Iron Chelation of Hetrombopag in Aplastic Anemia: A Post Hoc Analysis of a Phase II Study

Iron overload is a significant feature of patients with aplastic anemia. Most SAA patients depend on red blood cell transfusions, resulting in secondary iron overload, especially IST-refractory SAA (rSAA) patients. In a previous study, up to 45.8% of patients with aplastic anemia with iron overload achieved hematologic response after iron chelation therapy, which suggests that iron chelation may restore hematopoietic function in patients with iron overload. Hetrombopag is the only CFDA-approved thrombopoietin receptor agonist (TPO-RA) used for SAA in China. This drug is a small-molecule non-peptide TPO-RA, and its iron chelation domain is like that of eltrombopag. Eltrombopag is a potent iron chelator that decreases cellular iron levels and further enhances iron mobilization with deferasirox. We speculated that hetrombopag also affects iron chelation. Thus, we conducted a post hoc analysis of the clinical trial data to evaluate the impact of hetrombopag on iron metabolism in patients with SAA.

Thirty-five patients, who had available longitudinal data on serum ferritin (SF) levels from the clinical trial of a prospective, multicentre, single-arm, open-label, phase II clinical study (NCT03557099) evaluating the safety and efficacy of hetrombopag olamine tablets in IST-refractory SAA patients, were included in this study. There were 23 males and 12 females with a median age of 45 (19-62) years. The median SF level at baseline was 1335.7 (109.4-9696) ng/ml. Moreover, 24 patients (68.6%) had an SF level ≥ 1000 ng/ml, seven patients had an SF level of 500-999 ng/ml, and four patients had an SF level < 500 ng/ml.

At 18 weeks, the median SF level was 1162.1 (5.4-7374.0) ng/ml, decreased from baseline of 1335.7 (109.4-9696) ng/ml (Z = -2.408, P = 0.016). The median decrease was by 18.1% (median ΔSF 230.8ng/ml). Additionally, 18 patients (51.4%) met the criteria for a decrease in SF, with a median decline of 49.0 (18.1-95.5) % from the baseline (median ΔSF 917.2ng/ml, range from 104.0 to 7030.0 ng/ml). Among the 24 patients with iron overload, the median SF level decreased by 15.7% (median ΔSF 395.8ng/ml). Three out of four patients whose baseline SF level was < 500 ng/ml showed decreased SF levels (283.9 ng/ml to 133.3 ng/ml; 109.4 ng/ml to 5.4 ng/ml; and 322.9 ng/ml to 14.7 ng/ml). Finally, two patients developed iron deficiency.

SF levels were evaluated in 21 cases at 52 weeks. The median SF levels were similar between 18 and 52 weeks (762.9 ng/ml vs. 850.3 ng/ml, Z = -0.539, P = 0.590). Only two patients (9.5%) showed a further decrease in SF, and both had iron overload at baseline. Twelve patients had long-term SF data (> 100 weeks) and were still on hetrombopag treatment. The median SF value was lower compared to that of 52 weeks (845.4ng/ml vs. 1053.4 ng/ml, Z = -2.275, P = 0.019). In addition, a decrease in SF was found in 75.0% of hematologic responders and 31.6% of non-responders. Among the 24 patients with iron overload, 12 had decreased SF levels by up to 51% of the baseline.

In conclusion, hetrombopag has a powerful and rapid iron chelation effect. SAA patients with iron overload can obtain more benefits than expected under the dual impact of TPO-RA and iron chelation of hetrombopag. However, for SAA patients without iron overload, hetrombopag may cause iron deficiency. Therefore, SF should be monitored routinely throughout treatment with hetrombopag, especially in the early stage of treatment.

Chen:Takeda Pharmaceutical Company Limited: Research Funding, Speakers Bureau.