重组人血小板生成素治疗肿瘤患者化疗后血小板减少症的疗效和安全性：Ⅱ／Ⅲ期及补充多中心随机对照临床试验的汇总分析

Effectiveness and safety of recombinant human thrombopoietin on treating chemotherapy-induced thrombocytopenia: data pool analysis of phase Ⅱ /Ⅲ and complement multi-center clinical trials

目的:汇总Ⅱ/Ⅲ期和补充多中心临床试验资料,评价重组人血小板生成素(recombinant human thrombopoietin,rh-TPO)治疗实体肿瘤患者化疗后血小板(platelet,PLT)减少症的临床疗效和安全性。方法:3个试验共入组受试者276例,其中Ⅱ期试验入组63例,Ⅲ期试验入组154例,补充临床试验入组59例;其后剔除5例、脱落41例,共有230例纳入符合方案(pre-protocol,PP)数据集;所有患者均经组织学或细胞学证实患有实体肿瘤。Ⅱ期临床试验和补充临床试验为随机交叉自身对照试验,Ⅲ期临床试验中受试者按是否参加随机交叉对照分为随机交叉自身对照试验部分和非随机交叉自身对照部分。将接受rh-TPO用药的试验周期定义为用药周期,未用rh-TPO的周期定义为空白对照周期,试验期间的化疗方案和剂量均维持不变。将所有临床试验数据合并并进行疗效和安全性分析。结果:意向性治疗人群(intention-to-treat,ITT)数据集及PP数据集均显示出非常显著的一致性变化(以ITT集数据为例)。与对照周期相比,rh-TPO治疗可显著减轻化疗对PLT损伤的程度[化疗后PLT下降的最低值:(63.02±46.48)×109vs(49.47±31.41)×109个/L,P=0.002],缩短损伤和恢复时间[恢复至75×109个/L以上需要的天数:(11.18±9.71)vs(17.8±10.46)d,P=0.000],大幅提高血小板恢复水平[末次随访时PLT检测值:(211.21±119.20)×109vs(138.13±71.54)×109个/L,P=0.000;化疗后PLT最高值:(262.78±162.60)×109vs(149.36±73.26)×109个/L,P=0.000;末次随访时PLT与基线的差值:(79.64±118.06)×109vs(-8.92±102.50)×109个/L,P=0.000]。rh-TPO还可降低PLT输注患者的比例(12.21%vs 19.85%,P=0.017),减少PLT输注例次(0.22±0.72)vs(0.37±0.90)次,P=0.010)和输注量[(1.66±6.09)vs(2.77±7.08)U,P=0.009];补充试验中,PLT输注患者比例减少更为显著(13.79%vs 33.93%,P=0.0082)。用药前后血红蛋白含量和白细胞计数变化、肝肾功能、凝血功能的差异均无统计学意义(P>0.05)。276例患者中仅出现11例次不良反应,多为发热(6例)或寒战(2例)。结论:实体肿瘤患者化疗后给予国产rh-TPO可显著减轻化疗对PLT的损伤程度,缩短损伤和恢复时间,大幅提高PLT水平,降低患者PLT输注的例次和数量,且无严重不良反应。

Objective ： To assess the effectiveness and safety of recombinant human thrombopoietin （rh-TP0） on chemo therapy-induced thrombocytopenia（CIT） in patients with solid tumor. Methods： A total of 276 cases were enrolled in 3 studies, 63 cases in Phase ]I study, 154 cases in Phase HI study and 59 cases in complement study. A total of 230 cases were enrolled pre-protocol （PP） group, except of 5 protocol deviations, 41 lost-follow-ups. All of the patients had solid tumor which was confirmed by histology or cytology. Phase ]I and complement trials were randomized crossover self-con trol trials. It was divided into randomized-crossover-self-control part and non-randomized-crossover-self-control part inPhase HI trial depending on if the subject was joined by randomized-crossover. The period when rh-TPO subject was administered was defined as an administration period, and the other period was defined as a control period. The chemical therapeutic regimen and dosage did not change during the trials. All of the trials＇ data were pooled together to compare the efficacy and safety profile. Results： They showed the utilized changes both in intention-to-treat （ITF） group and PP group when compared with the treated cycle and control cycle （following example with ITF group data）. Compared with the con- trol period, rh-TPO could significantly decrease the degree of CIT （ minimal mean platelet count ： （ [ 63.02 ＋ 46.48 ] x 109 VS [49.47 ＋ 31.41 ] X 109/L, P = 0. 002） ; shorten the thrombocytopenia duration induced by chemotherapy （days of platelet count recovered to 75 x 109/L： [ 11.18 ± 9.71 ] vs [ 17.8 ± 10.46 ] d, P = 0. 000 ） ; and highly increase recover level of platelet count （platelet count of last visit： [211.21 ± 119. 201 x 109 vs [ 138.13 ±71.54] x 109/L, P =0. 000; maximal mean platelet count： [262.78 ±162.60] x 109 vs [149.36 ±73.26] x 109/L, P =0. 000; platelet count＇ s difference between the last visit and baseline： [79.64 ±118.06] vs [ - 8.92 ± 102.50], P = 0. 000）. On the other hand, rh-TPO could decrease the ratio of patients who had to be transfused with platelet （12.21% vs 19.85% ,P = 0. 017） ; and decrease the time （[0.22 ±0.72] vs [0.37 _＋0.901 time, P=0.010） and the quantity （[1.66 ＋6.09±vs [2.77 ± 7.08 ] U, P = 0. 009） of platelet transfusion. It was much more significantly in the complement trial （13.79% vs 33.93% , P =0. 0082）. There were no significant differences before and after treatment on Hb, WBC, liver and renal func- tion and blood coagulation （P 〉 0.05）. There were only 11 eases who met side effects during the studies, most of whom pres- ented fever （6 eases） and chill （2 eases）. Conclusion： Administration of rh-TPO after chemotherapycan may significantly reduce the degree and duration of thromboeytopenia induced by chemotherapy and promote platelet recovery of patients with solid tumors. It also decreased the capability of platelet transfusion, and severe side effects were not found.