A Pilot Study of a Thrombopoietin-Receptor Agonist, Eltrombopag, in Patients With Low to Int-2 Risk Myelodysplastic Syndrome (MDS)
Condition: Myelodysplastic Syndromes; Thrombocytopenia
MeSH terms: Preleukemia; Myelodysplastic Syndromes; Thrombocytopenia; Syndrome
Intervention: Eltrombopag
Intervention description: Eltrombopag will be initiated at 50 mg/day (Asians 25 mg/day) and dose adjusted up to 150mg/day based response and safety
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Hematopoiesis; Thrombocytopenia; Autoimmunity; Megakaryocytes; Bone Marrow Fibrosis; Myelodysplastic Syndrome; MDS

Summary:

      Background:

        -  Myelodysplastic syndromes (MDS) are bone marrow disorders characterized by anemia,
           neutropenia, and thrombocytopenia (low red blood cell, white blood cell, and platelet
           counts). Patients with MDS are at risk for symptomatic anemia, infection, and bleeding,
           as well as a risk of progression to acute leukemia. Standard treatments for MDS have
           significant relapse rates. MDS patients with thrombocytopenia who fail standard
           therapies require regular, expensive, and inconvenient platelet transfusions, and are at
           risk for further serious bleeding complications.

        -  Eltrombopag is a drug designed to mimic the protein thrombopoietin, which causes the
           body to make more platelets. Eltrombopag has been able to increase platelet counts in
           healthy volunteers and in patients with chronic ITP (a disease where patients destroy
           their own platelets very rapidly and thus develop thrombocytopenia), but researchers do
           not know if the drug can increase platelet counts in patients with MDS.

      Objectives:

        -  To find out whether eltrombopag can improve platelet counts in patients with MDS.

        -  To determine whether eltrombopag is safe for patients with MDS.

      Eligibility:

        -  Patients 18 years of age and older who have consistently low blood platelet counts
           related to MDS that has not responded to conventional treatment.

        -  Platelet count ≤ 30,000/μL or platelet-transfusion-dependence (requiring at least 4
           platelet transfusions in the 8 weeks prior to study entry); OR hemoglobin less than 9.0
           gr/dL or red cell transfusion-dependence (requiring at least 4 units of PRBCs in the
           eight weeks prior to study entry) OR ANC≤500

      Design:

        -  Treatment with eltrombopag tablets once per day for 16-20 weeks.

        -  Participants will be monitored closely throughout the initial treatment, with weekly
           blood tests and separate evaluations at the National Institutes of Health (NIH)
           treatment center every 4 weeks. Bone marrow biopsies may be conducted to check for
           abnormalities in bone marrow.

        -  If patients show signs of improved platelet counts after 90 days, treatment will
           continue with additional doses of eltrombopag.

        -  Patients who discontinue taking eltrombopag will be evaluated at the NIH treatment
           center 4 weeks after ending treatment, and again 6 months after ending treatment to
           check for potential side effects.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Diagnosis of MDS, with WHO classification of refractory anemia, refractory cytopenia with
        unilineage dysplasia (RCUD), RARS, RCMD-RS, or RCMD.

        IPSS risk scores of low, intermediate-1, or intermediate-2.

        Platelet count less than or equal to 30,000/ microL or platelet-transfusion-dependence
        (requiring at least 4 platelet transfusions in the 8 weeks prior to study entry); or
        hemoglobin less than 9.0 gr/dL or red cell transfusion-dependence (requiring at least 4
        units of PRBCs in the eight weeks prior to study entry) OR ANC less than or equal to 500

        Age greater than or equal to 18 years old

        Treatment naive or off all other treatments for MDS (except stable dosing of filgrastim
        [G-CSF], erythropoietin, and transfusion support) for at least four weeks. G-CSF can be
        used before, during and after the protocol treatment for subjects with documented
        neutropenia (<500/UI) as long as they meet the criteria for other cytopenia as stated
        above. G-CSF must be held for 3 weeks prior to enrollment bone marrow biopsy and prior to
        each study assessment bone marrow biopsy, unless clinically indicated to avoid infections
        per PI discretion.

        Adequate liver function, as evidenced by total serum bilirubin less than or equal to 1.5
        times the upper limit of normal patients with Gilbert's disease are eligible, provided
        intermittent indirect hyperbilirubinemia, AST or ALT less than or equal to 5 times the
        upper limit of normal.

        A serum creatinine concentration less than or equal to 2 times ULN

        EXCLUSION CRITERIA:

        WHO classification of chronic myelomonocytic leukemia (CMML), RAEB-1, RAEB-2, AML

        Treatment with horse or rabbit ATG or Campath within 6 months of study entry

        Subjects with liver cirrhosis including subjects infected with Hepatitis B or C

        Subjects with HIV

        Infection not adequately responding to appropriate therapy

        History of malignancy treated with chemotherapy and cytogenetic abnormalities suggestive of
        secondary myelodysplasia.

        Moribund status or concurrent hepatic, renal, neurologic, pulmonary, infectious, or
        metabolic disease of such severity that it would preclude the patient s ability to tolerate
        protocol therapy

        Life expectancy of less than 3 months

        Hypersensitivity to eltrombopag or its components

        Female subjects who are nursing or pregnant or are unwilling to take oral contraceptives or
        refrain from pregnancy if of childbearing potential

        Unable to understand the investigational nature of the study or give informed consent or
        does not have a legally authorized representative or surrogate that can provide informed
        consent per section