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For first-line treatment of severe aplastic anemia, adding eltrombopag (Promacta) to standard immunosuppressive therapy improved the rate, speed, and depth of hematologic response in the phase III RACE trial.

The oral thrombopoietin-receptor agonist given along with horse antithymocyte globulin (ATG) and cyclosporine yielded a complete response at 3 months in 22% of patients compared with 10% on ATG and cyclosporine alone (OR 3.2, 95% CI 1.3-7.8). By 6 months, those rates were 32% and 20%, respectively.

Median time to first response was 3.0 months with the eltrombopag combination compared with 8.8 months with the standard regimen, Régis Peffault de Latour, MD, PhD, of Saint-Louis Hospital and Université de Paris, and colleagues reported in the .

Overall response rates with eltrombopag and without it were 59% versus 31% at 3 months and 68% versus 41% at 6 months. Two-year event-free survival rates were 46% and 34%, respectively.

Eltrombopag didn't add toxicity to the immunosuppressive regimen either; rather, it led to earlier transfusion independence, fewer complications from pancytopenia, and better quality of life.

After 30 years of failed attempts to improve on standard therapy, RACE is "an important trial that supports horse ATG-cyclosporine plus eltrombopag as the new standard in severe aplastic anemia," Phillip Scheinberg, MD, PhD, of the Hospital A Beneficência Portuguesa in São Paulo, wrote in an .

The higher rate of initial response with eltrombopag "is of great positive consequence, given that refractory severe aplastic anemia is a complex clinical scenario and often leads to death (usually from infection) if the persistent severe pancytopenia is not reversed," he added.

So far, there haven't been differences in relapse, high-risk clonal evolution or death in the trial, but longer-term follow-up underway should determine whether those emerge later, Scheinberg wrote.

However, "survival and long-term outcomes are associated with the quality of hematologic response at 3 months and with the presence of early recovery after the administration of ATG," so there is hope that those benefits will pan out with eltrombopag, Peffault de Latour's group wrote.

RACE (Randomized, Multicenter Trial Comparing Horse ATG Plus Cyclosporine With or Without Eltrombopag as First-Line) was an investigator-led, open-label trial spearheaded by the European Society for Blood and Marrow Transplantation.

It included 197 patients at 24 sites in six European countries who had a confirmed new diagnosis of severe or very severe aplastic anemia, were 15 years of age or older, and were not eligible for frontline hematopoietic stem-cell transplantation.

The experimental arm started eltrombopag (150 mg/d) on day 14 and continued it through 6 months, or through 3 months if there was a complete response at that point.

"An important unanswered question is whether the results of the current trial could have been better if, instead of starting eltrombopag on day 14, it was initiated on day 1 with immunosuppression," Scheinberg pointed out.

Starting the combination together on day 1 yielded the best outcomes in the that laid the groundwork for RACE, albeit in a different patient population -- severe aplastic anemia patients who had not had a response to initial immunosuppression.

Peffault de Latour's group noted that the separation in initiation in RACE was to "prevent possible cumulative toxicity from concomitant administration of ATG."

Predictors of response were less severe aplastic anemia and younger age at baseline, but not presence, expansion, or appearance of new mutant clones.

While those findings from exploratory analysis of somatic mutations with next-generation sequencing need confirmation, they should "discourage physicians from overinterpreting the presence of mutant clones at diagnosis or after therapy in isolation," Scheinberg argued. The researchers added that "therapeutic decisions (i.e., commitment to hematopoietic stem-cell transplantation) should be made only in the presence of clear clinical indications."

Scheinberg concluded: "It is hoped that it will not take another 30 years before the next important advancement occurs in the medical management of severe aplastic anemia."

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