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

Abstract

We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin (hATG) and cyclosporin A (CsA) with (n = 49) or without (n = 49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR + IST and IST groups was similar (65% vs 53%; P = .218); however, the complete response (CR) rate was significantly higher in the ELTR + IST group (31% vs 12%; P = .027). In severity subgroups, the ORR was 89% vs 57% (P = .028) in favor of IST + ELTR in SAA, but it did not differ in patients with vSAA (52% vs 50%; P = .902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared with 17% of initial ELTR(+) patients (P = .016). No significant difference in ELTR + IST and IST groups was observed in the 3-year overall survival (OS) (89% vs 91%; P = .673) or the 3-year event-free survival (EFS) (53% vs 41%; P = .326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. This trial was registered at Clinicaltrials.gov as #NCT03413306.

Graphical abstract

Figure 1.

Cumulative incidence of hematologic response by treatment group and depending on theseverity ofAA. (A) Cumulative incidence of OR by treatment group. (B) Cumulative incidence of CR by treatment group. (C) Cumulative incidence of OR in SAA (ANC ≥0.2 × 10⁹/L) patients by treatment group. (D) Cumulative incidence of OR in vSAA (ANC <0.2 × 10⁹/L) patients by treatment group. Shaded areas are 95% CIs. Competing events included death. The start of the second-line treatment with hATG/CsA ± ELTR and HSCT was considered censoring. P values are given for the 4-month point. The cumulative incidence of the overall response at 4 months was 65% (95% CI, 52-79) in the ELTR + IST group and 54% (95% CI, 40-69) in the IST group (A). The cumulative incidences for complete response at 4 months were 31% (95% CI, 18-44) and 13% (95% CI, 3-22), respectively (B). The cumulative incidence of the overall response at 4 months in patients with SAA (ANC ≥0.2 × 10⁹/L) was 89% (95% CI, 89-100) in the ELTR + IST group and 57% (95% CI, 35-79) in the IST group (C). The cumulative incidence of the overall response at 4 months in patients with vSAA (ANC <0.2 × 10⁹/L) was 52% (95% CI, 34-70) and 52% (95% CI, 33-72) (D).

Figure 2.

OS, EFS, and cumulative incidence of relapse of patients with SAA by treatment group.