Romiplostim dose–response in patients with myelodysplastic syndromes

Aim

To characterize the romiplostim dose–response in subjects with low or intermediate-1 risk myelodysplastic syndromes (MDS) receiving subcutaneous romiplostim.

Methods

Data from 44 MDS subjects receiving subcutaneous romiplostim (dose range 300–1500 μg week⁻¹) were used to develop a pharmacodynamic model consisting of a romiplostim-sensitive progenitor cell compartment linked to the peripheral blood compartment through four transit compartments representing the maturation in the bone marrow from megakaryocytes to platelets. A kinetics of drug effect model was used to quantify the stimulatory effect of romiplostim on the proliferation of sensitive progenitor cells and pharmacodynamics-mediated disposition was modelled by assuming the kinetics of drug effect constant (k_DE) to be proportional to the change in platelet count relative to baseline.

Results

The estimated values (between subject variability) for baseline platelet count, mean transit time, and k_DE were 24 × 10⁹ l⁻¹ (47%), 9.6 days (44%) and 0.28 days⁻¹, respectively. MDS subjects had a shorter platelet lifespan (42 h) than healthy subjects (257 h). Romiplostim effect was described for responders (78%) and non-responders (22%). The average weekly stimulatory effect of romiplostim on the production rate of sensitive progenitor cells at baseline was 269% per 100 μg week⁻¹ for responders. Body weight, age, gender and race were not statistically related to romiplostim pharmacodynamic parameters. Visual predictive checks confirmed the model adequacy.

Conclusion

The time course of platelet counts in MDS subjects receiving subcutaneous administration of escalating doses of romiplostim was characterized and showed a linear dose–response for romiplostim responders to increase the platelet counts.     

Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura

The underlying problem in idiopathic thrombocytopenic purpura (ITP) has traditionally been recognized as accelerated platelet destruction. However, recent studies have provided evidence that the pathophysiology of ITP is more complex, and impaired platelet production has emerged as one of the mechanisms contributing to the thrombocytopenia. On these grounds, second-generation thrombopoietic agents have been used in clinical trials to stimulate platelet production in ITP patients who are not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin (TPO) but still bind and activate the TPO receptor. Studies have been completed for two TPO receptor agonists: romiplostim (formerly AMG 531) and eltrombopag (formerly SB497115). Romiplostim is a recombinant protein defined as a peptibody. Results of phase I-II trials published recently demonstrated that romiplostim given as a weekly subcutaneous injection for 1-6 weeks results in doubling of platelet counts and an increase to >50 x 10(9)/L in most treated patients with minimal adverse effects. Eltrombopag is an orally available, small organic compound. In a randomized, double-blind, placebo-controlled phase III trial, ITP patients were given daily oral treatment with placebo or eltrombopag 50 mg. Platelet responses were observed in 59% of eltrombopag-treated patients and in 16% of patients in the placebo arm. No significant adverse events were seen. Other thrombopoietic agents in development, such as AKR-501 (formerly YM 477), appear promising in healthy volunteers. Ongoing phase III clinical trials will reveal the potential of these agents in the management of ITP prior to splenectomy and for long-term maintenance therapy, as well as their relative benefit compared with standard of care treatment.     

大剂量甲泼尼龙和大剂量丙种球蛋白冲击治疗成人重症特发性血小板减少性紫癜短期疗效评估

目的观察大剂量甲泼尼龙（HDMP）和大剂量丙种球蛋白（HDIVIG）冲击治疗重症特发性血小板减少性紫癜（ITP）的短期疗效。方法 32例血小板〈10×10^9/L的成人重症ITP患者随机分成HDMP和HDIVIG两组。HDMP组18例,给予甲泼尼龙1.0g/d,连用3d,接泼尼松1.5mg/（kg·d）。HDIVIG组14例,给予丙种球蛋白0.4g/（kg·d）,连用3d,接泼尼松1.5mg/（kg·d）。治疗后7～10d测血小板数目。结果 HDMP组和HDIVIG组血小板上升至20×10^9/L需（4.1±1.8）天和（3.3±1.6）d。达50×10^9/L分别为（6.5±2.7）d和（5.9±2.5）d,差异均无统计学意义（P分别〉0.20和〉0.50）。结论大剂量甲泼尼龙和大剂量丙种球蛋白治疗成人重症ITP短期提升血小板疗效相似。甲泼尼龙相对廉价,可广泛使用。     

特发性血小板减少性紫癜患者血小板生成素及网织血小板的检测意义

目的探讨检测血小板生成素（TPO）浓度及网织血小板（RP）百分率在特发性血小板减少性紫癜（ITP）发病机制中的作用。方法选取我院50例ITP患者（ITP组）和30例体检正常者（对照组）的临床资料,应用夹心酶联免疫吸附试验测定2组TPO浓度;流式细胞术检测2组RP百分率。采用全自动血细胞分析仪检测外周血血小板计数;采用常规细胞染色显微镜下直接计数法检测骨髓巨核细胞数。结果ITP组和对照组的血小板计数分别为（30．65±18．34）×10^9／L和（222．60±45．32）×10^0／L,RP百分率分别为（28．11±14．08）％和（8．19±2．46）％,巨核细胞数分别为（132．58±73．95）个／4cm2和（20．10±7．64）个／4m2,2组间血小板计数、RP百分率、巨核细胞数比较差异均有统计学意义（均P〈0．05）,TPO浓度分别为（76．65±32．50）ng／L和（75．36±26．32）ng／L,2组比较差异无统计学意义（P〉0．05）。结论TPO浓度和RP百分率对提高ITP诊断水平及指导临床有一定的意义,可作为血小板减少性疾病鉴别诊断的有用指标。同时ITP患者TPO浓度的检测对于针对性应用促进血小板生成的TPO模拟物的治疗提供理论依据。     

Pharmacodynamics-mediated drug disposition (PDMDD) and precursor pool lifespan model for single dose of romiplostim in healthy subjects

The objective of this study was to characterize the pharmacokinetics and pharmacodynamics (PK-PD) of romiplostim after single-dose administration in healthy subjects. The mean serum romiplostim concentrations (PK data) and mean platelet counts (PD data) collected from 32 subjects receiving a single intravenous (0.3, 1 and 10 μg/kg) or subcutaneous (0.1, 0.3, 1, and 2 μg/kg) dose were fitted simultaneously to a mechanistic PK-PD model based on pharmacodynamics-mediated drug disposition (PDMDD) and a precursor pool lifespan concept. The two-compartment PK model incorporated receptor-mediated endocytosis and linear mechanisms as parallel elimination pathways. The maximal concentration of receptors (assumed to be proportional to the platelet count), the equilibrium dissociation constant, and the first-order internalization rate constant for endocytosis of the drug-receptor complex were 0.022 fg/platelet, 0.131 ng/mL, and 0.173 h?1, respectively. Romiplostim concentration stimulates the production of platelet precursors via the Hill function, where the SC?? was 0.052 ng/mL and S (max) was 11.2. The estimated precursor cell and platelet lifespans were 5.9 and 10.5 days, respectively. Model-based simulations revealed that the romiplostim exposure and the platelet response are both dependent on the dose administered and the baseline platelet counts. Also, weekly dosing produced a sustained PD response while dosing intervals ≥2 weeks resulted in fluctuating platelet counts. Thus, the mechanistic PK-PD model was suitable for describing the romiplostim PK-PD interplay (PDMDD), the dose-dependent platelet stimulation, and the lifespans of thrombopoietic cell populations.     

抗幽门螺杆菌治疗用于特发性血小板减少性紫癜的疗效观察

目的探讨抗幽门螺杆菌（HP）在特发性血小板减少性紫癜（ITP）治疗中的作用。方法145例HP阳性ITP患者根据血小板计数分为血小板小于50×10^9及血小板大于50×10^9两组。血小板小于50×10^9／LHP阳性患者95例,按人院顺序随机分为联合治疗组与单用糖皮质激素组。联合治疗组给予根除HP及糖皮质激素治疗,单用糖皮质激素组未给予根除HP治疗,其余治疗同联合治疗组。血小板大于50×10^9／LHP阳性、无明显出血征象者50例,按入院顺序随机分为抗HP治疗组与对照组。抗HP治疗组进行单纯正规抗HP治疗,对照组未用任何药物治疗,定期复查血常规。结果联合治疗组总有效率（92％）明显高于单用糖皮质激素治疗组（75％）（X2=5．01,P〈0．05）,2年内复发率（19％）明显低于单用糖皮质激素组（49％）（x2=9．69,P〈0．01）。单纯根除HP治疗对ITP患者有一定疗效。结论根除HP是合并HP感染的ITP患者行之有效的治疗方法。     

Romiplostim: a review of its use in immune thrombocytopenia

Romiplostim (Nplate?) is an Fc-peptide fusion protein (peptibody) that acts as a thrombopoietin receptor agonist; it has no amino acid sequence homology with endogenous thrombopoietin. This article reviews the clinical efficacy and tolerability of subcutaneous romiplostim in adults with immune thrombocytopenia (ITP), as well as summarizing its pharmacological properties. The efficacy of 12 or 24 weeks' therapy with subcutaneous romiplostim was compared with that of placebo in patients with ITP in three randomized, double-blind, multicentre, phase III trials. In the two 24-week trials, the durable platelet response rate (primary endpoint) was significantly higher with romiplostim than with placebo in both splenectomized and nonsplenectomized patients. In addition, the majority of romiplostim recipients were able to discontinue or reduce their concurrent ITP therapy, and romiplostim improved health-related quality of life (HR-QOL). In the 12-week trial in splenectomized or nonsplenectomized Japanese patients with ITP, the median number of weeks with a platelet response (primary endpoint) was significantly higher with romiplostim than with placebo. Two extension studies (with median durations of romiplostim treatment of 78 and 100 weeks) demonstrated that long-term therapy with romiplostim maintained platelet counts in the target range in patients with ITP. In a randomized, open-label, multicentre, 52-week, phase IIIb trial, romiplostim was more effective than the medical standard of care in nonsplenectomized patients with ITP who had received at least one prior ITP treatment. Significantly fewer patients receiving romiplostim versus the medical standard of care experienced treatment failure or required splenectomy (co-primary endpoints), and clinically meaningful improvements from baseline in HR-QOL scores were seen with romiplostim. Subcutaneous romiplostim was generally well tolerated in patients with ITP; in short-term trials, the majority of adverse events were of mild to moderate severity and appeared to be related to the underlying thrombocytopenia. The incidence of bleeding events of at least grade 3 severity did not significantly differ between romiplostim and placebo recipients, and was significantly lower with romiplostim than with the medical standard of care. Romiplostim did not appear to be associated with an increased risk of haematological malignancies or an increased risk of thrombotic events. Although binding antibodies against romiplostim or thrombopoietin developed in some romiplostim recipients, with neutralizing antibodies to romiplostim detected in two romiplostim recipients, antibodies cross reacting to thrombopoietin have not been detected. Romiplostim was associated with modest increases in bone marrow reticulin in some patients with ITP; reductions in reticulin were usually seen when romiplostim was discontinued. In conclusion, subcutaneous romiplostim is a valuable agent for use in patients with refractory chronic ITP.     

腹腔镜脾切除治疗术前血小板计数＜10×109/L的复发性原发免疫性血小板减少症的疗效

目的 探讨腹腔镜下脾切除术（LS）治疗血小板计数（PLT）＜10×109/L的复发性原发免疫性血小板减少症（ITP）的临床疗效。方法 回顾性分析我院 2006年 3月—2016年 6月期间行 LS治疗的 17例复发性 ITP患者的临床资料。男8例,女9例;平均年龄（42.18±15.70）岁,术前1 d PLT＜10×109/L,中位病程为2（1,5.5）年,伴有脾大者6例。结果 17例 ITP 患者均顺利完成 LS,手术时间（156.76±17.90）min,术中中位出血量 50（20,175）mL,术后住院时间（7.47±1.94）d。17例患者术前凝血酶原时间等凝血功能均未见明显异常,LS术中均未发生难以控制的出血,术后均未发生皮下气肿、感染、腹腔包裹性积液等并发症。LS术后短期内总体有效12例,包括完全反应者11例和部分反应者1例。术后1 d PLT≥100×109/L者术后有效率明显高于PLT＜100×109/L者（P＜0.05）,不同年龄、性别、病程、是否伴有脾大和术前免疫球蛋白封闭治疗等因素间术后有效率差异无统计学意义。结论 LS治疗 PLT＜10×109/L的复发性ITP患者安全、有效,术后1 d PLT可能成为预测LS治疗ITP短期疗效的指标。     

两种方法治疗成人重型特发性血小板减少性紫瘢的疗效对比

目的:探讨大剂量地寒米松与大剂量丙种球蛋白两种方法治疗成人重型特发性血小板减少性紫癜(ITP)的疗效.方法:对入院时外周血小板计数(PLT)<10×109/L且出血倾向明显105例重症ITP患者随机分为两组:大剂最地塞米松组(A组)54例,用地塞米松40mg/d连续口服4 d,强的松1 mg/kg体质量口服;大剂量丙种球蛋白组(B组)51例,丙种球蛋白0.4 g·kg-1·d连续静脉滴注5天,强的松1 mg/kg体质量口服,连续监测治疗效果.结果:大剂量地寒米松组(A组)和大剂量丙种球蛋白组(B组)的总有效率分别是70.4%和92.2%,两组差异有显著性(P<0.05).A组、B组PLT≥50×109/L时间分别为(3.8±1.2)天,(2.9±1.4)天;≥100×109/L时间分别为(6.5±1.8)天,(5.1±1.9)天;PLT的峰值(×109/L)分别为(320±69)×109/L,(351±120)×109/L.结论:大剂量丙种球蛋白升高血小板效果比大剂量地塞米松好,而且大剂量丙种球蛋白使PLT上升更迅速,峰值高,上升至正常稳定时间长.     

脾切除治疗特发性血小板减少性紫癜的疗效观察

目的观察脾切除治疗特发性血小板减少性紫癜（ITP）患者的疗效。方法对9例ITP患者在皮质激素治疗效果不佳、有皮质激素治疗禁忌、不能耐受皮质激素治疗或其他自身原因拒绝接受皮质激素治疗的情况下采用脾切除治疗。结果术后第1、4、7天血小板平均值由术前的35×10^9／L分别上升为98×10^9／L、179×10^9和235×10^9／L;术后随访半年以上,显效7例,总有效率88．9％。结论脾切除治疗仍是ITP患者值得推荐的一种方法,尤其是药物治疗无效、有禁忌或不能耐受药物治疗的患者。     

Plasma fibrinogen levels, leucocyte and platelet counts in male Zimbabwean hypertensives.

Plasma fibrinogen levels, leucocytes and platelets are among the many factors known to influence haemostasis. Impaired haemostatic processes in hypertension are thought to contribute to the other cardiovascular diseases seen in this condition. This study compares the level of plasma fibrinogen, and leucocyte and platelet counts between 17 male hypertensives and 24 male normotensives. The results for the hypertensives were: leucocyte count mean 5.45 x 10(9)/L, platelet count mean 234.7 x 10(9)/L, and plasma fibrinogen 4.13 g/L. The results for the normotensives were: leucocyte count mean 4.83 x 10(9)/L, platelet count mean 222.9 x 10(9)/L, and plasma fibrinogen 3.27 g/L. The hypertensives had higher plasma fibrinogen levels, and leucocyte and platelet counts compared to the normotensives, but this only reached statistical significance for the plasma fibrinogen levels (p < 0.025).     

Leukostasis associated with blood transfusion in acute myeloid leukaemia.

Three patients with acute myeloblastic leukaemia and blast cell counts greater than 100 X 10(9)/1 (100 000/mm3) died unexpectedly soon after blood transfusion. In two cases postmortem examination disclosed cerebral leukostasis. Analysis of the records from the MRC's fourth and fifth acute myeloid leukaemia trials showed that in the first week after diagnosis mortality was five times greater in patients with blast counts above 100 X 10(9)/1 than in patients with lower counts. Age and platelet count did not explain this excess. The mean haemoglobin concentration in the patients with high blast counts who died within the first week was 10.5 +/- 2.8 g/dl, which was significantly higher than that in the surviving group (7.6 +/- 2.4 g/dl). Only half the patients received chemotherapy within two days of diagnosis. Leukostasis is an important cause of early death in patients with high blast counts, and the increase in viscosity produced by transfusing to a haemoglobin concentration above 10 g/dl may lead to sudden deterioration. Transfusion to such concentrations should be avoided until the blast count has been reduced by early chemotherapy.     

依诺肝素钠诱导血小板减少症

1例63岁男性患者行二尖瓣和主动脉瓣置换术,术后第1天开始给予依诺肝素钠抗凝治疗（4000 U,2次/d皮下注射）。术前及术后第1天血小板计数均正常。术后第2天血小板计数为41×10^9/L,给予重组人白细胞介素11皮下注射（1.5 mg/次,1次/d）。术后第3天血小板计数为22×10^9/L,遂停用依诺肝素钠。术后第4、5天血小板计数分别为45×109/L、59×10^9/L。第6天复查,血小板计数为128×10^9/L。     

New treatments for idiopathic thrombocytopenic purpura: rethinking old hypotheses

Background: The efficacy of thrombopoietin (TPO) mimetics in patients with idiopathic thrombocytopenic purpura (ITP) reaffirms that impaired platelet production is an important mechanism. New strategies to reduce platelet destruction, like rituximab, are also effective. Objectives: To describe the efficacy and safety of rituximab and the TPO mimetics, romiplostim and eltrombopag, and how they relate to ITP pathogenesis. Methods: Narrative review summarizing full publications and meeting abstracts. Results/conclusions: A 4-week course of rituximab is associated with a platelet count response in 60% of patients with ITP, and durable responses have been observed. Subtle increases in infection have been reported. Romiplostim and eltrombopag are each associated with a 60 – 85% response while on treatment. Transient bone marrow reticulin with romiplostim and elevated liver enzymes with eltrombopag are rare side effects. The application of these agents in non-splenectomized patients requires further study.     

原发性免疫性血小板减少症的治疗进展

原发性免疫性血小板减少症是一种免疫介导的获得性血小板减少所致出血性疾病,其患者外周血小板计数＜100×10^9/L,但没有引起血小板减少的明显诱因或基础疾病。近年来,随着对此疾病发病机制的认识逐渐深入,在其治疗方面也有了很多新的进展。     

局部放射治疗对鼻咽癌患者血象的影响

目的:探讨局部放射治疗对鼻咽癌患者血象的影响.方法:对50例鼻咽癌患者予以SEMENT医用加速器外照射治疗,放疗期间每周行血常规检查并记录放疗剂量进行统计分析.结果:(1)白细胞平均值为6.0×109/L,中性粒细胞平均值为4.5×109/L,淋巴细胞平均值为0.72×109/L,红细胞平均值为4.4×1012/L,血红蛋白平均值为129.2 g/L,血小板平均值为210.1×109/L.白细胞第六周(约50Gy)开始下降明显达18.2%(P=0.000),淋巴细胞第一周明显下降达44.4%(P=0.000);血小板的变化以第四周(约30Gy)下降达低值,较放疗前减少12.4%(P=0.005),随后缓慢回升但无明显差异.结论:单纯局部放疗对鼻咽癌患者血象影响不大,但淋巴细胞对放射治疗较为敏感.     

米卡芬净致急性溶血反应并肾衰竭

1例76岁男性患者因肺部感染给予米卡芬净50 mg加入0.9%氯化钠注射液100 ml静脉滴注,1次/d。首次用药后90 min,患者出现寒战、发热,尿色呈暗褐色。实验室检查：外周血白细胞计数25.2×10^9/L,血红蛋白73 g/L,血小板计数179×10^9/L,尿素氮6.4 mmol/L,肌酐96μmol/L,降钙素原14.13 ng/ml,凝血酶原时间17 s,活化部分凝血活酶时间44 s,D-二聚体8.7 mg/L;尿白细胞（＋＋＋）,隐血（＋＋＋）,尿胆原（＋＋＋）,酮体（＋＋＋）,尿蛋白（＋＋＋）,亚硝酸盐阳性。考虑为急性溶血反应。停用米卡芬净,静脉注射甲泼尼龙40 mg,并给予水化利尿和碱化尿液治疗。患者尿量在4 h内由100-150 ml/h减至10-20 ml/h,尿色呈酱油样。次日复查：白细胞计数18.6×10^9/L,红细胞计数1.7×10^12/L,血红蛋白57 g/L,血小板计数116×10^9/L,网织红细胞0.05;白蛋白25 g/L,间接胆红素20.4μmol/L,天冬氨酸转氨酶108 U/L,丙氨酸转氨酶42 U/L,尿素氮17.9 mmol/L,肌酐230μmol/L,直接抗人球蛋白试验阳性。考虑并发急性肾衰竭。给予积极抗感染治疗,同时行连续性肾脏替代性治疗、输注红细胞悬液、输注血浆。10 d后,患者仍处于无尿状态,黄疸进行性加重,家属放弃治疗。     

替考拉宁致血小板减少

1例57岁女性患者因左股骨颈骨折行髋关节置换术。术后17d患者出现发热,20d血培养示沃氏葡萄球菌阳性。给予替考拉宁0．4g入0．9％氯化钠100ml、1次／12h静脉滴注,头孢唑肟2．0g．2次／d口服。第4天患者双侧小腿出现瘀斑,血小板计数由249×10^9／L降至25×10^9／L。停用替考拉宁,头孢唑肟继续使用,第7天血小板计数恢复至104×10^9／L,瘀斑基本消退。     

联合使用免疫抑制剂治疗难治性原发免疫性血小板减少症

目的观察联合多种免疫抑制剂治疗难治性原发免疫性血小板减少症(ITP)的疗效和安全性。方法37例难治性ITP患者随机分为治疗组17例和对照组20例。对照组先予甲基强的松龙每天1g及免疫球蛋白每天0.4g.kg-1.d-1静脉滴注,3～5d血小板上升后接受强的松1mg.kg-1.d-1口服,2周后逐渐减量至维持治疗;治疗组联合2～3种静脉免疫抑制剂(免疫球蛋白每天0.4g.kg-1.d-1,长春新碱每天2mg,甲基强的松龙1g)治疗3～5d,血小板迅速上升后给予联合2～3种口服免疫抑制剂(包括达那唑200mg每天2次,环孢素50mg每天2次,吗替麦考酚酯1g每天2次)。维持治疗3～6个月。治疗结束后随访1～3年。结果治疗组总有效率为88.2%高于对照组的55.0%,差异有统计学意义(P<0.01)。治疗组血小板计数平均99.8×109/L,高于对照组的22.4×109/L;治疗组血小板稳定时间平均19.1个月,高于对照组的1.5个月,差异均有统计学意义(P<0.01)。总体耐受性良好,无1例出现严重并发症。结论联合多种免疫抑制剂治疗难治性ITP安全有效,且可长期维持血小板值稳定于安全范围。     

根除幽门螺杆菌疗法治疗难治性免疫性血小板减少性紫癜的研究

目的研究根除幽门螺杆菌(Hp)疗法治疗难治性免疫性血小板减少性紫癜(RITP)的效果。方法35例RITP患者作为治疗观察对象,先对患者进行C尿素呼吸试验(C-UBT)诊断和抗血小板抗体IgG(PA-IgG)检测,根据结果等信息对患者进行根除Hp治疗。观察并比较治疗前和治疗后1、2、3个月患者血小板计数(PLT)和PA-IgG水平。结果治疗后1、2、3个月,患者PLT水平分别为(31.50±8.45)×10⁹/L、(38.70±7.39)×10⁹/L、(46.91±5.41)×10⁹/L,明显高于治疗前的(23.14±5.67)×10⁹/L,PAIgG水平分别为(363.74±102.31)μg/10⁷血小板、(273.64±94.26)μg/10⁷血小板、(223.20±75.21)μg/10⁷血小板,明显低于治疗前的(422.30±100.24)μg/10⁷血小板,差异均具有统计学意义(P<0.05)。结论对RITP患者采用根除Hp治疗,可加快患者PLT和PA-IgG水平恢复,该治疗方式应用效果理想,值得推广使用。