The addition of the oral thrombopoietin-receptor agonist eltrombopag to standard immunosuppressive therapy improves the haematologic response among previously untreated patients with severe aplastic anaemia, without increasing toxic effects.

The phase 3 RACE trial, conducted at 24 sites across six European countries, compared the efficacy and safety of horse antithymocyte globulin (ATG) plus cyclosporine with or without eltrombopag as front-line therapy in 197 patients with severe or very severe aplastic anaemia.

Preliminary results have previously been reported in the limbic.

Now published in the NEJM, the study’s primary endpoint of a haematologic complete response at 3 months was 10% with immunosuppression alone (Group A) and 22% with immunosuppression plus eltrombopag (Group B) (OR 3.2; p=0.01).

At 6 months, the overall response rate was 41% with immunosuppression alone and 68% with immunosuppression and eltrombopag.

The addition of eltrombopag from day 14 – to prevent possible cumulative toxicity from concomitant administration of ATG – reduced the median time to a first response from 8.8 months with immunosuppression alone to 3.0 months.

“Among the patients who had a response, the time to platelet transfusion independence was 68 days (interquartile range, 34 to 151) in Group A and 40 days (interquartile range, 20 to 80) in Group B. The time to red-cell transfusion independence was 140 days (interquartile range, 62 to 252) in Group A and 51 days (interquartile range, 23 to 122) in Group B.”

The 2-year overall survival was similar in both groups (85% v 90%).

“Nevertheless, eltrombopag added to standard immunosuppressive therapy significantly increased event-free survival from 34% to 46% at 2 years through the reduction in initial refractoriness to immunosuppression,” the study said.

Safety outcomes

The incidence of all adverse events, including infectious and hepatic complications, was similar in the two groups.

Six patients (3 in each group) had an interrupted course of horse ATG because of safety reasons or the physician’s decision. Cyclosporine was permanently discontinued within the first 6 months in 18 patients (11 in Group A and 7 in Group B), predominantly because of renal toxicity.

The study also found that the prevalence of somatic mutations was not higher in the eltrombopag group than in the standard-therapy group.

“We were surprised to find, however, that the percentage of patients with mutations increased from 29% at baseline to 66% at 6 months in Group A and from 31% at baseline to 55% at 6 months in Group B,” they said.

An editorial in the journal said the exploratory analysis of somatic mutations was noteworthy because the presence of clones at baseline, their expansion, and the appearance of new clones in both groups were not predictive of a lack of response or other dire outcomes.

“This observation is important given a theoretical concern that eltrombopag could promote expansion of mutant clones, although this expansion has not been confirmed.”

“Thus, the data from this analysis should discourage physicians from overinterpreting the presence of mutant clones at diagnosis or after therapy in isolation, and the detection of these clones does not warrant high-risk procedures such as hematopoietic stem-cell transplantation.”

The editorial questioned whether the results of the trial could have been better if, instead of starting eltrombopag on day 14, it was initiated on day 1 with immunosuppression.

“The latter regimen was associated with the best outcomes in the NIH trial.” it said.

Australian perspective

Haematologist Professor Erica Wood told the limbic that the results of the RACE trial were very encouraging, with improvements in blood counts and reduced requirements for transfusion support for patients who responded.

“This is a very serious illness with poor outcomes and where we need new treatments,” she said.

Professor Wood, Head of the Transfusion Research Unit at Monash University, said an Australian trial of a second-generation thrombopoietin-receptor agonist was also underway.

“Avatrombopag may have some advantages in that it is more potent, a bit simpler with the dosing and may have fewer liver side effects which is very attractive.”

The MRFF-funded DIAAMOND trial is open across 12 Australian sites and may expand to New Zealand due to the level of interest. It includes adult patients with both untreated or relapsed and refractory aplastic anaemia.

“In the RACE trial it was encouraging that for people on the eltrombopag arm, some of them had responded by around 3 months but there were also people who took longer to respond. One of the important questions is how long do you need to be on treatment overall, and whether therapy should be continued if people respond.”

“So the optimal duration of treatment for these agents is not known yet and that’s why it is important to have this long term follow-up for both efficacy and safety. Registries can also help here. In the DIAAMOND study, people are also co-enrolled in the Aplastic Anaemia and Other Bone Marrow Failure Syndromes Registry and we will use that for longer term follow-up after the trial is completed.”

Dr Wood also noted the thrombopoietin-receptor agonist is given from Day 1 with the ATG and cyclosporine in the DIAAMOND trial, not from day 14 as in the RACE trial.

“The NIH study suggested that starting on Day 1 was safe and also seemed to improve the response rate. We had the benefit of some of that information when we were planning our study.”

Eltrombopag in Australia is currently subsidised on the PBS for patients with severe chronic immune idiopathic thrombocytopenic purpura (ITP).

Disclosures: The RACE trial was supported by Novartis, Pfizer and Alexion Pharma.