RACE study results released, eltrombopag combination therapy is expected to become the new standard of treatment for severe aplastic anemia

Aplastic anemia is a bone marrow failure disease characterized by pancytopenia.
Severe/very severe aplastic anemia (SAA/vSAA) has progressive anemia, bleeding and infection, and has a high mortality rate [1,2]
.

For patients who are not suitable for hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy (IST) with cyclosporine combined with antithymocyte globulin (ATG) is the standard treatment for SAA [3]
.

However, about 1/3 of patients are ineffective to standard immunotherapy, and 20% to 40% of patients who respond to initial treatment will experience disease recurrence.
How to improve the hematological remission rate of SAA patients is imminent [4]
.

A non-randomized phase 1-2 study of the National Institutes of Health (NIH) explored the efficacy and safety of eltrombopag combined with IST in treatment-naïve patients with SAA [5]
.

Recently, the results of the randomized controlled RACE study were published in full in the top journal New England Journal of Medicine, adding confirmation to the efficacy and safety of this program [6]
.

Methods | The investigator-initiated, prospective, randomized, controlled study RACE (NCT02099747) was a multicenter, open-label, randomized, controlled Phase 3 study of 197 treatment-naïve patients over 15 years of age who were not eligible for first-line hematopoietic stem cell transplantation.
SAA/vSAA patients
.

Patients were randomly assigned to the IST group (n=101), and the treatment regimen was equine antithymocyte globulin (hATG) 40 mg/kg x 4 days + cyclosporine A (CsA) 5 mg/kg/day in sufficient doses for 1 year and then tapering , or Eltrombopag combined with IST group (n=96), the treatment plan is based on the above IST, from the 14th day in combination with Eltrombopag 150mg/day (half of East Asian descent) for 6 months (if early 3 months for complete remission)
.

The primary endpoint of the study was the hematologic complete response rate (CR) at 3 months, defined as hemoglobin levels >100 g/L, absolute neutrophil counts >1.
0 × 109/L, and platelet counts >100 in patients who did not receive blood transfusions × 109/L
.

Secondary endpoints include hematologic overall response rate (ORR, ie CR + partial response [PR], PR criteria are no longer meeting the SAA criteria, red blood cells and platelets are free from transfusion dependence, but do not meet the CR criteria), response time,
etc.

Eltrombopag combined with IST resulted in a higher quality and faster hematologic response with comparable baseline characteristics, with a median follow-up of 24 months
.

The study met its primary endpoint: Eltrombopag in combination with IST significantly improved CR at 3 months compared with IST alone (OR 3.
2; P=0.
01, Figure 1)
.

In addition, the 3-month ORR, 6-month CR and ORR of Eltrombopag combined with IST group were significantly higher than those of IST group[6,7]
.

Figure 1.
Hematologic remission rates at 3 and 6 months by treatment group.
Patients in the Eltrombopag group responded faster: median time to first response, median time to best response, and time to independence from transfusion The time was shorter than the IST group (Table 1)
.

Table 1 Time of onset of action In summary, at all landmark time points, the efficacy of eltrombopag combined with IST was superior to IST, with higher quality and faster hematologic remission, thus enabling patients to obtain multi-faceted clinical outcomes Benefits include earlier weaning from transfusion dependence, fewer complications, and better quality of life [1]
.

Eltrombopag combined with IST did not produce additional toxic side effects and did not increase the rate of clonal evolution.
Overall safety analysis showed that the incidence of all adverse events (including infections and liver complications) was similar between the two groups, that is, Eltrombopag combined with IST.
No additional toxic side effects were produced
.

After verification by the central laboratory, a total of 3 patients had clonal evolution (requiring 2 abnormal karyotypes at an interval of 3 months), 1 patient in the IST group (chromosome 7 monosomy), and 2 patients in the eltrombopag group (del[13q].
]), and there was no MDS/AML in either group
.

At baseline, 30% of patients had somatic mutations in addition to PIGA mutations
.

The most commonly mutated genes include DNMT3A, BCOR, BCORL1 and PIGA
.

At 6 and 24 months, some patients in both groups developed de novo mutations
.

The change of mutation frequency in the two groups with time is shown in Figure 2
.

However, neither baseline mutations nor de novo mutations were associated with efficacy or overall survival
.

The presence of somatic mutations should not be overinterpreted, the presence of mutations does not imply the need for HSCT, and treatment decisions (ie, whether to HSCT) should be made based on clear clinical indications
.

Figure 2 Proportion of Patients with Somatic Mutations During the trial of Eltrombopag in combination with IST to improve event-free survival, 22 patients died, 14 in the IST group and 8 in the Eltrombopag+IST group
.

There was no statistical difference in 2-year overall survival between the two groups (A vs B, 85% vs 90%)
.

A total of 23 patients underwent HSCT, 12 in the IST group and 11 in the eltropol group
.

There was no significant difference in cumulative relapse rates 18 months after remission
.

At 2 years, event-free survival (EFS) was significantly higher in the eltrombopag plus IST group than in the IST group: 2-year EFS in SAA/vSAA patients increased significantly from 34% to 46% (Figure 3)
.

Figure 3 Kaplan-Meier curve for event-free survival (an event defined as no response at 6 months, hematopoietic stem cell transplantation, any other treatment for aplastic anemia, clonal evolution, relapse, or death).
Studies have shown that in patients with severe aplastic anemia, the addition of eltrombopag to IST alone resulted in higher quality and faster remission in patients with SAA/vSAA without increased toxicity
.

The results of this study support the combination of eltrombopag with IST as a new standard of care for the non-transplant treatment of newly diagnosed severe aplastic anemia[1]
.

Reference: [1] Scheinberg P.
A New Standard Immunosuppression Regimen in Severe Aplastic Anemia[J].
N Engl J Med.
2022 Jan 6;386(1):89-90.
doi: 10.
1056/NEJMe2118143.
PMID: 34986290.
[2] Yang Wenrui, Han Bing, Chang Hong, et al.
Efficacy and safety of eltrombopag in the treatment of aplastic anemia: the results of a multi-center survey in China [J].
Chinese Journal of Hematology, 2020, 41(11): 890 -895.
DOI: 10.
3760/cma.
j.
issn.
0253-2727.
2020.
11.
002.
[3] Red blood cell disease (anemia) group of Chinese Society of Hematology.
Chinese expert consensus on diagnosis and treatment of aplastic anemia (2017 edition) [J].
Chinese Journal of Hematology, 2017, 038(001):1-5.
[4] https://nejmqianyan.
cn/article-info?permalinks=YXQYoa2109965&sg=AbW1NGsHw3NxPd6F.
[5] Townsley DM, Scheinberg P, Winkler T, et al.
Eltrombopag added to standard immunosuppression for aplastic anemia.
N Engl J Med 2017; 376: 1540-50.
[6] Peffault de Latour R, Kulasekararaj A, Iacbelli S, et al.
Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation[J].
Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.
N Engl J Med.
2022 Jan 6;386(1):11-23.
doi: 10.
1056/NEJMoa2109965.
PMID: 34986284.
[7] Antonio M.
Risitano on behalf of the RACE team, EBMT 2021, SAA working party session.
MCC No.
REV2201833 is valid on 2023-01-12, and the information expires and is deemed invalid
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The content of this article is for reference only by professionals such as medical and health care professionals
.

This indication has not been approved in China, and the relevant content is for academic exchange only
.

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