摘要
研究目的
初步探讨重组人红细胞生成素(rHuEPO)±重组人粒细胞集落刺激因子(G-CSF)治疗较低危骨髓增生异常综合征(MDS)的疗效和疗效影响因素。
研究方法
治疗方案为每日或隔日rHuEPO单独或联合G-CSF单次皮下注射,待红系达到完全缓解后rHuEPO或G-CSF逐渐减量至停用或维持疗效的最佳最小剂量。
2004年2月～2012年5月我院诊治的MDS患者中共有52例按国际预后积分系统(IPSS)分组为较低危(低危+中危1)的患者接受了至少8周以上的rHuEPO±G-CSF治疗。回顾性分析这些MDS患者的临床特征、治疗疗效、生存情况以及影响疗效的因素。
结果
52例较低危MDS患者中位年龄60(19-83)岁,男27例,女25例,其中难治性贫血(RA)4例,难治性贫血伴环形铁粒幼细胞(RARS)19例,难治性血细胞减少伴多系形态异常(RCMD)21例,难治性贫血伴原始细胞增多-1型(RAEB-1)7例,仅有5q缺失的MDS(5q-综合征)1例。中位血红蛋白计数为66.5(29～99) g/L,中位中性粒细胞绝对值计数(ANC)1.49(0～10.46)×109/L,中位血小板(PLT)计数96(15～683)×109/L。27例(51.9%)有骨髓多系病态造血,45例(86.5%)骨髓原始细胞<5%。中位红细胞爆式集落形成单位(BFU-E)(?)口红细胞集落形成单位(CFU-E)计数分别为12/105BMMNC和57.5/105BMMNC,低于正常参考值(分别为25～37/105BMMNC、68～93/105BMMNC)。43例患者血清促红细胞生成素(sEPO)水平<500mU/ml。按IPSS染色体核型预后分组,染色体核型分析以良好核型患者为主,为41例(78.8%),中等核型患者9例(17.3%),不良染色体核型2例(3.9%)。IPSS低危组患者11例(21.2%),中危-1患者为41例(78.8%)。WPSS分组极低危、低危、中危、较高危和高危组患者分别为11例(21.2%)、16例(30.8%)、19例(36.4%)、3例(5.8%)、3例(5.8%)。中位发病至接受治疗时间为12(0.33-84)月,96.2%患者以乏力、心悸、头晕、面色苍白等贫血相关症状为主要首发症状,28例(53.8%)患者处于输血依赖状态。
36例患者接受rHuEPO治疗,16例患者接受rHuEPO+G-CSF治疗。27/52例(51.9%)患者在治疗8周时起效,其中9例(33.3%)患者达完全缓解(CR),18例(66.7%)患者出现红系反应(HI-E)。27例有效患者的中位疗效持续时间为34(5-74)个月。rHuEPO和rHuEPO+G-CSF治疗组的有效率(50%&56.3%)以及疗效持续时间(34个月&46个月)均无明显差异(P>0.05)。单因素(包括年龄、性别、WHO诊断分型、多系病态造血、骨髓原始细胞比例、sEPO水平、BFU-E和CFU-E计数、染色体核型、IPSS和WPSS评分和危险度分组、输血依赖、rHuEPO治疗剂量、是否联合G-CSF治疗、从诊断到开始治疗时间间隔)和多因素(包括初诊时Hb水平<60g/1、sEPO分组以及sEPO<500IU/ml、BFU-E计数≥25、CFU-E分组、从诊断到开始治疗时间间隔分组、不同rHuEPO治疗剂量)统计分析结果表明初诊时sEPO水平<500IU/ml、BFU-E计数≥25/105BMMNC的患者接受中高剂量rHuEPO治疗可能取得较高疗效。非MDS-RARS患者在明确诊断5月内接受中剂量以上rHuEPO治疗则可能维持较长时间的疗效。52例患者中位随访36(2-81)个月,其中4例出现疾病进展,3例死亡,总体中位生存时间为46(2-99)个月,有效和无效患者的生存时间分别为52.5(16-99)个月和29(2-86)个月,两组患者比较差异明显(P'<0.05),中高剂量组患者的生存时间分别为47(6-81)个月和59.5(16～99)个月,均较低剂量组患者30.5(2-72)个月明显延长(P<0.05)。单因素(包括患者初诊时的年龄、性别、WHO诊断分型、多系病态造血、骨髓原始细胞比例、sEPO水平、Hb水平、BFU-E和CFU-E计数、染色体核型分析、IPSS或WPSS评分和危险度分组、输血依赖、1rHuEPO治疗剂量以及疗效、是否联合G-CSF治疗、从诊断到开始rHuEPO治疗时间间隔)和多因素(rHuEPO治疗剂量以及疗效)统计分析结果表明除rHuEPO治疗剂量(P=0.01)以及疗效(P=0.04)外,其他因素与rHuEPO治疗后患者的生存时间无关(P>0.05)。
结论
1.rHuEPO单用与联合G-CSF治疗方案对于改善较低危MDS患者贫血的有效率、疗效持续时间以及生存时间并无差异。因此,对于单纯贫血的较低危MDS患者而言,rHuEPO单独治疗能够取得较好的疗效。
2.初诊时sEPO水平<500IU/ml、BFU-E计数≥25/105BMMNC(?)的较低危MDS患者,接受中高剂量rHuEPO±G-CSF治疗的疗效较好。
3.诊断明确后5月内即接受中高剂量rHuEPO±G-CSF冶疗且有效的较低危(?)MDS-RARS患者,其疗效维持时间较长。
4.应用中高剂量rHuEPO±G-CSF治疗有效的较低危MDS患者的生存时间明显延长。
Objective
To investigate the erythroid response and influencing factors of lower-risk myelodysplastic syndrome (MDS) patients in the treatment with recombinant human erythropoietin (rHuEPO) alone or in combination with recombinant human granulocyte colony-stimulating factor(G-CSF).
Methods
Ttherapeutic schedule:rHuEPO alone or in combination with G-CSF subcutaneous injection daily or every other day and the dose would reduce slowly to stop or the minimum dose to maintain respone after the maximum response had been reached.
Between February2004to May2012, a total of52consecutive patients withInternational prognostic scoring system(IPSS) low or intermediate-1risk MDS received rHuEPO±G-CSF at least8weeks or more and their clinical features, efficacy, survival and the predictors of efficacy were analyzed retrospectively.
Results
In the52patients with lower-risk MDS, there are27male and25female patients and the median of age was60years. The number of patients with various subtypes is RS4,RARS19, RCMD(RS)21, RAEB-17, and5q-syndrome1. The median hemoglobin count of patients was66.5(range29-99)g/L and the median neutrophils count was1.49(range0-10.46)×109/L, the median platelet count was96(range115-683)x109/L. Multi-lineage dysplasia of bone marrow were found in27(51.9%)patients and the percentage of45(86.5%) patients was less than5%. The median BFU-E and CFU-E counts were12/105BMMNC和57.5/105BMMNC which were both below their normal reference value (range25-37/105BMMNC and68-93/105BMMNC). Serum erythropoietin levels of43patients were less than500mU/ml. According to the IPSS karyotape prognostic group,41(76.3%) patients were with good karyotype,9(17.3%)patents with intermediate karyotype and2(3.9%) patients with poor karyotape. Here are11(21.2%) patients in low-risk group of IPSS and41(78.2%) in intermedia-risk1. The patients in each risk group of WPSS are11(21.2%) in very low-risk,16(30.8%) in low-risk,19(36.4%) in intermedian-risk and6(11.6%) in high-risk group. The median time to disease was12(range0.33-84) months and first symptoms of96.2%patients were kinds of anemia symptoms.28(53.8%) patients were dependent on transfusion.
Statistical analysis showed that there were no significant difference in the general data, the condition of newly diagnosed patients, the basic level of clinical parameter, diagnostic classification and prognosis in the three groups (P>0.05) besides leukocyte and platelet.
36patients received rHuEPO and16received rHuEPO+G-CSF. The effective rate of52patients in rHuEPO±G-CSF group was51.9%(27/52).9(33.3%) patients obtained complete remission (CR) and18(66.7%) patients had erythroid response (HI-E). The median efficacy duration of27patients was3(range45-74) months. There is no difference of effective rate(50%&56.3%) and efficacy duration(34&46months) between rHuEPO and rHuEPO+G-CSF group (P>0.05). Univariate(age,gender,WHO diagnosis, mul-tilineage dysplasia, percentage of bone marrow blasts,sEPO level. BFU-E and CFU-E count, karyotype, IPSS or WPSS score value and risk category, transfusion requirement,rHuEPO therapy dose. addition of G-CSF,interval from diagnosis to onset of rHuEPO±G-CSF) and multivariate (Hb level<60g/l, sEPO<500IU/ml, BFU-Ecount≥25/105BMMNC, CFU-E count, interval from diagnosis to onset of rHuEPO±G-CSF、different doses of rHuEPO)statistical analysis showed that newly diagnosed patients with sEPO<500IU/ml and BFU-E count≥25/105BMMNC, may achieve higher efficacy when accepted moderate or high dose rHuEPO therapy.Un MDS-RARS patients may remain longer efficacy duration when they accepted moderate or high dose rHuEPO therapy within5months after diagnosis confirmed. Median follow-up was36(range2-81)months,4patients had disease progressions and3of them died. The median survival time of52patients was46(range2-99)months. There was significant difference in survival time between effective and ineffective patients (52.5&29months)(P<0.05). The survival time of patients in intermedian and high dose groups were significantly longer than lower dose group30.5months (range2-72)(P<0.05). Univariate(age,gender,WHO diagnosis, multilineage dysplasia, percentage of bone marrow blasts, sEPO level. Hb level, BFU-E and CFU-E count, karyotype, IPSS or WPSS score value and risk category, transfusion requirement, the dose and therapy response of rHuEPO,addition of G-CSF,interval from diagnosis to onset of rHuEPO±G-CSF) and multivariate (the dose and therapy response of rHuEPO)statistical analysis showed that other factors had no relationship with the survival time of patients after rHuEPO therapy (P>0.05) except the dose (P=0.01)and therapy response (P=0.04)of rHuEPO.
Conclusions
1. There was no significant difference in the effective rate, efficacy duration and survival time between lower-risk MDS patients of rHuEPO group and rHuEPO+G-CSF group. Therefore rHuEPO therapy alone can obtain good response for lower-risk MDS patients who have anemia alone.
2. Newly diagnosed lower-risk MDS patients with sEPO<500IU/ml and BFU-E count>25/105BMMNC, may achieve higher efficacy when accepted moderate or high dose rHuEPO therapy.
3. Lower-risknoMDS-RARS patients may remain longer efficacy duration when they accepted moderate or high dose rHuEPO therapy within5months after diagnosis confirmed.
4. Lower-risk MDS patients who received high dose therapy of rHuEPO±G-CSF and obtained good response had longer survival.
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