Eltrombopag and improved hematopoiesis in refractory aplastic anemia

Abstract

Background: Severe aplastic anemia, which is characterized by immune-mediated bone marrow hypoplasia and pancytopenia, can be treated effectively with immunosuppressive therapy or allogeneic transplantation. One third of patients have disease that is refractory to immunosuppression, with persistent, severe cytopenia and a profound deficit in hematopoietic stem cells and progenitor cells. Thrombopoietin may increase the number of hematopoietic stem cells and progenitor cells.

Methods: We conducted a phase 2 study involving patients with aplastic anemia that was refractory to immunosuppression to determine whether the oral thrombopoietin mimetic eltrombopag (Promacta) can improve blood counts. Twenty-five patients received eltrombopag at a dose of 50 mg, which could be increased, as needed, to a maximum dose of 150 mg daily, for a total of 12 weeks. Primary end points were clinically significant changes in blood counts or transfusion independence. Patients with a response continued to receive eltrombopag.

Results: Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes.

Conclusions: Treatment with eltrombopag was associated with multilineage clinical responses in some patients with refractory severe aplastic anemia. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00922883.).

Figure 1. Lineage Characteristics of Responses to Eltrombopag

The Venn diagrams show the numbers of patients with unilineage, bilineage, and trilineage hematologic responses. The numbers of patients with a response and their response pattern at 12 weeks are shown on the left. The numbers of patients who met the response criteria at the most recent follow-up assessment are shown on the right.

Figure 2. Longitudinal Hematologic Improvements in Patients Who Received Eltrombopag

Longitudinal blood counts for all 11 patients who met response criteria in one or more lineages at 12 weeks are shown. Panel A shows platelet counts in the 9 patients who met the criteria for a platelet response at 12 weeks or later. Panel B shows hemoglobin responses in 6 patients who met the criteria for a hemoglobin response at 12 weeks or later. Panel C shows neutrophil responses in 9 patients who met the criteria for a neutrophil response at 12 weeks or later. The dashed portion of the line for Patient 5 indicates the time after which eltrombopag was discontinued because of putative cataract formation. This patient received monthly therapeutic phlebotomy to treat iron overload between months 6 and 18.

Figure 3. Bone Marrow Cellularity at Baseline and at 8 Months or Longer in Four Patients with Trilineage Responses to Eltrombopag

Core bone marrow–biopsy specimens (hematoxylin and eosin) are shown for four patients who had a response to eltrombopag and were followed for 8 months or longer after the protocol initiation.