Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

Abstract

Background: Acquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia.

Methods: We enrolled 92 consecutive patients in a prospective phase 1-2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer.

Results: The rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag.

Conclusions: The addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167 .).

Figure 1. Study Design and Treatment Plan According to Cohort

All the patients received antithymocyte globulin (ATG) and cyclosporine. Three eltrombopag dosing schemes were implemented in consecutively enrolling cohorts. Results from each cohort informed the design of the subsequent cohort. In cohort 1, eltrombopag was initiated after ATG, owing to concern about overlapping hepatotoxic effects, especially when it is coadministered with ATG and cyclosporine. Since most responses in cohort 1 appeared within 3 months and in order to limit eltrombopag exposure, eltrombopag was discontinued at 3 months in cohort 2. Because the hepatotoxic effects in cohort 2 were found to be infrequent and the rate of complete response was lower than in cohort 1, in cohort 3 eltrombopag was initiated on day 1 with ATG and continued for 6 months. Details regarding the daily dosing scheme are provided in the Supplementary Appendix. The primary end point was the rate of complete hematologic response at 6 months. The rate of partial response and the overall response rate (which included patients with a partial or complete response) were secondary end points.

Figure 2. (facing page). CD34+ Cell Enumeration and Assay of Hematopoietic Progenitors

Panel A shows serial measurements of bone marrow cellularity in all 92 patients at baseline (green) and at 3 months and 6 months after the initiation of treatment (blue). Representative samples from bone marrow core biopsies (hematoxylin and eosin) obtained from Patient 7 at these three time points are shown. Each circle indicates one patient. The long horizontal bar indicates the mean, and the I bar the standard deviation. Panel B shows the serial quantification of CD34+ cells of the patients in cohort 3 at baseline (green) and at 3 months and 6 months after the initiation of treatment (blue). The long horizontal bar indicates the median, and the I bar the interquartile range. Representative flow-cytometric analyses at these three time points are shown for Patient 67; the numbers in the boxes represent the percentages of cells within the indicated fraction. SSC denotes side scatter. At 3 months, the median fraction of CD34+ cells in this cohort had increased from the baseline value by a factor of 3 (baseline value, 0.13%; value at 3 months, 0.45%; and value at 6 months, 0.37%). Similarly, the numbers of CD34+ cells in bone marrow increased during treatment in cohorts 1 and 2 (Fig. S5 in the Supplementary Appendix). Panel C shows representative serial flow-cytometric analyses of phenotypically defined hematopoietic stem cells (HSCs; CD34+CD38–CD45RA–CD90+CD49f+ phenotype with low rhodamine uptake) in the bone marrow of Patient 29 and in a sample obtained from a healthy person (control). Nucleated bone marrow cells were initially enriched for CD34+ cells by Magnetic Automated Cell Separation (MACS) and analyzed by means of flow cytometry for markers expressed on HSCs. Owing to the paucity of CD34+ cells at baseline, most of the cells that were measured had a CD34– phenotype. Representative flow-cytometric analyses of multipotent progenitors are shown in Figure S5 in the Supplementary Appendix. The P values were calculated by one-way analysis of variance.