A Pilot Study of the Thrombopoietin-Receptor Agonist Eltrombopag in Refractory Aplastic Anemia Patients

Severe aplastic anemia (SAA) is a life-threatening blood disease which can be effectively treated with immunosuppressive drug regimens or allogeneic stem cell transplantation. However, 20-40% of patients without transplant options do not respond to immunosuppressive therapies, and have persistent severe thrombocytopenia. Even patients that respond to immunosuppressive therapies with an improvement in their life-threatening neutropenia sometimes have persistent thrombocytopenia. Both groups of patients (i.e. nonresponders to immunosuppressive therapy and responders with persistent thrombocytopenia) require regular platelet transfusions, which are expensive and inconvenient, and are a risk for further serious bleeding complications.

Thrombopoietin (TPO) is the principal endogenous regulator of platelet production. On binding to the megakaryocyte progenitor TPO receptor, TPO initiates a number of signal transduction events to increase the production of mature megakaryocytes and platelets. Thrombopoietin also has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro and in animal models. A 2nd generation small molecule TPO-agonist, eltrombopag (Promacta ) has been shown to increase platelets in healthy subjects and in thrombocytopenic patients with chronic immune thrombocytopenic purpura (ITP) and hepatitis C virus (HCV) infection. Eltrombopag is administered orally and has been well-tolerated in clinical trials. Unlike recombinant TPO, it has not been found to induce autoantibodies. Eltrombopag received FDA accelerated approval on Nov 20, 2008 for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Because a paucity of megakaryocytes and decreased platelet production is responsible for thrombocytopenia in aplastic anemia patients, we now propose this Phase 2, non-randomized pilot study of eltrombopag in aplastic anemia patients with immunosuppressive therapy refractory thrombocytopenia.

Subjects will initiate study medication at an oral dose of 50 mg/day (25 mg/day for East Asians), which will be increased or decreased 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. Platelet treatment response is defined as platelet count increases to 20,000/microL above baseline at three months, 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 transfusions by an absolute number of at least 4 PRBC transfusions for eight consecutive weeks 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 less than 0.5 times 10(9)/L as at least a 100 percent increase or an absolute increase greater than 0.5 times 10(9)/L. Subjects with a platelet, erythroid, and/or neutrophil response at 12 weeks may continue study medication (extended access) until they meet an off study criteria. Subjects with platelet, erythroid, or neutrophil response at 12 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 trial until they met an off study criteria.

The primary objective is to assess the safety and efficacy of the oral thrombopoietin receptor agonist (TPO-R agonist) eltrombopag in aplastic anemia patients with immunosuppressive-therapy refractory thrombocytopenia.

Secondary objectives include the analysis of the incidence and severity of bleeding episodes, and the impact on quality of life.

The primary endpoint will be the portion of drug responders as defined by changes in the platelet count and/or platelet transfusion requirements, hemoglobin levels, number of red blood cell transfusions, or neutrophil counts as measured by International Working Group criteria and the toxicity profile as measured using the CTCAE criteria. Platelet treatment response is defined as platelet count increases to 20,000/microL above baseline at three months, or stable platelet counts with transfusion independence for a minimum of 8 weeks. Erythroid response for subjects with a pretreatment hemoglobin of less than 9g/dL will be defined as an increase in hemoglobin by greater than or equal to 1.5g/dL 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 pretreatment absolute neutrophil count (ANC) of less than 0.5 times 10(9)/L as at least a 100 percent increase in ANC, or an ANC increase greater than 0.5 times 10(9)/L.

Secondary endpoints will include incidence of bleeding; changes in serum thrombopoietin level (as measured by enzyme-linked immunosorbent assay, R\&D Systems), and health related quality of life (as measured by the Medical Outcomes Study 36-Item Short Form General Health Survey, version 2 [SF36v2J]; Quality-Metric) measured at 12 weeks.