Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia

Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia

  • Post category:Hematology
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Acquired aplastic anemia (AA) is a rare, life-threatening condition in children that results from immune-mediated destruction of stem and progenitor cells in the bone marrow. Standard treatments include allogeneic hematopoietic stem cell transplantation or immunosuppressive therapy with hATG and CsA, but these options have limitations. One potential way to improve treatment outcomes is to influence stem cell function, and previous studies have shown that eltrombopag (ELTR), a small molecule TPO agonist, can increase platelet production and induce hematologic responses in adult patients with severe AA. To directly evaluate the role of ELTR in children with severe AA, a randomized trial was initiated. The results showed that adding ELTR to standard IST with hATG and CsA significantly improved overall response rates and event-free survival compared to IST alone, without an increase in adverse events. This suggests that ELTR may be a promising addition to standard therapy for children with severe AA.


This study is an open-label, investigator-initiated, randomized, prospective multicenter trial aimed at evaluating the efficacy and safety of adding eltrombopag to standard immunosuppressive therapy for children and adolescents with severe aplastic anemia. Patients aged 2 to 18 years with previously untreated SAA without matched sibling donors were eligible. Patients were either treatment-naïve or previously treated with cyclosporine or granulocyte-stimulating factor (G-CSF) for <1 month. The primary endpoint of this study was the overall response rate at 4 months from treatment initiation, defined as the proportion of patients who achieved either a complete response or partial response. The key secondary endpoints included platelet count, neutrophil count, and hemoglobin level at 4 months; cumulative incidence of response and complete response; time to response; tolerability and toxicities of the treatment; overall survival (OS); EFS; cumulative incidence of relapse; clonal evolution; and evolution into clinical paroxysmal nocturnal hemoglobinuria.



This is a description of a study involving 100 pediatric patients, randomized into two groups, to compare standard IST treatment with ELTR+IST treatment. The study found no significant differences in the demographic and baseline characteristics of the patients, as well as the administration of G-CSF between the two groups. The median follow-up period for all patients was 2.19 years.

Hematological response

The experimental group had a significantly better hematologic response at 2 months, with higher ANC, platelet count, and transfusion independence. However, at 4 months, only the ANC was significantly higher in the experimental group. The ELTR + IST group had a higher ORR and CR rate than the IST group, with a significant difference in CR rate at 4 months. Patients with SAA in the ELTR + IST group had a significantly higher ORR than those in the IST group, but there was no difference in patients with vSAA. The ELTR + IST group showed a trend toward a faster response to PR, but the time to CR was similar in both groups. Discontinuation of CsA was similar between the groups for patients with OR who had no events.

Predictors of response

The adjusted odds ratios of response evaluated in multivariate logistic regressions separately for OR and CR. Only a higher initial ANC and PNH-negative status were significantly related to a higher ORR. For CR, the addition of ELTR to standard IST, higher initial ANC, and younger (2 to 5 years) and older (13 to 18 years) age of children were significantly correlated with the CR.

Adverse events (AEs)

The study found that both treatment groups had acceptable toxicities, with liver test abnormalities and skin hyperpigmentation observed more frequently and severely in the ELTR + IST group. There were no severe cutaneous eruptions, thrombotic events, or cataracts noted. Infectious complications and febrile neutropenia occurred in similar proportions in both groups. Two serious adverse events in the ELTR + IST group considered unrelated to ELTR led to early discontinuation of the drug, and liver test abnormalities were the only ELTR-related AEs that led to interruptions or discontinuation of ELTR treatment. The feasibility of treatment per protocol in the ELTR + IST group was relatively high, with a median cumulative dose of ELTR for 120 days per patient of 204 mg/kg and a median duration of ELTR treatment over 120 days of 99 days. The 4-month mortality in the study was 1%.

Long-term outcomes

Overall survival

There were 4 deaths in the ELTR + IST group: 1 patient died on day 30 from sepsis while on treatment, and 3 nonresponders died due to complications after HSCT. Three patients died in the IST group: 1 nonresponder died due to fatal sepsis, and 2 nonresponders died due to complications after HSCT. The estimated 3-year OS was comparable in both treatment groups: 91% in the IST group vs 89% in the ELTR + IST group (P = .673).


The study found that both treatment groups had acceptable toxicities, with liver test abnormalities and skin hyperpigmentation being more frequent and severe in the ELTR + IST group. There were no significant differences in infectious complications and febrile neutropenia between the groups. The cumulative incidence of relapse was comparable in both groups, with 24% of responders in the ELTR + IST group relapsing compared to 19% in the IST group. Among the relapsed patients, some achieved a response with a second course of treatment, while others underwent hematopoietic stem cell transplantation.

Nonresponders and second-line crossover treatment

Six nonresponders, two in the ELTR + IST group and four in the IST group, underwent HSCT as a second-line treatment. 12 of 16 nonresponders in the ELTR + IST group and 18 of 23 in the IST group received a second course of hATG/CsA with or without ELTR. At the 6-month response assessment, 11 of 18 initial ELTR(-) patients achieved a response compared with only 2 of 12 initial ELTR(+) patients. 15 nonresponders (9 in ELTR + IST, 6 in IST) underwent HSCT as the third line of treatment.

Clonal evolution

The study did not report any cases of myelodysplastic syndrome or acute myeloid leukemia after a median follow-up of 2.28 years. There were 3 cases of cytogenetic abnormality, with one patient considered clinically significant due to refractoriness to standard treatment. Two patients developed transient abnormalities and achieved a CR. No cases of clinical hemolytic PNH were reported in any treatment group, and follow-up evaluations for PNH status at 4 and 12 months after the start of treatment were conducted.


A randomized study suggests that the addition of ELTR to IST as a first-line treatment for pediatric patients with SAA improves hematological response and accelerates ANC and CR rates. The combination is particularly effective in patients with SAA and ANC ≥0.2 × 109/L. Adding ELTR to upfront IST can identify early nonresponders with profound residual stem cell deficiency who require HSCT. However, the current algorithm of SAA treatment in children remains HSCT from MSD as the first-line option, and ELTR with IST is effective as a second-line treatment for patients who do not respond to the first-line IST.



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