Avatrombopag, a promising novel thrombopoietin receptor agonist for refractory/relapsed/intolerant non-severe aplastic anemia: a phase 2 single-arm clinical trial

Abstract

Introduction: The therapeutic options for thrombocytopenia in non-severe aplastic anaemia (NSAA) are limited. Avatrombopag (AVA) is prescribed for thrombocytopenic diseases but not for NSAA.

Methods: Herein, we conducted a phase 2, non-randomized, single-arm trial to explore the efficacy and safety of AVA in refractory/relapsed/intolerant NSAA. AVA dose was initiated at 20 mg/d and titrated to a maximum of 60 mg/d. The primary endpoint was the haematological response at 3 months.

Results: Twenty-five patients were analyzed. The overall response rate (ORR) at 3 months was 56% (14/25), with 12% (3/25) achieving a complete response (CR). At a median follow-up of 7 (3-10) months, the OR and CR rates were 52% and 20%, respectively. Responders had a shorter duration of diagnosis of AVA administration than non-responders (10 (6-80) vs 37 (6-480) months, p = 0.027) and belonged to the relapsed/intolerant NSAA type (71% vs 27%, p = 0.047); 44% (8/18) patients previously treated with eltrombopag before enrollment responded at 3 months, with an average prior eltrombopag dose of median 72.5 (50-100) mg/d and an average AVA dose for a response of median 43.5 (20-60) mg/d. 3-month ORR had no significant correlation with eltrombopag exposure (p = 0.09), prior eltrombopag length (R²=0.11), or cumulative eltrombopag dose (R²=0.30). Only one patient relapsed after stopping AVA for 1 month. No serious AVA-related side effects or clone evolution were detected.

Conclusion: AVA is effective and well-tolerated in NSAA patients who are refractory, relapsed, or intolerant to CsA/tacrolimus ± eltrombopag. Earlier treatment and relapsed/intolerant AA may show a better short-term response rate. More studies are needed to define the optimal dose and the long-term efficacy (NCT04728789).

Keywords: Non-severe aplastic anemia; avatrombopag; efficacy; side effects; switch.

Figure 1.

The CONSORT flow diagram. 30 patients were assessed and 1 was excluded because of developing secondary MDS from AA. Twenty-nine eligible patients were enrolled and allocated to receive AVA, as the intention-to-treat group. Four patients were treated with AVA for less than two months, either due to loss of follow-up (n = 3) or withdrawal of consent (n = 1). Twenty-five patients were included in the efficacy analysis.

Figure 2.

Venn diagrams presenting the number of patients with the response for one or more lineages at 3 months (left) and last follow-up (right) at 3 months, 7 patients showed improvement in one lineage, 3 in two lineages, and 4 in three lineages. At a median of 7 (3–10) months follow-up, 11 patients showed a platelet response; 9 showed a haemoglobin response, and 7 showed a neutrophil response.

Figure 3.

The longitudinal measurement of platelet (PLT, A), haemoglobin (HGB, B), and neutrophil (NEU, C) in responders. At 3 months, 44% (11/25) patients showed platelet response, 37% (7/19) showed haemoglobin response, and 54% (7/13) showed neutrophil response. At 6 months, 58% (7/12) patients showed platelet response, 55% (6/11) showed haemoglobin response, and 83% (5/6) showed neutrophil response. At the last follow-up, 44% (11/25) of patients showed platelet response. 47% (9/19) of patients showed haemoglobin response. 54% (7/13) of patients showed a neutrophil response. One patient who achieved PR after 2-months of AVA treatment and maintenance for 1 month (Figure 3(A), patient no. 19) relapsed after 1 month of stopping AVA.

Figure 4.

Relationship between prior eltrombopag (EPAG) and 3-month overall response rate (ORR) to avatrombopag (AVA). 18 (72%) of the 25 patients were previously treated with EPAG for 8 (1–36) months at 72.5 (25–100) mg/d dosage; 44% (8/18) responded to AVA at 3 months. (A) Prior length of using EPAG showed no significant linear relationship with the 3-month ORR of AVA (R²=0.11). (B) There is no significant correlation between the previous cumulative EPAG dose and the 3-month ORR for AVA (R²=0.30).