Abstract
Background Incorporating thrombopoietin receptor agonists (TPO-RAs) into standard immunosuppressive therapy (IST) has significantly improved both the hematologic response rate and quality of remission in treatment-naïve patients with severe aplastic anemia (SAA). Romiplostim N01, a long-acting TPO-RA, has shown promising results in refractory aplastic anemia, achieving an overall hematologic response rate of 84%, with platelet responses in 65% of patients. Approximately 70% of patients experienced some degree of hematologic improvement within 3 months, highlighting its potential for frontline use. We therefore designed a single-arm, phase II clinical trial to evaluate the efficacy and safety of first-line romiplostim N01 in combination with intensified IST in patients with severe or very severe aplastic anemia (NCT 06613880).
Methods This study employed Simon's optimal two-stage design to estimate the sample size. The primary endpoint was overall response rate (ORR) at week 27. Historical ORR for ATG plus cyclosporine is 45%; the expected ORR with the addition of romiplostim N01 is 65%. With a one-sided alpha of 0.05 and 80% power, 43 patients were required. Considering a 10% of drop-out rate, the final sample size is 48. The screening period was up to 4 weeks. Treatment consisted of porcine ATG (pALG) 25 mg/kg/day on days 1-5, continuous cyclosporine 3-5 mg/kg/day, and romiplostim N01 starting at 10 μg/kg/week on day 1, titrated up to 20 μg/kg/week based on platelet count and clinical response (in 5 μg/kg increments). Secondary endpoints included superior response (defined as HGB >80 g/L and PLT >50×10⁹/L), ORR and complete response (CR), time to hematologic response, and incidence of adverse events.
Results A total of 48 patients were enrolled: 36 with SAA (75%) and 12 with very severe aplastic anemia (VSAA). One VSAA patient died of bacterial sepsis 3 days after pALG initiation, three patients were lost to follow-up at week 4, week 6 and week 22, respectively. Among the 45 evaluable patients at 3 months, the ORR was 80%, with a CR rate of 24.4% and 66.7% achieving superior responses. Among 34 evaluable SAA patients, 88.2% achieved hematologic response, including 29.4% with CR. In the VSAA subgroup (n=11), 54.5% achieved response and 9.1% achieved CR.
At 6 months, 37 patients were evaluable: the ORR was 86.5%, CR rate 40.5%, and 86.4% achieved superior responses. The median time to hematologic response was 7.5 weeks (range: 4–20). Among 26 evaluable SAA patients, 92.3% achieved hematologic response, including 42.3% with CR. In the VSAA subgroup (n=11), 72.7% achieved response and the CR rate increased to 36.4%.
Grade≥3 adverse events were reported in 9 patients, including infections (10.4%), allergic reactions (8.3%), liver dysfunction (2.1%), and acute coronary syndrome (2.1%).
Conclusions First-line romiplostim N01 combined with intensified IST demonstrates high efficacy, rapid onset of response, and favorable remission quality in patients with SAA/VSAA, supporting its promising therapeutic potential.
Keywords: Aplastic anemia, Romiplostim N01, Immunosuppressive therapy, Hematologic response
