海曲泊帕联合用药治疗免疫性血小板减少症中的临床研究进展

doi:10.12092/j.issn.1009-2501.2026.03.010

摘要/Abstract

摘要：

免疫性血小板减少症（immune thrombocy‐topenia，ITP）是一种由多种机制共同参与的获得性自身免疫病，导致血小板破坏和巨核细胞、血小板生成受损，主要表现为血小板水平下降和出血倾向，严重影响患者的生活质量和预后。ITP的治疗以提升血小板计数（platelet count，PLT），降低致命性出血的发生率以及改善患者生活质量为目标。为了提升疗效，减少不良反应，血小板生成素受体激动剂（TPO-RAs）的出现促使ITP的治疗转向联合治疗。海曲泊帕（Hetrombopag）是一种新型的口服二代小分子、非肽类TPO-RAs，可与血小板生成素受体（TPO-R）的跨膜区相结合，刺激巨核细胞增殖和分化，促进血小板生成。海曲泊帕与其他药物［糖皮质激素、重组人血小板生成素（rhT‐PO）与环孢素A］联合治疗ITP可以实现多靶点的治疗，通过整合不同药物的作用机制，能够更全面地干预ITP的发病过程，从而提高治疗效果，故本文就海曲泊帕联合用药在治疗ITP中的临床研究进展作一综述。

关键词: 海曲泊帕, 免疫性血小板减少症, 联合用药, 糖皮质激素, rhTPO, 环孢素A

Abstract:

Immune thrombocytopenia (ITP) is an acquired autoimmune disease involving multiple mechanisms, which leads to platelet destruction and macrocytosis and impaired platelet production, mainly manifested as decreased platelet levels and a tendency to bleed, which seriously affects the quality of life and prognosis of patients. Treatment of ITP aims to increase platelet count (PLT), reduce the incidence of fatal bleeding, and improve quality of life. To improve efficacy, reduce adverse reactions and the advent of thrombopoietin receptor agonists (TPO-RAs) prompted a shift in ITP treatment to combination therapy. Hetrombopag is a novel oral second generation small molecule, non-peptide TPO-RAs that binds to the transmembrane domain of thrombopoietin receptor (TPO-R), stimulates megakaryocyte proliferation and differentiation, and promotes platelet production. Hetrombopag combined with other drugs (glucocorticoid, rhTPO and cyclosporine A) in the treatment of ITP can achieve multi-target treatment, through the integration of different drug mechanisms of action, can more comprehensively intervene in the pathogenesis of ITP, so as to improve the therapeutic effect, so this article reviews the clinical research progress of hetrombopag combination in the treatment of ITP.

Key words: hetrombopag, immune thrombocytopenia, combination drug, glucocorticoids, rhTPO, cyclosporine A

中图分类号:

R558.2

蒋双妙, 朱怀军, 李丹滢. 海曲泊帕联合用药治疗免疫性血小板减少症中的临床研究进展[J]. 中国临床药理学与治疗学, 2026, 31(3): 382-391.

Shuangmiao JIANG, Huaijun ZHU, Danying LI. Clinical research advances in the treatment of immune thrombocytopenia with hetrombopag in combination therapy[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(3): 382-391.

图/表 2

参考文献 41

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Drug		Hetrombopag ^{[16, 26]}	Eltrombopag ^[27-28]	Avatrombopag ^{[27, 29, 30]}	Romiplostim ^{[27, 29, 31]}
TPO receptor binding form		Transmembrane	Transmembrane	Transmembrane	Intracellular
Main mechanism of action		Binds to the transmembrane domain of the TPO receptor, activates the signaling pathway, and promotes the proliferation and differentiation of megakaryocytes.			Fc peptide fusion protein, simulates TPO binding to receptors to activate signaling pathways
Dietary Influence		Yes	Yes	No	No
Method of administration		Oral	Oral	Oral	Intravenous/subcutaneous injection
Drug transformation/metabolism		Mainly metabolized through multiple glucuronide transferases.	Mainly metabolized by CYP1A2, CYP2C8, UGT1A1 and UGT1A3.	Mainly metabolized by CYP2C9 and CYP3A.	Cleared by the reticuloendothelial system via neonatal Fc receptors on endothelial cells.
ITP efficacy	Effectiveness	The efficiency of HETROM-2.5 is 58.9%, and the efficiency of HETROM-5 is 64.3%.	The response rate for patients with newly diagnosed or persistent ITP is 90%, the complete response rate is 75.9%, and the overall response rate for chronic ITP is about 50%-88%.	Compared with placebo, the platelet response rate of avatrombopag (20 mg/d) on day 8 was 65.63%.	Romiplostim can rapidly improve PLT, with an effective rate of 74%-93%. After the third week, about 62% of patients were still effective.
ITP efficacy	Median Time to onset	1-2 weeks	1-2 weeks	1-2 weeks	1-2 weeks
Adverse events	Thrombotic events	0.6%	6%	7%	5.9%
	Myelofibrosis risk	0.6%	The incidence was 6% during the two-year follow-up.	-	About 6.9% of patients with myelofibrosis grade 2 or higher.
	Elevated liver enzymes (≥3 grades)	0.4%	2%	-	-
	Pigmentation	-	3%-5%	-	-
	Cataract	0.4%	7%	-	The incidence was 9% at 8-year follow-up.

Drug		Hetrombopag ^{[16, 26]}	Eltrombopag ^[27-28]	Avatrombopag ^{[27, 29, 30]}	Romiplostim ^{[27, 29, 31]}
TPO receptor binding form		Transmembrane	Transmembrane	Transmembrane	Intracellular
Main mechanism of action		Binds to the transmembrane domain of the TPO receptor, activates the signaling pathway, and promotes the proliferation and differentiation of megakaryocytes.			Fc peptide fusion protein, simulates TPO binding to receptors to activate signaling pathways
Dietary Influence		Yes	Yes	No	No
Method of administration		Oral	Oral	Oral	Intravenous/subcutaneous injection
Drug transformation/metabolism		Mainly metabolized through multiple glucuronide transferases.	Mainly metabolized by CYP1A2, CYP2C8, UGT1A1 and UGT1A3.	Mainly metabolized by CYP2C9 and CYP3A.	Cleared by the reticuloendothelial system via neonatal Fc receptors on endothelial cells.
ITP efficacy	Effectiveness	The efficiency of HETROM-2.5 is 58.9%, and the efficiency of HETROM-5 is 64.3%.	The response rate for patients with newly diagnosed or persistent ITP is 90%, the complete response rate is 75.9%, and the overall response rate for chronic ITP is about 50%-88%.	Compared with placebo, the platelet response rate of avatrombopag (20 mg/d) on day 8 was 65.63%.	Romiplostim can rapidly improve PLT, with an effective rate of 74%-93%. After the third week, about 62% of patients were still effective.
ITP efficacy	Median Time to onset	1-2 weeks	1-2 weeks	1-2 weeks	1-2 weeks
Adverse events	Thrombotic events	0.6%	6%	7%	5.9%
	Myelofibrosis risk	0.6%	The incidence was 6% during the two-year follow-up.	-	About 6.9% of patients with myelofibrosis grade 2 or higher.
	Elevated liver enzymes (≥3 grades)	0.4%	2%	-	-
	Pigmentation	-	3%-5%	-	-
	Cataract	0.4%	7%	-	The incidence was 9% at 8-year follow-up.

Drugs	Year of publication	Number of patients (observation/control group)	Treatment regimen/dose	Duration of treatment	ITP efficacy	Adverse events
Hetrombopag	2021^[26]	424 (168/171/85)	Observation group: HETROM-2.5/5, which can be gradually adjusted to a maximum of 7.5 mg/d according to PLT. Control group: Treatment with placebo.	44 weeks	After 8 weeks of treatment, the effective rate of the three groups was 58.9% vs.64.3% vs.5.9%. Patients had a sustainable platelet response through 24 weeks, with a response rate of 39.9% at ≥75% visits and a median duration of overall response of 49.7%.	Adverse event rates were 91.7% vs. 94.7% vs. 95.3%.
Hetrombopag	2023^[32]	29	Hetrombopag 2.5-7.5 mg was subsequently adjusted to the maximum dose of 7.5 mg/d according to PLT.	1 month	The total effective rate was 79.3%, and the median onset time of hetrombopag was 9 (3-15) days. For patients with severe ITP, the overall response rate was 75%.	One case of elevated transaminase occurred during the treatment, and the overall adverse reactions were safe and controllable.
Hetrombopag	2024^[34]	63	The dose of eltrombopag before conversion was 25-75 mg/d, and the dose of hetrombopag was 2.5-7.5 mg/d after conversion.	24 weeks	After switching to hetrombopag, 88.9% (56/63) of patients achieved platelet response. Before switching, the platelet response rates for patients with platelet counts below 30×10?/L and between 30×10?/L and 50×10?/L were 66.7% (8/12) and 88.9% (8/9), respectively.	Treatment-related adverse events occurred in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment.
Hetrombopag +prednisone	2024^[36]	40 (20/20)	Observation group: hetrombopag (2.5 mg/d) combined with prednisone (0.5 mg/d) Control group: prednisone (0.5 mg/d)	6 weeks	The proportions of patients with PLT≥50×10?/L and ≥30×10?/L were 90% vs. 50% and 90% vs. 65%, respectively.	Adverse event rate was 50% vs. 60%.
Hetrombopag +prednisone	2024^[37]	82 (41/41)	Observation group: hetrombopag (2.5 mg/d) combined with prednisone (60 mg/d) Control group: prednisone (60 mg/d)	3 months	The total effective rate of the two groups was 95.12% vs. 80.49%.	Adverse event rate was 14.64% vs. 7.32%.
Hetrombopag+dexamethasone	2023^[38]	60 (30/30)	Observation group: hetrombopag (2.5-5 mg/d) combined with dexamethasone (20 mg/d, ivgtt). Control group: dexamethasone (20 mg/d, ivgtt).	12 weeks	The total efficiency of the two groups: 93.33% vs. 73.33%.	Adverse event rate was 20.00% vs. 16.67%.
Hetrombopag+rhTPO	2023^[39]	20	Hetrombopag (5 mg/d) combined with rhTPO (300 U·kg^-1·d^-1)	28 days	15% of patients had a partial platelet response, and 85% had a complete platelet response. The median time to reach PLT levels of 30×10?/ L, 50×10?/L, and 100×10?/ L was 4.5, 6 and 7 days, respectively.	Two patients had abnormal liver function, all grade 1-2.
Hetrombopag+rhTPO	2023^[40]	255 (98/157)	Observation group: hetrombopag (2.5 mg/d) combined with rhTPO (300 U·kg^-1·d^-1) Control group: rhTPO (300 U·kg^-1·d^-1)	21 days	The total efficiency of the two groups was 79.59% vs. 66.88%, the cumulative endpoint rate was 81.32% vs. 68.68%, and the median effective time was 8 d vs. 10 d.	Adverse event rate was 11.22% vs. 9.55%.
Hetrombopag+CsA	2024^[41]	52 (26/26)	Observation group: hetrombopag (7.5 mg/d) combined with CsA (3-5 mg/kg, bid) Control group: dexamethasone (40 mg/d) combined with rhTPO (15000 U)	2-20 months	The total effective rate was 73% in both groups. At 14 and 28 days of treatment, PLT in the observation group was significantly higher than that in the control group.	Adverse event rate was 35% vs. 46 %.

Drugs	Year of publication	Number of patients (observation/control group)	Treatment regimen/dose	Duration of treatment	ITP efficacy	Adverse events
Hetrombopag	2021^[26]	424 (168/171/85)	Observation group: HETROM-2.5/5, which can be gradually adjusted to a maximum of 7.5 mg/d according to PLT. Control group: Treatment with placebo.	44 weeks	After 8 weeks of treatment, the effective rate of the three groups was 58.9% vs.64.3% vs.5.9%. Patients had a sustainable platelet response through 24 weeks, with a response rate of 39.9% at ≥75% visits and a median duration of overall response of 49.7%.	Adverse event rates were 91.7% vs. 94.7% vs. 95.3%.
Hetrombopag	2023^[32]	29	Hetrombopag 2.5-7.5 mg was subsequently adjusted to the maximum dose of 7.5 mg/d according to PLT.	1 month	The total effective rate was 79.3%, and the median onset time of hetrombopag was 9 (3-15) days. For patients with severe ITP, the overall response rate was 75%.	One case of elevated transaminase occurred during the treatment, and the overall adverse reactions were safe and controllable.
Hetrombopag	2024^[34]	63	The dose of eltrombopag before conversion was 25-75 mg/d, and the dose of hetrombopag was 2.5-7.5 mg/d after conversion.	24 weeks	After switching to hetrombopag, 88.9% (56/63) of patients achieved platelet response. Before switching, the platelet response rates for patients with platelet counts below 30×10?/L and between 30×10?/L and 50×10?/L were 66.7% (8/12) and 88.9% (8/9), respectively.	Treatment-related adverse events occurred in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment.
Hetrombopag +prednisone	2024^[36]	40 (20/20)	Observation group: hetrombopag (2.5 mg/d) combined with prednisone (0.5 mg/d) Control group: prednisone (0.5 mg/d)	6 weeks	The proportions of patients with PLT≥50×10?/L and ≥30×10?/L were 90% vs. 50% and 90% vs. 65%, respectively.	Adverse event rate was 50% vs. 60%.
Hetrombopag +prednisone	2024^[37]	82 (41/41)	Observation group: hetrombopag (2.5 mg/d) combined with prednisone (60 mg/d) Control group: prednisone (60 mg/d)	3 months	The total effective rate of the two groups was 95.12% vs. 80.49%.	Adverse event rate was 14.64% vs. 7.32%.
Hetrombopag+dexamethasone	2023^[38]	60 (30/30)	Observation group: hetrombopag (2.5-5 mg/d) combined with dexamethasone (20 mg/d, ivgtt). Control group: dexamethasone (20 mg/d, ivgtt).	12 weeks	The total efficiency of the two groups: 93.33% vs. 73.33%.	Adverse event rate was 20.00% vs. 16.67%.
Hetrombopag+rhTPO	2023^[39]	20	Hetrombopag (5 mg/d) combined with rhTPO (300 U·kg^-1·d^-1)	28 days	15% of patients had a partial platelet response, and 85% had a complete platelet response. The median time to reach PLT levels of 30×10?/ L, 50×10?/L, and 100×10?/ L was 4.5, 6 and 7 days, respectively.	Two patients had abnormal liver function, all grade 1-2.
Hetrombopag+rhTPO	2023^[40]	255 (98/157)	Observation group: hetrombopag (2.5 mg/d) combined with rhTPO (300 U·kg^-1·d^-1) Control group: rhTPO (300 U·kg^-1·d^-1)	21 days	The total efficiency of the two groups was 79.59% vs. 66.88%, the cumulative endpoint rate was 81.32% vs. 68.68%, and the median effective time was 8 d vs. 10 d.	Adverse event rate was 11.22% vs. 9.55%.
Hetrombopag+CsA	2024^[41]	52 (26/26)	Observation group: hetrombopag (7.5 mg/d) combined with CsA (3-5 mg/kg, bid) Control group: dexamethasone (40 mg/d) combined with rhTPO (15000 U)	2-20 months	The total effective rate was 73% in both groups. At 14 and 28 days of treatment, PLT in the observation group was significantly higher than that in the control group.	Adverse event rate was 35% vs. 46 %.

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