Anemia, Chronic Myelomonocytic Leukemia, De Novo Myelodysplastic Syndrome, Myelodysplastic Syndrome
Conditions
Brief summary
This randomized phase III trial studies lenalidomide to see how well it works with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia. Lenalidomide may stop the growth of myelodysplastic syndrome by blocking blood flow to the cells. Colony stimulating factors, such as epoetin alfa, may increase the number of immune cells found in bone marrow or peripheral blood. It is not yet known whether lenalidomide is more effective with or without epoetin alfa in treating patients with myelodysplastic syndrome and anemia.
Detailed description
PRIMARY OBJECTIVE: I. To compare the rate of major erythroid response (MER) between lenalidomide monotherapy and combined treatment of lenalidomide and epoetin alfa in erythropoietin non-responsive low-/intermediate-1 (Int-1)-risk myelodysplastic syndrome (MDS) patients or erythropoietin treatment naïve patients with low probability of erythropoietin benefit. SECONDARY OBJECTIVES: I. To compare the time to MER by treatment assignment. II. To evaluate the duration of MER by treatment assignment. III. To estimate the frequency of MER to salvage combination therapy in patients who fail to experience a MER with lenalidomide monotherapy. IV. To evaluate and compare the frequency of minor erythroid response by treatment assignment. V. To investigate the mechanism and target of lenalidomide action in patients with chromosome 5q31.1 deletion. VI. To evaluate the frequency of cytogenetic response and progression, and the relation between cytogenetic pattern and erythroid response. VII. To evaluate the frequency of bone marrow response (complete response \[CR\] + partial response \[PR\]). VIII. To evaluate the relationship between erythroid response and laboratory correlates outlined below: VIIIa. Pretreatment and on study endogenous erythropoietin level (Arm A). VIIIb. To evaluate the effect of CD45 isoform profile on lenalidomide enhancement of erythropoietin-induced STAT5 phosphorylation in CD71\^Hi erythroid precursors and the relationship to erythroid response. VIIIc. To characterize molecular targets relevant to lenalidomide cytotoxicity in del5q31.1 cells. VIIId. To evaluate the frequency of cryptic chromosome 5q31.1 deletions in patients with non-del5q31.1 MDS by array-based genomic scan, and to determine the relationship to hematologic response. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Patients with del 5q31.1 karyotype are assigned to Arm A. ARM A: Patients receive lenalidomide orally (PO) once daily (QD) on days 1-21. Patients undergo bone marrow biopsy at screening and during follow-up. Patients undergo blood specimen collection on study. ARM B: Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa subcutaneously (SC) once weekly. Patients undergo bone marrow biopsy at screening and during follow-up. Patients undergo blood specimen collection on study. In both arms, treatment repeats every 28 days for 4 cycles. Patients who achieve a major erythroid response (MER) may continue treatment beyond 4 cycles in the absence of disease progression, disease conversion to acute myeloid leukemia, or unacceptable toxicity. Patients in Arm A who fail to achieve MER or who achieve MER but relapse after 16 weeks of treatment with lenalidomide may crossover and receive treatment in Arm B. After completion of study treatment, patients are followed up for 6 months.
Interventions
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy
BIOLOGICALEpoetin Alfa
Given SC
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLenalidomide
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>= 18 years * NOTE: Results of the bone marrow biopsy and aspirate as well as cytogenetics are mandatory to register subjects onto study, which are indispensable to determine International Prognostic Scoring System (IPSS) category needed for eligibility; please note that it is not necessary to wait for the week 16, week 32, or week bone marrow and cytogenetic results prior to starting the next cycle unless deemed necessary by the treating physician; one example of this exception can include if the subject shows signs of progression, such as increased peripheral blood blast percentage; at that juncture, the treating physician may prefer to await the results prior to starting a new cycle; if a cycle is started, and based on the bone marrow results it is felt by the treating physician that the subject should not continue on treatment, please be sure to note this information on the case report forms at end of treatment * Patient must have documented diagnosis of MDS lasting at least three months (MDS duration \>= 3 months) according to World Health Organization (WHO) criteria or non-proliferative chronic myelomonocytic leukemia (CMML) (white blood cell \[WBC\] \< 12,000/mcL) * Patient must have International Prognostic Scoring System (IPSS) categories of low- or intermediate-1-risk disease; patients must have IPSS score determined by cytogenetic analysis prior to randomization; patients must have cytogenetic analysis done (to calculate IPSS); if the current bone marrow biopsy is a dry tap, patients with cytogenetic failure and \< 10% marrow blasts will be eligible; subjects with cytogenetic failure must have previous cytogenetic results (fluorescence in situ hybridization \[FISH\] is not a substitute) within the last 6 months post last type of MDS treatment (in this case, not referring to growth factors as type of MDS treatment) * Must have symptomatic anemia untransfused with hemoglobin \< 9.5 g/dL =\< 8 weeks prior to randomization or with red blood cells (RBC) transfusion dependence (i.e., \>= 2 units/month) confirmed for =\< 8 weeks before randomization * NOTE: For non-transfusion dependent patients (i.e., receiving \< 2 units/4 weeks x 8 weeks pre-study) who receive periodic transfusions, the mean 8 week pre-transfusion hemoglobin should be used to determine protocol eligibility and response reference * For non-transfusion dependent patients, a minimum of 2 pre-transfusion or un-transfused hemoglobin values are required * Applies only for patients without the deletion 5q 31.1; patients must have failed treatment with an erythropoietic growth factor, or have a low probability of response to rhu-erythropoietin; patients with low probability of response to rhu-erythropoietin or prior erythropoietin failures are defined as follows: * Prior erythropoietin failure-requires a minimum trial of \>= 40,000 units epoetin alfa/week x 8 weeks or equivalent dose of darbepoetin alfa for 8 weeks with failure to achieve transfusion independence in dependent patients or a failure to achieve a \>= 2 g rise in hemoglobin sustained for \>= 4 weeks in non-transfusion dependent patients * Low erythropoietin response profile-rhu-erythropoietin and epoetin alfa-naïve patients receiving \>= 2U packed (p)RBC/month for a minimum of 8 weeks, and serum erythropoietin \> 500 mU/mL in the 8 weeks prior to randomization for a hemoglobin \< 9.5 g/dL * Patients must be off all non-transfusion therapy for MDS for 28 days prior to initiation of study treatment, including all types of growth factors; patients may receive hydrocortisone prophylactically to prevent transfusion reactions * Patients must have a serum erythropoietin level documented before randomization and =\< 56 days before day 1 of study treatment; NOTE: hemoglobin must be \< 9.5 g/dL at time that serum erythropoietin is drawn * Effective contraception must be used by patients participating in lenalidomide therapy, and all patients must agree to counseling by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure; females of childbearing potential (FCBP) must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control: one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before starting lenalidomide, during lenalidomide therapy, during dose interruptions, and for at least 28 days following discontinuation of lenalidomide therapy; females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed; males receiving lenalidomide must agree to use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy * Platelet count \>= 50,000/mcL (50 x 10\^9/L) without platelet transfusion (within 56 days prior to randomization) * Absolute neutrophil count (ANC) \>= 500 cells/mcL (0.5 x 10\^9/L); hence ANC must be \>= 500/mcL without myeloid growth factor support (within 56 days prior to randomization) * Serum creatinine =\< 1.5 times upper limit of normal (ULN) (within 56 days prior to randomization) * Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) or serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) =\< 2.0 x ULN (within 56 days prior to randomization) * Serum total bilirubin \< 3.0 mg/dL (within 56 days prior to randomization) * Inclusion criteria for crossover registration from Arm A (lenalidomide alone) to Arm B (lenalidomide and epoetin alfa): * Patients must have completed 16 weeks of monotherapy with lenalidomide * Patients must show failure to achieve MER (major erythroid response) or have achieved MER but relapsed on Arm A
Exclusion criteria
* Patients must not have documented iron deficiency; all patients must have documented marrow iron stores; if marrow iron stain is not available, the transferrin saturation must be \> 20% or a serum ferritin \> 100 ng/mL * Women must not be pregnant or breastfeeding; females of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24 hours prior to starting cycle 1 of lenalidomide; a female of childbearing potential (FCBP) is any woman, regardless of whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months; FCBP must also agree to ongoing pregnancy testing) * Patients must not have prior therapy with lenalidomide * Patients must not have a diagnosis of uncontrolled seizure or uncontrolled hypertension * Patients must not have proliferative (WBC \>= 12,000/mcL) chronic myelomonocytic leukemia (CMML); WBC must be \< 12,000/mcL * Patients must not have MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases * Prior thalidomide therapy is allowed, however, patients must not have prior \>= grade-3 allergic reactions to thalidomide * Patients must not have prior history of desquamating rash from thalidomide at time of study entry * Patients must not have clinically significant anemia resulting from iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding * Patients must not have used cytotoxic chemotherapeutic agents or experimental agents (agents that are not commercially available) for the treatment of MDS within 8 weeks of randomization * Patients must not have prior history of malignancy other than MDS (except basal cell or squamous skin cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been confirmed free of disease for \>= 3 years * Patients must not have any serious medical condition or any other unstable medical co-morbidity, or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study * Patients must not have a history of thrombo-embolic events within 3 years prior to study randomization * Patients must not have known human immunodeficiency virus (HIV)-1 seropositivity because HIV can be an alternate cause of anemia. * Patients must not have a known allergic reaction to epoetin alfa (Procrit) or human serum albumin *
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Major Erythroid Response (MER) | Assessed after completion of 16 weeks of treatment | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Major Erythroid Response (MER) | Assessed every cycle during treatment and then 3 and 6 months after last protocol treatment | Time to major erythroid response (MER) is defined in responders as the time from randomization to the documented date of MER. For transfusion independent patients, the date of MER is the first date of the elevation in hemoglobin level of more than 2 g/dL that has been sustained for at least 8 weeks. For transfusion dependent patients, the date of MER is the beginning date of the time interval of transfusion independence that has been sustained for at least eight weeks. |
| Duration of Major Erythroid Response (MER) | Assessed every cycle during treatment and then 3 and 6 months after last protocol treatment | Duration of major erythroid response (MER) is defined as the time interval between the documented date of MER and the earliest date of resumption of red blood cell transfusions ≥ 2 units in an 8-week period, a reduction in hemoglobin concentration ≥ 2 g/dL in the absence of acute infection, gastrointestinal bleeding and hemolysis, or death. |
| Proportion of Patients With Major Erythroid Response (MER) to Salvage Combination Therapy | Assessed after completion of 16 weeks of treatment | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. |
| Proportion of Patients With Minor Erythroid Response | Assessed every cycle during treatment and after completion of 16 weeks of treatment | The definition of minor erythroid response: the mean hemoglobin is sustained 1.0 to 2.0 g/dL above the baseline value for a minimum of 8 weeks; or a 50% or greater decrease in 8-week red blood cell transfusion requirements compared to baseline. |
| Proportion of Patients With Major Erythroid Response (MER) Among Those With Chromosome 5q31.1 Deletion | Assessed after completion of 16 weeks of treatment | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. |
| Proportion of Patients With Bone Marrow Response | Assessed at 16 weeks | Bone marrow response includes complete remission (CR) and partial remission (PR). Complete remission (CR): Bone marrow showing \< 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia. When erythroid precursors constitute \< 50% of bone marrow nucleated cells, the percent of blasts is based on all nucleated cells; when there are ≥ 50% erythroid cells, the percent blasts should be based on the non-erythroid cells. Partial remission (PR): All of the CR criteria (if abnormal prior to treatment), except blasts decreased by 50% over pre-treatment, or a less advanced Myelodysplastic Syndromes (MDS) World Health Organization (WHO) classification than pretreatment. Cellularity and morphology are not relevant. |
| Proportion of Patients With Cytogenetic Response | Assessed at baseline and after completion of 16 weeks of treatment | Evaluation of cytogenetic response requires 20 analyzable metaphases when using conventional techniques. Analysis of data will require 20 metaphases before and after treatment, which must be done on bone marrow only (peripheral blood is not a substitute). Fluorescent in situ hybridization (FISH) may be used as a supplement to follow a specifically defined cytogenetic abnormality, but it is not a substitute for conventional cytogenetic studies. Cytogenetic response is defined as follows: Complete response: Restoration of a normal karyotype in patients with a documented pre-existing clonal (\>2 metaphases abnormal) chromosome abnormalities. Partial response: \> 50% reduction in the percentage of bone marrow metaphases with only clonal abnormality. |
| Association Between Major Erythroid Response and Cytogenetic Response | Assessed at baseline and after completion of 16 weeks of treatment | Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. Evaluation of cytogenetic response requires 20 analyzable metaphases before and after treatment, which must be done on bone marrow only. Fluorescent in situ hybridization (FISH) may be used as a supplement to follow a specifically defined cytogenetic abnormality, but it is not a substitute for conventional cytogenetic studies. Cytogenetic response is defined as follows: Complete response: Restoration of a normal karyotype in patients with a documented pre-existing clonal (\>2 metaphases abnormal) chromosome abnormalities. Partial response: \> 50% reduction in the percentage of bone marrow metaphases with only clonal abnormality. |
| Pretreatment Endogenous Erythropoietin Level | Assessed at baseline and after completion of 16 weeks of treatment | Pretreatment endogenous erythropoietin level was assessed at baseline. The association between pretreatment endogenous erythropoietin level and major erythroid response was evaluated among patients who received lenalidomide alone. Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAmit K Verma
ECOG-ACRIN Cancer Research Group
Participant flow
Recruitment details
From April 2009 through May 2016, the trial enrolled a total of 247 patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Lenalidomide; Chromosome 5q31.1 Deletion) Patients receive lenalidomide PO QD on days 1-21. | 38 |
| Arm A (Lenalidomide; Randomization) Patients receive lenalidomide PO QD on days 1-21. | 103 |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) Patients receive lenalidomide PO QD on days 1-21 and epoetin alfa SC once weekly. | 106 |
| Total | 247 |
Baseline characteristics
| Characteristic | Arm A (Lenalidomide; Chromosome 5q31.1 Deletion) | Arm A (Lenalidomide; Randomization) | Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Total |
|---|---|---|---|---|
| Age, Continuous | 77 years | 74 years | 73 years | 74 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 96 Participants | 97 Participants | 227 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 8 Participants | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 4 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) White | 35 Participants | 97 Participants | 96 Participants | 228 Participants |
| Sex: Female, Male Female | 26 Participants | 33 Participants | 28 Participants | 87 Participants |
| Sex: Female, Male Male | 12 Participants | 70 Participants | 78 Participants | 160 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 29 / 141 | 29 / 106 | 0 / 53 |
| other Total, other adverse events | 137 / 139 | 105 / 106 | 52 / 53 |
| serious Total, serious adverse events | 123 / 139 | 98 / 106 | 49 / 53 |
Outcome results
Primary
Proportion of Patients With Major Erythroid Response (MER)
Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients.
Time frame: Assessed after completion of 16 weeks of treatment
Population: Evaluable patients randomized to either arm A or arm B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Proportion of Patients With Major Erythroid Response (MER) | 0.115 proportion of participants |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Proportion of Patients With Major Erythroid Response (MER) | 0.283 proportion of participants |
p-value: 0.004Fisher Exact
Secondary
Association Between Major Erythroid Response and Cytogenetic Response
Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients. Evaluation of cytogenetic response requires 20 analyzable metaphases before and after treatment, which must be done on bone marrow only. Fluorescent in situ hybridization (FISH) may be used as a supplement to follow a specifically defined cytogenetic abnormality, but it is not a substitute for conventional cytogenetic studies. Cytogenetic response is defined as follows: Complete response: Restoration of a normal karyotype in patients with a documented pre-existing clonal (\>2 metaphases abnormal) chromosome abnormalities. Partial response: \> 50% reduction in the percentage of bone marrow metaphases with only clonal abnormality.
Time frame: Assessed at baseline and after completion of 16 weeks of treatment
Population: Evaluable patients in both arms A and B who had both major erythroid response data and cytogenetic response data
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A (Lenalidomide; Randomization) | Association Between Major Erythroid Response and Cytogenetic Response | Cytogenetic response | 4 Participants |
| Arm A (Lenalidomide; Randomization) | Association Between Major Erythroid Response and Cytogenetic Response | No cytogenetic response | 19 Participants |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Association Between Major Erythroid Response and Cytogenetic Response | Cytogenetic response | 5 Participants |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Association Between Major Erythroid Response and Cytogenetic Response | No cytogenetic response | 78 Participants |
Secondary
Duration of Major Erythroid Response (MER)
Duration of major erythroid response (MER) is defined as the time interval between the documented date of MER and the earliest date of resumption of red blood cell transfusions ≥ 2 units in an 8-week period, a reduction in hemoglobin concentration ≥ 2 g/dL in the absence of acute infection, gastrointestinal bleeding and hemolysis, or death.
Time frame: Assessed every cycle during treatment and then 3 and 6 months after last protocol treatment
Population: Only evaluable patients who achieved MER among randomized patients were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Duration of Major Erythroid Response (MER) | 13 months |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Duration of Major Erythroid Response (MER) | 23.8 months |
Secondary
Pretreatment Endogenous Erythropoietin Level
Pretreatment endogenous erythropoietin level was assessed at baseline. The association between pretreatment endogenous erythropoietin level and major erythroid response was evaluated among patients who received lenalidomide alone. Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients.
Time frame: Assessed at baseline and after completion of 16 weeks of treatment
Population: All patients randomized to arm A and all patients with 5q31.1 deletion that received lenalidomide alone
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Pretreatment Endogenous Erythropoietin Level | 514.5 mU/mL |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Pretreatment Endogenous Erythropoietin Level | 150 mU/mL |
p-value: 0.0002Wilcoxon (Mann-Whitney)
Secondary
Proportion of Patients With Bone Marrow Response
Bone marrow response includes complete remission (CR) and partial remission (PR). Complete remission (CR): Bone marrow showing \< 5% myeloblasts with normal maturation of all cell lines, with no evidence for dysplasia. When erythroid precursors constitute \< 50% of bone marrow nucleated cells, the percent of blasts is based on all nucleated cells; when there are ≥ 50% erythroid cells, the percent blasts should be based on the non-erythroid cells. Partial remission (PR): All of the CR criteria (if abnormal prior to treatment), except blasts decreased by 50% over pre-treatment, or a less advanced Myelodysplastic Syndromes (MDS) World Health Organization (WHO) classification than pretreatment. Cellularity and morphology are not relevant.
Time frame: Assessed at 16 weeks
Population: Evaluable patients randomized to either arm A or arm B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Proportion of Patients With Bone Marrow Response | 0.01 proportion of participants |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Proportion of Patients With Bone Marrow Response | 0.03 proportion of participants |
Secondary
Proportion of Patients With Cytogenetic Response
Evaluation of cytogenetic response requires 20 analyzable metaphases when using conventional techniques. Analysis of data will require 20 metaphases before and after treatment, which must be done on bone marrow only (peripheral blood is not a substitute). Fluorescent in situ hybridization (FISH) may be used as a supplement to follow a specifically defined cytogenetic abnormality, but it is not a substitute for conventional cytogenetic studies. Cytogenetic response is defined as follows: Complete response: Restoration of a normal karyotype in patients with a documented pre-existing clonal (\>2 metaphases abnormal) chromosome abnormalities. Partial response: \> 50% reduction in the percentage of bone marrow metaphases with only clonal abnormality.
Time frame: Assessed at baseline and after completion of 16 weeks of treatment
Population: Evaluable patients randomized to either arm A or arm B who had cytogenetic response data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Proportion of Patients With Cytogenetic Response | 0.07 proportion of participants |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Proportion of Patients With Cytogenetic Response | 0.10 proportion of participants |
Secondary
Proportion of Patients With Major Erythroid Response (MER) Among Those With Chromosome 5q31.1 Deletion
Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients.
Time frame: Assessed after completion of 16 weeks of treatment
Population: All patients with chromosome 5q31.1 deletion in arm A
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Proportion of Patients With Major Erythroid Response (MER) Among Those With Chromosome 5q31.1 Deletion | 0.632 proportion of participants |
Secondary
Proportion of Patients With Major Erythroid Response (MER) to Salvage Combination Therapy
Major erythroid response is defined as transfusion-independence for ≥ 8 consecutive weeks for patients who were red blood cell transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value; or a \> 2 g/dL rise in hemoglobin without transfusion for non-transfusion dependent patients.
Time frame: Assessed after completion of 16 weeks of treatment
Population: Evaluable patients who fail to experience a MER with lenalidomide monotherapy and receive salvage combination therapy (crossover from arm A to arm B)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Proportion of Patients With Major Erythroid Response (MER) to Salvage Combination Therapy | 0.25 proportion of participants |
Secondary
Proportion of Patients With Minor Erythroid Response
The definition of minor erythroid response: the mean hemoglobin is sustained 1.0 to 2.0 g/dL above the baseline value for a minimum of 8 weeks; or a 50% or greater decrease in 8-week red blood cell transfusion requirements compared to baseline.
Time frame: Assessed every cycle during treatment and after completion of 16 weeks of treatment
Population: Evaluable patients randomized to either arm A or arm B
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Proportion of Patients With Minor Erythroid Response | 0.208 proportion of participants |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Proportion of Patients With Minor Erythroid Response | 0.182 proportion of participants |
Secondary
Time to Major Erythroid Response (MER)
Time to major erythroid response (MER) is defined in responders as the time from randomization to the documented date of MER. For transfusion independent patients, the date of MER is the first date of the elevation in hemoglobin level of more than 2 g/dL that has been sustained for at least 8 weeks. For transfusion dependent patients, the date of MER is the beginning date of the time interval of transfusion independence that has been sustained for at least eight weeks.
Time frame: Assessed every cycle during treatment and then 3 and 6 months after last protocol treatment
Population: Only evaluable patients who achieved MER among randomized patients were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Lenalidomide; Randomization) | Time to Major Erythroid Response (MER) | 3.6 months |
| Arm B (Lenalidomide + Epoetin Alfa; Randomization) | Time to Major Erythroid Response (MER) | 3.7 months |
Other Pre-specified
Proportion of Patients With Cryptic Chromosome 5q31.1 Deletions
To evaluate the frequency of cryptic chromosome 5q31.1 deletions in patients with non-del5q31.1 MDS by array based genomic scan, and to determine the relationship to hematologic response.
Time frame: Assessed at baseline and after completion of 16 weeks of treatment
Other Pre-specified
RNA and Protein Expression Level of Cdc25C, PP2A and Their Phosphatase Substrates, Cdc2phospho-Tyr15 and Cdc25Cphospho-Ser216
To characterize molecular targets relevant to lenalidomide cytotoxicity in del5q31.1 cells.
Time frame: Assessed at baseline and after completion of 16 weeks of treatment
Other Pre-specified
The Association Between CD45 Isoform Profile and ex Vivo Augmentation of STAT5 Phosphorylation by Lenalidomide
To evaluate the effect of CD45 isoform profile on lenalidomide enhancement of erythropoietin-induced STAT5 phosphorylation in CD71Hi erythroid precursors and the relationship to erythroid response.
Time frame: Assessed at baseline and after completion of 16 weeks of treatment