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
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      The myelodysplastic syndromes (MDS) are bone marrow disorders characterized by anemia,
      neutropenia, and thrombocytopenia. Patients with MDS are at risk for symptomatic anemia,
      infection, and bleeding, as well as a variable risk of progression to acute leukemia. With
      the exception of stem cell transplant, the standard treatments for MDS are rarely curative,
      and relapse rates are significant. MDS patients with cytopenias who fail standard therapies
      require regular blood or platelet transfusions which are expensive and inconvenient, and are
      at risk for serious bleeding complications.

      Thrombopoietin (TPO) is the principal regulator of platelet production by megakaryocytes in
      the bone marrow. A 2nd generation TPO-agonist, eltrombopag (Promacta ) has been shown to
      increase platelets in thrombocytopenic patients with chronic immune thrombocytopenic purpura
      (ITP). Eltrombopag is administered orally, is well-tolerated, and is FDA approved for the
      treatment of thrombocytopenia in patients with chronic ITP who failed to respond to standard
      treatment.

      Because the management of MDS patients with persistent cytopenias remains unsatisfactory and
      novel therapeutic approaches are needed, we propose a non-randomized, pilot, phase II study
      of eltrombopag in low to Int-2 risk MDS subjects with thrombocytopenia and anemia cytopenias
      who are either untreated or cytopenias that persist despite treatment with standard therapies
      to assess its utility in these settings.

      Subjects will initiate study medication at an oral dose of 50 mg/day (25 mg/day for East
      Asians), which will be adjusted as clinically indicated to the lowest dose that maintains a
      stable platelet count greater than or equal to 20,000/microL above baseline while maximizing
      tolerability. Treatment response will be any increase in a cytopenia, in the lineage that
      fulfilled eligibility criteria for enrollment and will be defined as: (a) platelet count
      increases to 20,000/microL above baseline at 16 or 20 weeks , or stable platelet counts with
      transfusion independence for a minimum of 8 weeks in subjects who were previously transfusion
      dependent; (b) erythroid response for subjects with a pretreatment hemoglobin of less than 9
      g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL without
      packed red blood cell (PRBC) transfusion support, or a reduction in the units of PRBC
      transfusions by at least 50% during the eight consecutive weeks prior to response assessment
      compared with the pretreatment transfusion number in the previous 8 weeks; (c) neutrophil
      response will be defined in those with a pretreatment absolute neutrophil count (ANC) of <
      0.5 times 10(9)/L as at least a 100% increase or an absolute increase > 0.5 times 10(9)/L.
      Subjects meeting a response may remain on the extended access until they meet an off study
      criteria or the study is closed.

      Subjects with response at 16 or 20 weeks may be consented for entry into the extended access
      part of the trial. In the event that a subject is transfused platelets for a count
      >10,000/microL without a medical indication during the study period, the subject may continue
      on study drug and the response assessment may be extended for an additional 4 weeks to week
      20, at the discretion of the principal investigator. Subjects with evidence for a clinical
      response in any lineage at 16 weeks but not yet meeting full primary endpoint response
      criteria, and who are tolerating investigational treatment, may receive an additional 4 weeks
      of eltrombopag and be reassessed after 20 weeks. At that time, if they meet primary endpoint
      response criteria, they will be eligible to enter the extended access part of the study. If
      they do not meet primary endpoint response criteria, eltrombopag will be discontinued.

      Primary objective is to assess the efficacy of eltrombopag in patients with low to Int-2 risk
      MDS. Safety of eltrombopag in this subject population will be assessed concurrently.

      Secondary objectives include the toxicity profile of extended treatment with eltrombopag
      (treatment longer than 4 months), reduction in incidence and severity of bleeding episodes,
      and response following extended access to study drug (treatment longer than 4 months).

      The primary endpoint will be the portion of drug responders as defined by changes in the
      platelet count and/or platelet transfusion requirements, or the proportion of subjects who
      meet erythroid response, or neutrophil response criteria.. Platelet response is defined as
      platelet count increases to 20,000/microL above baseline at 16 or 20 weeks, or stable
      platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response
      for subjects with a pretreatment hemoglobin of less than 9 g/dL will be defined as an
      increase in hemoglobin by greater than or equal to 1.5g/dL without packed red blood cell
      (PRBC) transfusion support, or a reduction in the units of PRBC transfusions by at least 50%
      during the eight consecutive weeks prior to response assessment compared with the
      pretreatment transfusion number in the previous 8 weeks. Neutrophil response will be defined
      in those with a pretreatment absolute neutrophil count (ANC) of <0.5 times 10(9)/L as at
      least a 100% increase or an absolute increase > 0.5 times 10(9)/L. Subjects with an
      erythroid, and/or neutrophil response at 16 weeks may continue study medication (extended
      access) until they meet an off study criteria. Subjects with erythroid, or neutrophil
      response at 16 weeks may continue study medication for an additional 4 weeks (to ensure
      eligibility) prior to being consented for entry into the extended access part of the trial.
      Patients may remain on the extended access until they met an off study criteria.

      The toxicity profile will be measured using the CTCAE Version 4.0 criteria.

      Secondary endpoints will include incidence of grade 2 or higher bleeding events as measured
      by CTCAE v. 4.0; changes in serum thrombopoietin level, measured at 4 months; and progression
      to higher risk MDS as measured by IWG criteria.
    

Intervention name(s): Eltrombopag
Intervention type(s): Drug
Intervention description(s): Eltrombopag will be initiated at 50 mg/day (Asians 25 mg/day) and dose adjusted up to 150mg/day based response and safety
Other intervention name(s): PROMACTA
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hematopoiesis; Thrombocytopenia; Autoimmunity; Megakaryocytes; Bone Marrow Fibrosis; Myelodysplastic Syndrome; MDS