Phase II Study of Lenalidomide and Eltrombopag in Patients With Symptomatic Anemia

This phase II trial studies how well lenalidomide (LEN) and eltrombopag olamine (ELT) work in treating patients with symptomatic anemia in low or intermediate myelodysplastic syndrome (MDS). Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Eltrombopag olamine may increase the number of white blood cells and platelets found in bone marrow or peripheral blood. Giving lenalidomide and eltrombopag olamine may be an effective treatment for myelodysplastic syndrome.

PRIMARY OBJECTIVES (not Outcome Measures):

I. To evaluate the rate of hematologic improvement of the eltrombopag (eltrombopag olamine)/lenalidomide combination (as per Modified International Working Group \[IWG\] criteria).

II. To evaluate the safety and tolerability of the combination.

SECONDARY OBJECTIVES (not Outcome Measures):

I. To compare the time to hematologic improvement. II. To evaluate the duration of hematologic improvement III. To evaluate the effect of combination treatment on platelet counts, platelet transfusions and bleeding events.

IV. To evaluate the frequency of bone marrow response (complete response \[CR\] + partial response \[PR\]) and cytogenetic response.

V. To evaluate the relationship between mutations in bone marrow stem cells and response.

VI. To evaluate the relationship between various stem and progenitor alterations and response.

OUTLINE: Patients are initially assigned to 1 of 2 treatment arms.

ARM A: Patients with platelet counts \>= 50,000 receive lenalidomide orally (PO) daily or every other day (QOD) on days 1-21. If platelet counts fall below 50,000, patients discontinue lenalidomide and receive eltrombopag olamine PO daily or QOD until platelet count is maintained above 50,000 for 2 weeks. Patients then resume lenalidomide PO daily or QOD. If platelets fall below 50,000 again, patients receive eltrombopag olamine as before. When platelet counts are maintained above 50,000 for 2 weeks, patients resume lenalidomide concurrently with eltrombopag for all subsequent courses.

ARM B: Patients with platelet counts \< 50,000 receive eltrombopag olamine PO daily or QOD on days 1-28 until platelet counts is maintained above 50,000 for 2 weeks. Patients then receive treatment as in Arm A.

In both arms, treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 5 years.

Eligible patients with a diagnosis of MDS or non-proliferative chronic myelomonocytic leukemia (CMML) (WBC ≤ 12,000/mL) of at least 3-month duration according to WHO criteria and International Prognostic Scoring System categories of low or intermediate-1-risk disease. Patients either had symptomatic anemia untransfused with hemoglobin ≤ 10 g/dL in the 8 weeks before starting the study or had RBC transfusion dependence (i.e., ≥ 2 units/mo) confirmed 8 weeks before starting the study and/or PLTs \<50,000 k/uL with hemoglobin \>10.0 g/dL. Patients must not have received prior therapy with LEN (for \> 2 months) nor ELT

Eligibility Criteria:
Inclusion Criteria:

* Patient must have a documented diagnosis of myelodysplastic syndrome (MDS) of at least three months duration (MDS duration \>= 3 months) according to World Health Organization (WHO) criteria or non-proliferative chronic myelomonocytic leukemia (CMML) (white blood cells \[WBC\] =\< 12,000/L)
* Patients must have International Prognostic Scoring System (IPSS) categories of low- or intermediate-1-risk disease
* Patients must have symptomatic anemia untransfused with hemoglobin =\< 9.5 g/dL within 8 weeks of registration or with red blood cell (RBC) transfusion-dependence (i.e., \>= 2 units/month) confirmed for a minimum of 8 weeks before randomization
* Patients must have IPSS score determined by cytogenetic analysis prior to randomization; patients with cytogenetic failure and =\< 10% marrow blasts will be eligible
* Patients must be off all disease modifying therapy for MDS for 28 days prior to initiation of study treatment; patients may receive hydrocortisone prophylactically to prevent transfusion reactions
* 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/100 mL or soluble transferring receptor \< 5 mg/L.
* Women must not be pregnant or breastfeeding; females of childbearing potential should have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL); the first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing lenalidomide
* Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program; able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid \[ASA\] may use warfarin or low molecular weight heparin)
* Women of childbearing potential and sexually active males must agree to use 2 methods of an accepted and effective method of contraception and counseled on the potential teratogenic effects of lenalidomide; effective contraception must be used by patients for at least 4 weeks before beginning lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for 4 weeks following discontinuation of lenalidomide therapy; reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months; two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method; females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed; sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females of childbearing potential; it is not known whether CC-5013 (lenalidomide) is present in the semen of patients receiving the drug; therefore, males receiving CC-5013 (lenalidomide) must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy
* Patients must not have received prior therapy with lenalidomide (for more than 2 months) nor eltrombopag
* Patients must not have uncontrolled hypertension
* Patients must have absolute neutrophil count (ANC) \>= 500 cells/L (0.5 x 10\^9/L)
* Eastern Cooperative Oncology Group (ECOG) performance 0-3
* Subject is able to understand and comply with protocol requirements and instructions
* Patient has signed and dated informed consent
* Prothrombin time (PT/international normalized ratio \[INR\]) and activated partial thromboplastin time (aPTT) must be within 80 to 120% of the normal range at baseline

Exclusion Criteria:

* Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association \[NYHA\] grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a corrected QT interval (QTc) \> 450 msec
* Patients determined to be at increased risk of arterial or venous thrombosis by the investigator
* Bone marrow fibrosis that leads to a dry tap
* Female subjects who are nursing or pregnant (positive serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test) at screening or pre-dose on day 1
* Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication
* Patients with documented liver cirrhosis
* Patients with splenomegaly with a spleen size \> 16 cm