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

Figures & data

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.

Table 1. Baseline characteristics of the intent-to-treat (n = 29) and the evaluable patients (n = 25).

Baseline, number or median (range)	Intent-to-treat	Evaluable
Sex	29	25
Male	14	13
Female	15	12
Age of enrolment, years	49 (20–75)	51 (20–75)
The median duration from dx to AVA, months	21 (6–480)	19 (6–480)
Type of aplastic anaemia
relapsed/intolerant	13	13
refractory	16	12
Lineage number of cytopenia
Cytopenia = 1	4	4
Cytopenia = 2	10	9
Cytopenia = 3	15	12
PLT, ×109/L	14 (1–30)	16 (1–30)
HGB, g/L	89 (41–166)	94 (41–166)
WBC, ×109/L	3.04 (1.41–8.01)	2.95 (1.41–8.01)
ANC, ×109/L	1.42 (0.39–4.86)	1.48 (0.39–4.86)
RET, ×109/L	39.4 (12.6–71.3)	43.5 (18.9–71.3)
ALT, U/L	11 (4–447)	11 (4–447)
Tbil, µmol/L	10.4 (5–30.6)	11.6 (5–30.6)
Cr, µmol/L	80 (41–135)	80 (41–135)
Fer, ng/mL	547 (23–37,149)	547 (23–37,149)
PNH ≥ 1%	3	3
BM cellularity, %	26 (8–39)	28 (8–39)
Length of EPAG treatment, months*	8 (1–36)	8 (1–36)
Average EPAG dose, mg/d	75 (22.9–100)	72.5 (25–100)
Cumulative EPAG dose, mg	19,500 (750–57,750)	19,500 (750–54,000)
Prior CsA/FK506, months	8 (4–129)	6 (4–129)

*7 did not expose to EPAG.

AVA: avatrombopag; dx: diagnosis; EPAG: eltrombopag; CsA: cyclosporin A; FK506: tacrolimus; PLT: platelets; HGB: hemoglobin; ANC: absolute neutrophil count; WBC: white blood cells; RET: reticulocyte; ALT: alanine aminotransferase; TBil: total bilirubin; Cr: creatine; Fer: ferritin; PNH: paroxysmal nocturnal hemoglobinuria; BM: bone marrow.

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.

Table 2. Comparisons of baseline characteristics between responders and non-responders.

Baseline	Responders n = 14	Non-responders n = 11	p-value
Sex			0.11
Male	5	8
Female	9	3
Age of enrollment, years	48.5 (20–67)	51 (20–75)	0.64
Median duration from dx to AVA, months	10 (6–80)	37 (7–480)	0.027
Type of aplastic anemia			0.047
Relapsed/intolerant	10	3
Refractory	4	8
Lineage number of cytopenia			0.18
Cytopenia = 1	2	2
Cytopenia = 2	3	6
Cytopenia = 3	9	3
PLT, ×109/L	15 (2–30)	18 (1–29)	0.89
HGB, g/L	90.5 (52–166)	109 (41–134)	0.78
WBC, ×109/L	2.785 (1.41–5)	3.15 (2.05–8.01)	0.31
ANC, ×109/L	1.395 (0.39–3.51)	1.64 (0.91–4.86)	0.46
RET, ×109/L	45.2 (18.9–71.3)	43.4 (35.2–51.6)	0.87
ALT, U/L	10.5 (6–118)	12 (4–447)	0.32
Tbil, µmol/L	9 (5–16.8)	13.4 (7.1–30.6)	0.085
Cr, µmol/L	72 (41–107)	89 (54–135)	0.037
Fer, ng/mL	348.5 (23–1736)	1008 (82–37,149)	0.37
PNH ≥ 1%	2	1	1.00
BM cellularity, %	27.5 (9–39)	28 (8–37)	0.78
Length of EPAG treatment, months	5.5 (1–36), n = 8	8.5 (1–27), n = 10	0.89
Average EPAG dose, mg/d	72.5 (50–100)	62.5 (25–100)	0.68
Cumulative EPAG dose, mg	13,500 (1875–54,000)	21,000 (750–49,500)	0.86
Prior CsA/FK506, months	6 (4–36)	11 (5–129)	0.31
Follow-up, months	7 (3–10)	8.5 (3–10)	0.39

AVA: avatrombopag; dx: diagnosis; EPAG: eltrombopag; CsA: cyclosporin A; FK506: tacrolimus; PLT: platelets; HGB: hemoglobin; ANC: absolute neutrophil count; WBC: white blood cells; RET: reticulocyte; ALT: alanine aminotransferase; TBil: total bilirubin; Cr: creatine; Fer: ferritin; PNH: paroxysmal nocturnal hemoglobinuria; BM: bone marrow.

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).

Data availability statement

Data are included in Supplementary files. The full study protocol can be obtained upon a reasonable request to the corresponding author.