Romiplostim for aplastic anemia: beyond an eltrombopag alternative

The combination of anti-thymocyte globulin (ATG), cyclosporine (CsA), and eltrombopag (EPAG) is widely regarded as the standard first-line therapy for patients with severe aplastic anemia (SAA) who are ineligible for allogeneic hematopoietic stem cell transplantation from an HLA-matched sibling donor.¹ In adult patients, the addition of EPAG has been shown to increase both the response rate at six months to ATG plus CsA and the failure-free survival rate at two years by 20-30%. However, this benefit has not been consistently observed in pediatric patients, highlighting an ongoing unmet need for children with SAA who lack a matched donor.^2,3

Romiplostim (ROMI), a thrombopoietin receptor agonist (TPO-RA), has primarily been used in the treatment of immune thrombocytopenia (ITP), particularly in patients refractory to EPAG. Although some patients with EPAG-refractory ITP respond to ROMI, the thrombopoietic potential of the two TPO-RA is generally considered comparable. Since the initial report from the National Institutes of Health group in the United States demonstrated the efficacy of EPAG in SAA patients refractory to immunosuppressive therapy (IST),⁴ studies have been exploring the therapeutic efficacy of ROMI in this context.

An initial French study using a ROMI dose of up to 10 μg/kg per week showed a limited efficacy.⁵ In contrast, a phase II/III trial conducted in Japan and Korea used a higher dose (20 μg/kg/week) in IST-refractory patients and demonstrated a response rate of 84% at week 27 in at least one hematopoietic lineage.⁶ Subsequently, the efficacy of ROMI in patients refractory to the maximum dose of EPAG (100 mg/day) was evaluated in Japan and China. Table 1 summarizes four studies that reported similar response rates of approximately 70%, suggesting that ROMI at 20 μg/kg/ week may exert a more potent hematopoietic effect than EPAG at 100 mg/day, which is considered equivalent to 200 mg/day, in Caucasian populations.

Given these encouraging results, pediatric hematologists have begun to explore the use of ROMI in treatment-naïve pediatric patients with SAA. In this issue of Haematologica, Bordbar et al. report remarkably high overall response rates (ORR) of 89.5% at week 27 and 86.7% at week 40, with minimal toxicities, in 19 pediatric patients with SAA treated with ATG, CsA, and ROMI (median ROMI dose: 12 μg/kg/week).⁷ These results are notably higher than the previously reported 6-month ORR in the 60% range among pediatric patients treated with ATG, CsA, and EPAG at six months,^2,3 and even surpass the 68% ORR observed in adult patients treated with the same regimen.¹ Supporting evidence comes from a recent study conducted in Japan, Korea, and Taiwan, which reported an ORR of 87% at week 27 in 17 patients (12 with SAA and 5 with non-severe AA) treated with ATG, CsA, and ROMI, despite the use of rabbit-derived ATG.⁸ Although a direct comparison of ROMI and EPAG in SAA is needed to determine their superiority, these findings suggest that ROMI (20 μg/kg/week) may more effectively increase the response to ATG and CsA than EPAG (100 mg/day) in patients with SAA.

Table 1.Efficacy of romiplostim in patients refractory to eltrombopag.

Figure 1.Proposed mechanism of thrombopoietin receptor agonist-mediated enhancement of response to anti-thymocyte globulin plus cyclosporine in severe aplastic anemia. (A) In patients treated with anti-thymocyte globulin (ATG) + cyclosporine (CsA) alone, while some HLA class I allele-lacking (HLA[-]) hematopoietic stem cells (HSC) evade immune attack and survive, their expansion is limited, resulting in incomplete hematopoietic recovery. (B) In patients treated with thrombopoietin-receptor agonist (TPO-RA) in addition to immunosuppression, HLA(-) HSC not only escape immune attack but also undergo marked expansion, leading to improved hematopoiesis. TPO-RA: thrombopoietin receptor agonist.

Eltrombopag, a small-molecule TPO mimetic, stimulates hematopoietic stem cell (HSC) proliferation by binding to the transmembrane domain of the TPO receptor and entering the cells independently of the receptor. In contrast, ROMI is a fusion protein composed of an IgG Fc fragment and a peptide that targets the extracellular domain of the TPO receptor, exerting its effect exclusively via receptor binding. The thrombopoietic effect of ROMI at a dose of 10 μg/kg/week is roughly comparable to that of EPAG at 50 mg/day in Japanese patients with ITP. Why, then, does ROMI at 20 μg/kg/week appear more effective than EPAG at 100 mg/day in patients with AA?

One plausible explanation may lie in the pharmacokinetics. Subcutaneously administered ROMI reaches the bone marrow without degradation by digestive enzymes and is thought to persist at a relatively high concentration in the bone marrow microenvironment. Conversely, the oral formulation of EPAG is more susceptible to digestive and dietary effects. Additionally, EPAG may have a shorter half-life in children owing to increased metabolic clearance, resulting in lower bone marrow drug levels. It is also possible that ROMI stimulates primitive HSC more effectively by inducing molecular mechanisms that involve RHOA signaling.⁹

The precise mechanism by which TPO-RA enhance ORR in SAA remains unclear. If their benefit is derived solely from stimulating residual healthy HSC, the hematologic response would not be expected to persist after discontinuation of the TPO-RA, especially given that ATG plus CsA is not fully immunoablative and that the T-cell-mediated attack on HSC likely persists in a substantial proportion of patients (Figure 1A). However, in clinical practice, hematologic responses are often durable, lasting many years, or even lifelong, without continued CsA maintenance.

Recent studies have revealed that HSC lacking the expression of HLA class I due to chromosome 6p loss of heterozygosity or inactivating mutations in HLA genes are detectable in nearly 50% of patients with AA at the time of their diagnosis.¹⁰ These immune-evasive HSC can escape T-cell-mediated destruction, but they initially fail to support hematopoiesis unless stimulated by agents such as TPORA. During this delay, patients are at risk of life-threatening infections following ATG therapy. The concomitant use of TPO-RA may promote hematologic recovery by supporting the proliferation of these immune-escape HSC (Figure 1B). ROMI may offer a unique advantage over EPAG in facilitating escape hematopoiesis when used in combination with ATG and CsA.

Footnotes

• Received August 13, 2025
• Accepted August 27, 2025

Correspondence

S. Nakao snakao8205@staff.kanazawa-u.ac.jp

Disclosures

The author reports receiving honoraria for lectures from Kyowa Kirin and Novartis.