of platelet counts and platelet transfusion independence. Minor platelet response: participants with a minimum pretreatment platelet of <100,000/mm^3, a ≥ 50% increase in platelet count with a net increase >10,000/mm^3 for a consecutive 56-day period in the absence of platelet transfusions.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Evaluable participants from the modified intent to treat population. Participants must have a baseline platelet count <100 * 10^9/L to be included in the analysis.

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	15
Major	2 1.4%
Minor	0 0%
None	13 8.8%

10. Secondary Outcome

Title	Participant Counts of Absolute Neutrophil Count (ANC) Response
Description	Major neutrophil response: participants with a minimum pretreatment ANC concentration of < 1500/mm^3 in all values obtained within 56 days of start of treatment, a ≥ 100% increase or an absolute increase of ≥ 500/mm^3, whichever was greater (at least to be ≥ 500/mm^3), sustained for 56 consecutive days. Minor neutrophil response: participants with a minimum pretreatment ANC concentration of < 1500/mm^3, an increase in ANC concentration of ≥ 100% sustained for 56 consecutive days.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Evaluable participants from the modified intent to treat population. Evaluable participants are required to have a baseline absolute neutrophil count (ANC) <1 * 10^9/L.

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	27
Major	9
Minor	0
None	18

11. Secondary Outcome

Title	Participants With Complete or Partial Bone Marrow Improvement
Description	Bone marrow aspirates were assessed by a central reviewer. A complete bone marrow improvement required a baseline French-American-British (FAB) classification (see Baseline Characteristics) of refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML) and a during study assessment of no MDS. A partial bone marrow improvement reflected an improved FAB classification compared to baseline (e.g. RARS to RA) but evidence of MDS continued to exist.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Modified intent to treat population of participants with adequate bone marrow aspirate at baseline.

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	94
Complete bone marrow improvement	22 14.9%
Partial bone marrow improvement	15 10.1%

12. Secondary Outcome

Title	Participants With Bone Marrow Progression
Description	Bone marrow aspirate was assessed by a central reviewer. Progression is represented in two categories according to changes from baseline in French-American-British (FAB) classification (see Baseline Characteristics): Baseline classification of refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) to a during treatment (plus 30 days) classification of refractory anemia with excess blasts (RAEB). Any baseline FAB classification to a during treatment (plus 30 days) classification of acute myeloid leukemia (AML).
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

Modified intent to treat population of participants with adequate bone marrow aspirate at baseline.

Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
Measure Participants	94
RA/RARS to RAEB	11 7.4%
RA/RARS/RAEB/CMML to AML	6 4.1%

Adverse Events

Time Frame	Up to 2 years
Arm/Group Title	Lenalidomide
Arm/Group Description	The protocol initially employed a syncopated dosage regimen in which 10 mg of lenalidomide was taken orally once daily on Days 1 to 21 of a 28-day cycle, but was subsequently amended to employ a continuous dosage regimen in which 10 mg of lenalidomide was taken without a planned rest period. Participants who initially began therapy on the syncopated regimen and who did not experience dose-limiting adverse events (AEs) were allowed to switch to the continuous regimen.
All Cause Mortality
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	89/148 (60.1%)
Blood and lymphatic system disorders
Neutropenia	10/148 (6.8%)
Anaemia NOS	8/148 (5.4%)
Febrile Neutropenia	8/148 (5.4%)
Thrombocytopenia	6/148 (4.1%)
Leukopenia NOS	3/148 (2%)
Pancytopenia	3/148 (2%)
Coagulopathy	1/148 (0.7%)
Cardiac disorders
Cardiac Failure Congestive	6/148 (4.1%)
Atrial Fibrillation	3/148 (2%)
Cardiac Failure NOS	2/148 (1.4%)
Myocardial Infarction	2/148 (1.4%)
Cardio-Respiratory Arrest	1/148 (0.7%)
Cardiomyopathy NOS	1/148 (0.7%)
Diastolic Dysfunction	1/148 (0.7%)
Pulmonary Oedema NOS	1/148 (0.7%)
Tachyarrhythmia	1/148 (0.7%)
Ear and labyrinth disorders
Vertigo	1/148 (0.7%)
Gastrointestinal disorders
Vomiting NOS	5/148 (3.4%)
Abdominal Pain NOS	4/148 (2.7%)
Diarrhoea NOS	4/148 (2.7%)
Gastroenteritis NOS	3/148 (2%)
Nausea	3/148 (2%)
Rectal Haemorrhage	2/148 (1.4%)
Colitis Ischaemic	1/148 (0.7%)
Colonic Polyp	1/148 (0.7%)
Constipation	1/148 (0.7%)
Dysphagia	1/148 (0.7%)
Gastritis NOS	1/148 (0.7%)
Gastrooesophageal Reflux Disease	1/148 (0.7%)
Hiatus Hernia	1/148 (0.7%)
Intestinal Perforation NOS	1/148 (0.7%)
Irritable Bowel Syndrome	1/148 (0.7%)
Oesophageal Perforation	1/148 (0.7%)
Perirectal Abscess	1/148 (0.7%)
General disorders
Pyrexia	4/148 (2.7%)
Asthenia	2/148 (1.4%)
Fall	2/148 (1.4%)
Fatigue	2/148 (1.4%)
Multi-Organ Failure	2/148 (1.4%)
Chest Pain	1/148 (0.7%)
Intermittent Pyrexia	1/148 (0.7%)
Rigors	1/148 (0.7%)
Sudden Death	1/148 (0.7%)
Hepatobiliary disorders
Cholecystitis NOS	1/148 (0.7%)
Hyperbilirubinaemia	1/148 (0.7%)
Immune system disorders
Hypersensitivity NOS	1/148 (0.7%)
Infections and infestations
Pneumonia Not Otherwise Specified (NOS)	15/148 (10.1%)
Sepsis NOS	6/148 (4.1%)
Bacteraemia	2/148 (1.4%)
Cellulitis	2/148 (1.4%)
Infection NOS	2/148 (1.4%)
Urinary Tract Infection NOS	2/148 (1.4%)
Bronchitis Acute NOS	1/148 (0.7%)
Central Line Infection	1/148 (0.7%)
Clostridial Infection NOS	1/148 (0.7%)
Enterobacter Sepsis	1/148 (0.7%)
Groin Infection	1/148 (0.7%)
Herpes Zoster	1/148 (0.7%)
Influenza	1/148 (0.7%)
Klebsiella Sepsis	1/148 (0.7%)
Lobar Pneumonia NOS	1/148 (0.7%)
Post Procedural Site Wound Infection	1/148 (0.7%)
Sinusitis Acute NOS	1/148 (0.7%)
Sinusitis NOS	1/148 (0.7%)
Vaginosis Fungal NOS	1/148 (0.7%)
Injury, poisoning and procedural complications
Femoral Neck Fracture	2/148 (1.4%)
Femur Fracture	2/148 (1.4%)
Medical Device Complication	2/148 (1.4%)
Comminuted Fracture	1/148 (0.7%)
Hip Fracture	1/148 (0.7%)
Overdose NOS	1/148 (0.7%)
Spinal Compression Fracture	1/148 (0.7%)
Investigations
Blood Creatinine Increased	1/148 (0.7%)
Troponin I Increased	1/148 (0.7%)
Metabolism and nutrition disorders
Dehydration	8/148 (5.4%)
Hypernatraemia	1/148 (0.7%)
Hypoglycaemia NOS	1/148 (0.7%)
Musculoskeletal and connective tissue disorders
Arthrlagia	1/148 (0.7%)
Back Pain	1/148 (0.7%)
Localised Osteoarthritis	1/148 (0.7%)
Osteolysis	1/148 (0.7%)
Periarthritis	1/148 (0.7%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute Leukaemia NOS	7/148 (4.7%)
Acute Myeloid Leukaemia NOS	3/148 (2%)
B-Cell Lymphoma NOS	1/148 (0.7%)
Carcinoid Tumour of the Small Bowel	1/148 (0.7%)
Lung Cancer Metastatic	1/148 (0.7%)
Multiple Myeloma	1/148 (0.7%)
Ovarian Cancer NOS	1/148 (0.7%)
Refractory Anaemia with Excess Blasts in Transformation	1/148 (0.7%)
Thymoma NOS	1/148 (0.7%)
Nervous system disorders
Dizziness	3/148 (2%)
Cerebrovascular Accident	2/148 (1.4%)
Depressed Level of Consciousness	2/148 (1.4%)
Syncope	2/148 (1.4%)
Transient Ischaemic Attack	2/148 (1.4%)
Aphasia	1/148 (0.7%)
Cerebral Haemorrhage	1/148 (0.7%)
Convulsions NOS	1/148 (0.7%)
Dementia NOS	1/148 (0.7%)
Headache	1/148 (0.7%)
Hypertensive Encephalopathy	1/148 (0.7%)
Migraine NOS	1/148 (0.7%)
Senile Dementia NOS	1/148 (0.7%)
Subarachnoid Haemorrhage NOS	1/148 (0.7%)
Subdural Haematoma	1/148 (0.7%)
Renal and urinary disorders
Renal Failure NOS	2/148 (1.4%)
Azotaemia	1/148 (0.7%)
Renal Failure Acute	1/148 (0.7%)
Reproductive system and breast disorders
Cervical Dysplasia	1/148 (0.7%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	5/148 (3.4%)
Dyspnoea NOS	2/148 (1.4%)
Pleural Effusion	2/148 (1.4%)
Pneumonitis NOS	2/148 (1.4%)
Pulmonary Hypertension NOS	2/148 (1.4%)
Asthma NOS	1/148 (0.7%)
Chronic Obstructive Airways Disease Exacerbated	1/148 (0.7%)
Epistaxis	1/148 (0.7%)
Lung Infiltration NOS	1/148 (0.7%)
Respiratory Distress	1/148 (0.7%)
Respiratory Failure	1/148 (0.7%)
Skin and subcutaneous tissue disorders
Rash NOS	2/148 (1.4%)
Acute Febrile Neutrophilic Dermatosis	1/148 (0.7%)
Dermatitis Medicamentosa	1/148 (0.7%)
Vascular disorders
Deep Vein Thrombosis	5/148 (3.4%)
Hypotension NOS	1/148 (0.7%)
Peripheral Ischaemia	1/148 (0.7%)
Thrombophlebitis Superficial	1/148 (0.7%)
Other (Not Including Serious) Adverse Events
	Lenalidomide
	Affected / at Risk (%)	# Events
Total	148/148 (100%)
Blood and lymphatic system disorders
Thrombocytopenia	93/148 (62.8%)
Neutropenia	91/148 (61.5%)
Anaemia NOS	32/148 (21.6%)
Leukopenia NOS	19/148 (12.8%)
Cardiac disorders
Palpitations	10/148 (6.8%)
Endocrine disorders
Acquired Hypothyroidism	14/148 (9.5%)
Eye disorders
Conjunctivitis	9/148 (6.1%)
Vision Blurred	8/148 (5.4%)
Gastrointestinal disorders
Diarrhoea Not Otherwise Specified (NOS)	87/148 (58.8%)
Nausea	41/148 (27.7%)
Constipation	39/148 (26.4%)
Abdominal Pain NOS	24/148 (16.2%)
Vomiting NOS	18/148 (12.2%)
Abdominal Pain Upper	14/148 (9.5%)
Dry Mouth	12/148 (8.1%)
Loose Stools	12/148 (8.1%)
Toothache	11/148 (7.4%)
Flatulence	8/148 (5.4%)
General disorders
Fatigue	62/148 (41.9%)
Oedema Peripheral	40/148 (27%)
Pyrexia	37/148 (25%)
Asthenia	22/148 (14.9%)
Oedema NOS	18/148 (12.2%)
Pain NOS	14/148 (9.5%)
Fall	13/148 (8.8%)
Chest Pain	11/148 (7.4%)
Rigors	9/148 (6.1%)
Infections and infestations
Upper Respiratory Tract Infection NOS	33/148 (22.3%)
Urinary Tract Infection NOS	21/148 (14.2%)
Sinusitis NOS	19/148 (12.8%)
Cellulitis	12/148 (8.1%)
Influenza	11/148 (7.4%)
Herpes Simplex	8/148 (5.4%)
Investigations
Alanine Aminotransferase Increased	12/148 (8.1%)
Weight Decreased	12/148 (8.1%)
Metabolism and nutrition disorders
Hypokalaemia	22/148 (14.9%)
Anorexia	20/148 (13.5%)
Hypomagnesaemia	11/148 (7.4%)
Appetite Decreased NOS	8/148 (5.4%)
Hypocalcaemia	8/148 (5.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	46/148 (31.1%)
Back Pain	39/148 (26.4%)
Muscle Cramp	31/148 (20.9%)
Pain in Limb	25/148 (16.9%)
Myalgia	19/148 (12.8%)
Peripheral Swelling	14/148 (9.5%)
Pain in Foot	10/148 (6.8%)
Neck Pain	8/148 (5.4%)
Nervous system disorders
Dizziness	35/148 (23.6%)
Headache	33/148 (22.3%)
Hypoaesthesia	11/148 (7.4%)
Dysgeusia	10/148 (6.8%)
Paraesthesia	10/148 (6.8%)
Peripheral Neuropathy NOS	10/148 (6.8%)
Peripheral Sensory Neuropathy	8/148 (5.4%)
Psychiatric disorders
Insomnia	19/148 (12.8%)
Depression	14/148 (9.5%)
Anxiety	8/148 (5.4%)
Renal and urinary disorders
Dysuria	12/148 (8.1%)
Respiratory, thoracic and mediastinal disorders
Nasopharyngitis	44/148 (29.7%)
Cough	38/148 (25.7%)
Dyspnoea NOS	37/148 (25%)
Pharyngitis	29/148 (19.6%)
Epistaxis	24/148 (16.2%)
Bronchitis NOS	17/148 (11.5%)
Dyspnoea Exertional	16/148 (10.8%)
Rhinitis NOS	12/148 (8.1%)
Rhinorrhoea	8/148 (5.4%)
Skin and subcutaneous tissue disorders
Pruritus	66/148 (44.6%)
Rash NOS	54/148 (36.5%)
Dry Skin	21/148 (14.2%)
Contusion	18/148 (12.2%)
Night Sweats	16/148 (10.8%)
Sweating Increased	13/148 (8.8%)
Erythema	12/148 (8.1%)
Alopecia	10/148 (6.8%)
Ecchymosis	10/148 (6.8%)
Skin Lesions NOS	8/148 (5.4%)
Vascular disorders
Hypertension NOS	13/148 (8.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Unless approved by Celgene, single center data will not be published before multicenter data, unless more than 1 year has elapsed since completion of the Study. Thereafter, Investigator may publish single center data provided that Investigator shall: i) provide a copy of the publication to Celgene at least 60 days in advance of submission for publication; ii) delete Celgene Confidential Information and; iii) delay submission up to 90 additional days to permit intellectual property filings.