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Characterizing Long-Term Outcomes of Eltrombopag in Patients With Severe Aplastic Anemia

November 23, 2021

November 2021


In an analysis of a phase II trial published in Blood, researchers found that the addition of eltrombopag to standard immunosuppression led to similar rates of relapse and clonal evolution as immunosuppression alone in patients with severe aplastic anemia (AA). However, relapse and clonal evolution occurred earlier among eltrombopag-treated patients, with no increase in the rate of high-risk evolution to myeloid malignancy.

Lead author Bhavisha Patel, MD, a staff clinician and hematologist with the National Institutes of Health’s National Heart, Lung, and Blood Institute, told ASH Clinical News that these findings “will help us guide future interventions to decrease these long-term complications in this patient population.”

Previous research has demonstrated that the addition of eltrombopag to standard immunosuppression improved hematologic responses in patients with severe AA, but little is known about the rates and characteristics of long-term complications in this patient population, according to Dr. Patel and coauthors.

Treatment for severe aplastic anemia, including bone marrow transplant and immunosuppression, typically depends on patient age, comorbidities, and the availability of donors. While immunosuppression may be a useful option in older, unfit patients, Dr. Patel and colleagues explained that relapse or clonal evolution to myeloid malignancy may occur in half of patients who achieve an initial treatment response. In addition, the researchers noted that the cumulative incidence of relapse in this patient population has not generally improved with additional immunosuppression therapy or more potent treatment options.

In this phase II study, Dr. Patel and researchers evaluated the long-term outcomes of 178 patients with severe AA who had not been definitively treated with antithymocyte globulin (ATG)–based immunosuppression therapy. Patients either declined transplantation, lacked a suitable matched related donor, or were ineligible due medical comorbidities. All patients received a combination therapy consisting of immunosuppression, horse ATG (hATG), cyclosporine, and eltrombopag.

The study included three cohorts, with participants in each group receiving different eltrombopag treatment regimens:

  • cohort 1: eltrombopag from day 15 to 6 months (n=30)
  • cohort 2: eltrombopag from day 1 to 3 months (n=31)
  • cohort 3: eltrombopag from day 1 to 6 months (n=117)


Patients in each cohort received hATG from day 1 for 4 days as well as therapeutic cyclosporine from day 1 to 6 months. Dr. Patel added that another 86 patients had been recruited under an extension arm since the initial publication of the findings.

For comparison, the researchers included a historic group that consisted of 102 patients with severe AA who were treated with only immunosuppression. Also included in the historic group were patients from study control arms who received only hATG and cyclosporine.

At six months, the overall response rate was 81%, which was significantly higher than that of the historical group (67%). According to the investigators, the cumulative relapse rate was 39% in patients who responded to treatment. Thrombocytopenia was the most prominent feature of relapse, followed by neutropenia.

They also observed that relapse occurred at distinct timepoints: shortly after six months (when cyclosporine maintenance dose was lowered and eltrombopag was discontinued) and again after two years (when maintenance course was completed). Two-thirds of relapses occurred before two years, with a median time to relapse of 280 days (range = 194-2,703).

At four years, the rate of clonal evolution was 15% in all patients who received treatment, which was similar to the rates observed in the historical group. High-risk evolution to a myeloid malignancy was observed in 5.7% of the eltrombopag-treated patients, compared with 10.3% of the historical group who received only immunosuppression. However, median time to high-risk clonal evolution was much earlier in the eltrombopag-treated group (186 vs. 777 days).

Most patients who relapsed underwent retreatment with therapeutic doses of cyclosporine with or without eltrombopag. Approximately two-thirds of patients responded to retreatment with this regimen.

At four years, overall survival rates were 92.5% and 85% in the eltrombopag- and immunosuppression-treated groups, respectively. Most patient deaths were due to infections with concurrent neutropenia. The authors added that incidence of clonal evolution or chromosome 7 abnormality was associated with worse overall survival.

“As expected, not having a response to treatment conferred a poorer prognosis, but to our surprise, survival was not different between patients with complete and partial response,” Dr. Patel and coauthors wrote.

While the findings confirm the “excellent” survival outcomes with eltrombopag in patients with severe AA, “the pattern of high-risk clonal evolution also emphasizes

the importance of earlier, more frequent marrow evaluations with this treatment regimen,” the authors concluded.

Dr. Patel also explained that “the major limitation of the study is the historical comparator arm, which may have biased our analysis.” She added that the findings should be confirmed shortly in the randomized control RACE trial, which is currently ongoing in Europe.

The authors report no relevant conflicts of interest.


Patel BA, Groarke EM, Lotter J, et al. Long-term outcomes in severe aplastic anemia patients treated with immunosuppression and eltrombopag: a phase 2 study [published online ahead of print, 2021 Sep 15]. Blood. 2021 Sep 15. doi: 10.1182/blood.2021012130.


  January 2022


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