Bone Marrow Fecundity: Turning Over New Stem cells in Aplastic Anemia

An insurmountable limitation in treating bone marrow failure has always been the number of residual stem cells. That is, until now. Dr. Danielle M. Townsley and colleagues from the National Institutes of Health have demonstrated in a nonrandomized historically controlled trial that the addition of eltrombopag, an oral thrombopoetin-receptor agonist, to standard therapy, improves rates of hematologic response in patients with severe aplastic anemia.

The empty bone marrow seen on trephine core biopsy in aplastic anemia is a stark and accurate indication of depleted hematopoietic precursors; the cells are simply not there. Sensitive flow cytometry designed to enumerate the immature precursor cells corroborates this morphologic impression. Multiple lines of evidence have established immune-mediated destruction of stem cells as the cause of bone marrow failure. Cytotoxic lymphocytes, cytokines, and a relative paucity of T-regulatory cells leads to loss of stem-cell progenitors. The exact cause of immune dysregulation is unknown, but it may be associated with acquired mutations in cytotoxic T cells, leading to constitutive activation, in combination with the loss of the immune modulating effect of T-regulatory cells. As such, immunosuppression, in the form of horse antithymocyte globulin and cyclosporine, have been the cornerstone of therapy. The historical overall response rate to standard immunosuppressive therapy in aplastic anemia is 66 percent. With the addition of eltrombopag to standard immunosuppressive therapy, Dr. Townsley and colleagues have improved the overall response rate to 94 percent at six months.

The researchers divided patients two years and older with previously untreated severe aplastic anemia into three cohorts. All cohorts were treated with a standard immunosuppression regimen of ATGAM (Pfizer Inc.) and cyclosporine. Eltrombopag was added to the standard regimen in three dosing schedules varying in the timing and duration of eltrombopag therapy. The primary efficacy endpoint was complete hematologic response at six months, defined as an absolute neutrophil count of at least 1,000/mm³, a hemoglobin level of at least 10 g/dL, and a platelet count of at least 100,000/mm³. The primary safety endpoint included overall safety profile in the six months after initiation of therapy. Secondary endpoints included survival and clonal evolution, defined as a new clonal cytogenetic abnormality or characteristic changes in the bone marrow consistent with the myelodysplastic syndrome or acute myeloid leukemia.

The overall complete response rate in all three cohorts was 36 percent, a significant improvement over the historical control cohort (p<0.0001). The cohort with the longest duration of eltrombopag therapy had the highest complete response rate (p<0.0001). Significant adverse events attributed to the drug included grade 2 cutaneous eruptions in two patients. The overall survival rate at two years was 97 percent. Results of bone marrow cellularity and CD34⁺ cell counts are shown in the Figure.

A significant secondary endpoint in this study was clonal cytogenetic evolution. The potential for clonal cytogenetic evolution was of particular interest because of the well-known predisposition of patients with aplastic anemia to experience clonal hematopoiesis. In the milieu of bone marrow failure, the small number of residual stem cells attempt to maintain peripheral counts, which leads to telomere attrition resulting in chromosome instability and increasing the odds of harmful mutations. This eventuality was of particular concern in a trial in which both diminished immunosurveillance and growth promotion were stimulated in tandem. Clonal cytogenetic evolution occurred in seven patients at two years. It is important to note that the rates of clonal evolution in all three cohorts were within the range of what would be anticipated with immunosuppression alone.

The mechanism by which eltrombopag improves recovery of peripheral counts in aplastic anemia is unknown. The results are particularly surprising because endogenous levels of erythropoietin and other hematopoietic growth factors are markedly elevated in patients with aplastic anemia but are clearly unable to promote effective hematopoiesis. Furthermore, therapy with granulocyte colony-stimulating factor in aplastic anemia is usually ineffective. Dr. Townsley and colleagues speculate that improved bioavailability of the synthetic agonist may play a role in its efficacy.