Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Neoplasms

Rare Diseases

Syndrome

Anemia

Preleukemia

Myelodysplastic Syndromes

Hematologic Diseases

Bone Marrow Diseases

Precancerous Conditions

Chromosome 5q Deletion

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

All Drugs and Chemicals

Antineoplastic Agents

Chrysarobin

Lenalidomide

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Lenalidomide 10 mg by mouth (PO) daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent. Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and \< 60 mL/min.

Three placebo capsules once daily for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

One 10 mg Lenalidomide capsule + 2 placebo capsules or (3 placebo capsules) once daily for subjects with a creatinine clearance ≥ 60 mL/min. Alternatively-one 5 mg Lenalidomide capsule + 2 placebo capsules (or 3 placebo capsules) once daily for subjects with a creatinine clearance between 40 and 60 mL/min. Subjects may take study drug for at least 168 days unless there are intolerable side effects or disease progresses. Subjects may continue study drug beyond 168 days if they have an erythroid response (increase in their hemoglobin levels and fewer transfusions administered than before starting study drug)

3 placebo capsules once daily. Subjects may take study drug for at least 168 days unless there are intolerable side effects or disease progresses. Subjects may continue study drug beyond 168 days if they have an erythroid response (increase in their hemoglobin levels and fewer transfusions administered than before starting study drug)

Placebo

Albert Hoenekopp, MD

The purpose of this study is to investigate whether lenalidomide would reduce the number of red blood cell transfusions (RBC) needed in anemic (RBC transfusion-dependent) participants with low or intermediate-1 risk MDS without a deletion 5q chromosome abnormality. The study also investigated the safety of lenalidomide use in these participants. Two-thirds of the participants received oral lenalidomide and one-third of the participants received oral placebo.

A Study of Lenalidomide Versus Placebo in Subjects With Transfusion Dependent Anemia in Lower Risk Myelodysplastic Syndrome (MDS) Without Del 5q

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study To Compare The Efficacy And Safety of Lenalidomide (Revlimid®) Versus Placebo In Subjects With Transufsion-Dependent Anemia Due to IPSS Low Or Imtermidate-1 Risk Myelodysplastic Syndromes Without Deletion 5Q(31) And Unresponsive Or Refractory To Erthropoiesis-Stimulating Agents

The percentage of participants who achieved the 56-day RBC transfusion independent (TI) response was defined as the absence of any RBC transfusions during any consecutive "rolling" 56-day interval within the double-blind treatment phase (ie, Days 2 (Day 1 is the first study drug day) to 57, Days 3 to 58, etcetera). The double-blind treatment phase was defined as the period between the 1st dosing up until 28 days after the last study drug dose

The percentage of participants who achieved the 56-day RBC TI response was defined as the absence of any RBC transfusions during any consecutive "rolling" 56-day interval within the double-blind treatment phase (ie, Days 2 (Day 1 is the first study drug day) to 57, Days 3 to 58, etcetera). A participant who achieved at least a 56-day RBC-transfusion-independent response was considered a 56-day RBC-TI responder.

The 168-day RBC-transfusion-independent response was defined as the absence of any RBC transfusion during any consecutive "rolling" 168 days during the treatment period, for example Days 2 (Day 1 is the first study drug day) to 169, Days 3 to 170, Days 4 to 171, etcetera. A responder was defined as a participant who had a ≥ 168 consecutive days of RBC-transfusion-free period after the first dose of study drug in the treatment phase.

The duration of the first 56-day RBC transfusion-independence response was calculated for those who achieved a response and was dependent on whether a subsequent RBC transfusion was given after the transfusion-free period (response):

* For those who received a subsequent RBC transfusion after the response starts, the duration of response was not censored, and was calculated as response duration = last day of response - first day of response +1 where the last day of response was defined as 1 day before the first RBC transfusion which was given at 56 days or more after the response starts.
* For those who did not receive a subsequent RBC transfusion after the response started, the end day of the response was censored and duration of the response was calculated as response duration = date of last RBC transfusion assessment - first day of response+ 1. A responder was a participant who had a ≥ 56 consecutive days of RBC-transfusion-free period after the first study drug treatment period

A participant was considered as having achieved an erythroid response if the participant either:

- had a hemoglobin (Hgb) increase ≥1.5 g/dL compared to baseline and confirmed by another central laboratory hemoglobin value at 4 to 8 weeks after the first Hgb measurement that also increased ≥1.5 g/dL. All Hgb values during this time interval must have had a ≥ 1.5 g/dL increase (ie, no central laboratory Hgb increase during this timeframe could be less \<1.5 g/dL) OR - had a 50% reduction in the number of the RBC transfusion units over any consecutive 56 days period compared to the baseline transfusion burden.

The baseline transfusion burden is the number of units over 112 days by the randomization divided by 2. Only transfusions given for a pre-transfusion Hgb value of 9 g/dL or less were used in this response assessment.

The time to the first 56-day RBC-transfusion-independent response was calculated for participants who achieved a response. The day from the first dose of study drug to the date at which RBC-transfusion-independence starts was achieved and calculated using: Start date of the first response period - the date of the first study drug +1. A responder was defined as a participant who had a ≥ 56 consecutive days of RBC-transfusion-free period after the first dose of study drug in the treatment phase.

Progression to AML is part of the natural course of MDS and is a manifestation of disease progression. The time to progress to AML was calculated from the day of randomization to the first day when AML was diagnosed. Participants who died without AML were censored at the date of death. The participants who were lost to follow-up were censored at the last known day when participants did not have AML. Participants who did not progress to AML at the last follow-up contact were censored at the day of the last follow-up contact.

Overall survival was assessed using the time between randomization and the date of death or date of censoring. Participants who were alive at a data cutoff date and participants who were lost to follow-up were censored at the last date when participants were known to be alive.

A TEAE was defined as an AE that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug.

A serious adverse event (SAE) is any:

* Death;
* Life-threatening event;
* Any inpatient hospitalization or prolongation of existing hospitalization;
* Persistent or significant disability or incapacity;
* Congenital anomaly or birth defect;
* Any other important medical event

The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 3.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.

The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A participant was considered compliant at a visit if at least 15 out of the QLQ-C30 items in the questionnaire were checked.

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom).

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom).

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement.

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Domain was scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom).

The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Physical Functioning was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement.

The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). The EORTC QLQ-C30 Global Health Status/QOL scale was scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement.

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Emotional Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement.

The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. Improvement means at least 10 points better compared to baseline

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). Improvement means at least 10 points better compared to baseline.

The European Organization for Research and Treatment of Cancer QOL Questionnaire for Patients with Cancer (EORTC QLQ-C30) was a 30-item oncology-specific questionnaire. The questionnaire was developed to assess the quality of life of cancer patients. It contains 30 questions, 24 of which form 9 multi-item scales representing various aspects of HRQOL: 1 global scale, 5 functional scales (Physical, Role, Emotional, Cognitive and Social), and 3 symptom scales (Fatigue, Pain, and Nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Subscale scores are transformed to a 0 to 100 scale, with higher scores on functional scales indicating better function and higher score on symptom scales indicating worse symptoms. A change of at least 10 points on the standardized domain scores was required for it to be considered clinically meaningful.

Hospitalizations due to adverse events exclude those for transfusions, elective procedures or protocol-driven procedures. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

Hospitalizations due to adverse events exclude those for transfusions, elective procedures or protocol-driven procedures. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient

Celgene

Second primary malignancies were monitored as events of interest and reported as serious adverse events for at least 5 years from randomization unless the participants withdrew consent from the study, died or were lost to follow-up.

Participants received 3 placebo capsules by mouth QD for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent

Participants received lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression or intolerable side effects. Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance between 40 and 60 mL/min.

Participants received 3 placebo capsules by mouth daily for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

Participants receieved lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent.

Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and \< 60 mL/min.

Total

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

The baseline transfusion burden is the average number of RBC units/28 days during the 112 days prior to randomization.

Packed RBC (pRBC) Transfusion Burden

The Myelodysplastic Syndrome (MDS) IPSS score assesses the severity of MDS based on 3 prognostic factors each assigned a score: the percentage of bone marrow blasts, chromosome changes in the marrow cells (karyotype) and the presence of one or more low blood cell counts (cytopenias). The IPSS score is the sum of the bone marrow blast + karyotype + cytopenia score and ranges from 0 (low risk) to 3.5 (high risk). Prognosis is categorized as Low risk (score = 0), Intermediate-1 (score 0.5 to 1.0), Intermediate-2 (score 1.5 to 2.0) or High risk (score ≥ 2.5).

International Prognostic Scoring System (IPSS) Investigator Determined

The World Health Organization (WHO) 2008 classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q.

World Health Organization Classification 2008 of MDS by Central Review

Erythropoiesis-stimulating agents (ESA) are similar to the cytokine (erythropoietin) that stimulates red blood cell production (erythropoieisis). ESAs, structurally and biologically, are similar to naturally occurring protein erythropoietin. ESAs are used to maintain hemoglobin at the lowest level that both minimizes transfusions and best meets a person's needs

Prior Erythropoiesis-stimulating Agent (ESA) Treatment

Hemoglobin

A prespecified subgroup of participants with an erythroid differentiation gene expression signature predictive of lenalidomide response

Gene Expression Signature

The Intent-to-Treat (ITT) population includes all participants who were randomized.

Anne McClain, Senior Study Manager

3 placebo capsules by mouth (PO) daily (QD) for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

Lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent.

Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and \< 60 mL/min.

The Intent-to-Treat (ITT) population includes all participants who were randomized to either lenalidomide or placebo.

Percentage of Participants Who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days as Determined by an Independent Review Committee (IRC)

Analysis population includes ITT participants with an erythroid gene expression signature.

Percentage of Participants With a Erythroid Gene Signature Who Achieved RBC Transfusion Independence for ≥ 56 Days as Determined by an Independent Review Committee (IRC)

The ITT population includes all participants who were randomized to either lenalidomide or placebo.

Percentage of Participants Who Achieved RBC Transfusion Independence With a Duration of ≥ 24 Weeks (168 Days) as Determined by the Sponsor

The analysis was conducted only for those participants who achieved a 56-day transfusion independence response according to the sponsor's assessment. Responders in the intent to treat population.

Kaplan Meier Estimates of Duration of 56-day RBC Transfusion Independence Response as Determined by the Sponsor

Percentage of Participants Who Achieved an Erythroid Response Based on the Modified International Working Group (IWG) 2006 Criteria

The analysis was conducted only for those participants who achieved a 56-day TI response according to the sponsor's assessment. Responders in the intent to treat population.

Time to 56-Day RBC-Transfusion-Independent (TI) Response as Determined by the Sponsor

ITT population includes all participants who were randomized and received either lenalidomide or placebo. One participant in the placebo arm was diagnosed as having AML before enrollment and was excluded from all analyses of progression to AML.

Kaplan Meier Estimates for Progression to Acute Myeloid Leukemia (AML)

Kaplan Meier Estimate for Overall Survival (OS)

At least 1 TEAE

≥ 1 Treatment Related AE (TEAE)

≥ 1 Treatment related TEAE Causing Discontinuation

≥ 1 TEAE Leading to Dose Reduction

≥ 1 TEAE Leading to Dose Interruption

≥ 1 TEAE Leading to Dose Interruption & Reduction

≥ 1 TEAE Leading to Discontinuation of Study Drug

≥ 1 Serious TEAE

≥1 Treatment-Related Serious TEAE

≥1 Serious TEAE Leading to Dose Reduction

≥1 serious TEAE leading to dose interruption

≥1 SAE Causing Dose Interruption & reduction

≥1 Serious TEAE Leading to Stopping of Study Drug

≥1 Grade (GR) 3-4 TEAE

≥ 1 GR 3-4 Related TEAE

≥ 1 GR 3-4 Leading to Dose Reduction

≥ 1 GR 3-4 TEAE Leading to Dose Interruption

≥ 1 GR 3-4 TEAE dose Interruption &reduction

≥ 1 GR 3-4 TEAE Leading to Stopping of Study Med

≥ 1 GR 5 TEAE

≥1 GR Treatment Related 5 TEAE

3 placebo capsules by mouth (PO) daily (QD) for at least 168 days until disease progression occurred or intolerable side effects.

Lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression or intolerable side effects.

Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance between 40 and 60 mL/min.

.

Safety population includes all participants who received at least 1 dose of study drug.

Number of Participants With Treatment Emergent Adverse Events (TEAE)

Baseline

Week 12

Week 24

Week 36

Week 48

Analyses were performed based on the Health Related Quality of Life (HRQoL) evaluable population, defined as all randomized participants who completed the baseline assessment and at least one post-baseline assessment for the intent to treat population. Data is available up to Week 48 due to small sample after that.

Compliance Rates Using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) From Baseline to Week 48

.Lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent.

Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and \< 60 mL/min.

Analyses were performed based on the HRQoL evaluable population, defined as all randomized participants who completed the baseline assessment and at least one post-baseline assessment for the intent to treat population. Only those with available data at baseline and each time point are included.

Mean Change From Baseline in the EORTC QLQ-C30 Fatigue Domain at Week 12 and 24

3 placebo capsules by mouth (PO) daily (QD) for at least 168 days until disease progression occurred or intolerable side effects or withdrawal of consent.

Analyses were performed based on the Health Related Quality of Life (HRQoL) evaluable population, defined as all randomized participants who completed the baseline assessment and at least one post-baseline assessment for the intent to treat population. Only those with available data at baseline and each time point are included.

Mean Change From Baseline in the EORTC QLQ-C30 Dyspnea Domain at Week 12 and 24

Mean Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain at Week 12 and 24

Mean Change From Baseline in the EORTC QLQ-C30 Global Health Status/Quality of Life (QOL) Domain at Week 12 and 24

Lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent.

Lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and \< 60 mL/min.

.

Mean Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain at Week 12 and 24

Mean Change From Baseline in Fatigue Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Mean Change From Baseline in the Dyspnea Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Mean Change From Baseline in the Physical Functioning Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Mean Change From Baseline in the Global Health Status/QoL Domain Associated With the EORTC QLQ-C-30 Scale at Week 12 and Week 24

Mean Change From Baseline in the Emotional Functioning Domain Associated With the EORTC QLQ-C30 Scale at Weeks 12 and 24

Percentage of Participants With a Clinically Meaningful Improvement in QOL (EORTC QLQ-C-30 Scale) From Baseline in Fatigue Domain at Weeks 12 and 24

Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline in the Dyspnea Domain at Weeks 12 and 24

Analyses were performed based on the HRQoL evaluable population, defined as all randomized participants who completed the baseline assessment and at least one post-baseline assessment with the EORTC QLQ-C-30. Only those with available data at baseline and each time point are included.

Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline Within the Physical Functioning Domain at Weeks 12 and 24

Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline in the Global Health Status/QOL Domain at Weeks 12 and 24

Percentage of Participants With a Clinically Meaningful Improvement in HRQOL Associated With the EORTC QLQ-C-30 Scale From Baseline in the Emotional Functioning Domain at Weeks 12 and 24

A participant was considered as having achieved an erythroid response when:

- a Hgb increase ≥1.5 g/dL compared to baseline and confirmed by another central laboratory hemoglobin value at 4 to 8 weeks after the first Hgb measurement that had also increased ≥1.5 g/dL for at least 8 weeks. All Hgb values during this time interval must have had a ≥ 1.5 g/dL increase (ie, no central laboratory Hgb increase during this timeframe can be less than a 1.5 g/dL) OR - had an absolute reduction of 4 RBC transfusion units over any consecutive 56 days period compared to the baseline transfusion burden.

The baseline transfusion burden is the number of units over the 112 days prior to randomization divided by 2. Only transfusions given for a pre-transfusion Hgb value of 9.5 g/dL or less may be used in this response assessment.

Intent to treat population includes all participants who were randomized.

Percentage of Participants Who Achieved an Erythroid Response Based on Original IWG 2006 Criteria

Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Related to Adverse Events Per Person Year

Participants with at least one hospitalization.

Healthcare Resource Utilization (HRU): Duration of Hospitalizations Due to Adverse Events

Healthcare Resource Utilization (HRU): Number of Days of Hospitalization Due to Adverse Events Per Person-Years

Participants received 3 placebo capsules by mouth (PO) daily (QD) for at least 168 days until disease progression occurred, intolerable side effects or withdrawal of consent.

Participants received lenalidomide 10 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 60 mL/min for at least 168 days until disease progression, intolerable side effects or withdrawal of consent.

Participants received lenalidomide 5 mg PO daily plus 2 placebo capsules for participants with a creatinine clearance ≥ 40 and \< 60 mL/min.

Overall Study

Hematinics

Epoetin Alfa

Patients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks.

Patients received epoetin zeta (Retacrit®) 40000UI/week subcutaneously during 12 weeks.

Response has been evaluated at 12 weeks according to IWG 2006 criteria. Patients with response continued on epoetin zeta. In non-responders, the patients have been excluded from the protocol.

Epoetin Zeta

Sophie PARK, MD, PHD

In this trial, the investigators would like to understand why a small percentage of patients will be refractory to ESA (independently of International prognostic scoring system (IPSS) and % of blasts). In a retrospective study of the "Groupe Francophone des Myélodysplasies (GFM)" , the investigators showed that about 43% of patients are refractory or will relapse after initial response to ESA and it has been shown that these patients have a poorer survival. The investigators plan to give a 12-week treatment of Epoetin alfa or zeta in low risk MDS patients and measure different biological factors to predict response to ESA:

* evaluation by flow cytometry before and after treatment of the degree of dyserythropoiesis and dysgranulopoiesis which could explain the primary resistance or loss of response of a subset of patients,
* screening by molecular biology of predictive factors of response to ESA,
* Iron homeostasis will be measured via hepcidin, GDF-15 and ferritin levels.

Lower risk MDS patients, with LOW and INT-1 IPSS score, with anemia Hb\<10g/dl, requiring or not Red blood cel (RBC) transfusions, treated by erythropoiesis stimulating agent (ESA) according to national French recommendations ( epoetin zeta 40000 UI/week in lower risk MDS, \<10% blasts, with Hb\<10g/dl and sEPO\<500UI/l, for 12 weeks).

BM aspirates are collected prospectively at T0 and at W12 of ESA treatment.

BM aspirates will be collected prospectively at inclusion in all 70 patients, after 12 weeks, in 70 patients.

Fresh bone marrow samples will be centralized at Cochin hospital for flow cytometry analysis of dyserythropoiesis and gene sequencing (Hematology laboratory, Cochin, Paris). "Ogata flow cytometry score" will be assessed locally in Mulhouse, Creteil, Tours, Grenoble or Cochin. Patients have been reevaluated at week 12 by flow cytometry "Ogata score".

Blood plasma will be been collected for analysis of GDF-15 and hepcidin, and sent to Cochin (Institut Cochin, Paris). Hepcidin level was measured by LC-MS/MS method in Louis Mourier Hospital.

Red score analysis was done in a centralized manner in Cochin, according to the methods described previously. Basically, it was evaluated on CD36, CD71 CV and Hb level according to the gender.

Genomic studies and Bioinformatic analysis Mutations in a selected panel of 39 genes will be screened in the 70 samples by a Next-Generation Sequencing (NGS) assay.

Sample size justification and Statistical analysis Sample size computation was based on the secondary endpoint which was the response rate. The investigators expected a response rate of 50-60%, therefore about 30 patients will be responders and 30 patients non responders. With 10%-15% of non evaluable biological data, n=70 patients should be included.

Biological Predictive Factors of Response to ESA in Low Risk MDS Patients

Biological Predictive Factors of Response to Erythropoiesis Stimulating Agent (ESA) in Low Risk Myelodysplastic Syndromes (MDS) Patients

The flow cytometry (FCM) "Red score" described by Mathis et al, Leukemia 2013, ranges from 0 to 7 and includes CD36 and CD71 CV and Hb levels.

The "Ogata FCM score" described by Ogata et al, Haematologica 2009, ranges from 0 to 4 and includes parameters of dysgranulopoiesis and excess of CD34+ blasts

Gene mutations numbers, assessed by next generation sequencing on a 39 gene panel

Mean and median values of GDF15 (pg/ml) levels

Mean and median values of hepcidin (ng/ml)

Response rate will be evaluated by IWG 2006 criteria of erythroid response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study of Lenalidomide Versus Placebo in Subjects With Transfusion Dependent Anemia in Lower Risk Myelodysplastic Syndrome (MDS) Without Del 5q	NCT01029262	Anemia	Lenalidomide Placebo	18 Years -	Celgene
A Study of Lenalidomide Versus Placebo in Subjects With Transfusion Dependent Anemia in Lower Risk Myelodysplastic Syndrome (MDS) Without Del 5q	NCT01029262	Anemia	Lenalidomide Placebo	18 Years -	Celgene
Biological Predictive Factors of Response to ESA in Low Risk MDS Patients	NCT03598582	Myelodysplastic...	Epoetin Zeta	18 Years - 100 Years	Association pour la recherche sur les Affections Malignes en Immunologie Sanguine

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