浙贝母颗粒逆转急性白血病多药耐药临床研究

【作者】 叶霈智；

【导师】 陈信义；

【作者基本信息】 北京中医药大学 ， 中西医结合内科学， 2006， 博士

【摘要】 成人AL初治患者约有30%左右难治,CR后仍有60%左右最终复发难治,甚至造血干细胞移植后复发。难治性急性白血病对治疗反应差,诱导缓解率低,复发率高,生存期短,是白血病治疗中的难题,目前仍以联合化疗为主要治疗方法。多药耐药性(MDR)的形成是难治的主要原因。研究MDR现象产生的机制及克服方法是提高白血病疗效的主要途径之一。已被证实具有逆转肿瘤/白血病细胞多药耐药性的化合物、生物制剂和中药很多,但现有逆转剂大多数停留在体外研究阶段,且存在不良反应大、临床疗效不满意等缺点,临床应用受到限制。我科既往MDR相关研究表明,浙贝母生物碱体外具有逆转白血病细胞MDR的生物活性,并能增加急性白血病细胞内抗癌药物浓度。临床预实验显示,常规化疗加用浙贝母粉,治疗组完全缓解率显著高于对照组,对难治及复发白血病患者优势更为明显,且能提高Pgp高表达患者临床疗效。在上述研究基础上,我们在国内首次进行以中药为主,干预围化疗期难治性急性白血病前瞻性随机、双盲、多中心临床研究。严格遵守随机双盲临床研究原则,统一制定临床研究方案和病例观察表,拟定规范的难治性白血病诊断标准;由计算机产生随机排列表划分治疗组和对照组,两组比例为1:1。在使用标准化疗方案的同时,于化疗开始前3天加用颗粒剂,治疗组为浙贝母颗粒,每次1袋(10g),每日3次;对照组为麦芽颗粒,每次1袋(10g),每日3次。除此以外,不加用任何具有逆转白血病多药耐药性的中西药。所有病例均连续服药14天,以标准化疗疗程为一个治疗周期。若一个疗程无效,可随下一周期化疗继续服用颗粒剂,继续观察一个疗程,并记作另一人次。研究者使用统一制定的《浙贝母颗粒逆转急性白血病多药耐药临床研究》CRF表,参加临床研究者需经过一定的培训,充分了解临床研究方案,严格记录化疗前后各项指标(骨髓及外周原始细胞、外周血象、MDR相关蛋白、安全性指标)和不良事件,判定临床疗效。最终对研究结果分两次揭盲,并进行统计分析。本次研究病例来源于在全国12家医院,为2004年1月～2006年4月间住院患者,共127例(治疗组66例,对照组61例)。研究结果表明:①两组患者性别、年龄、病型、病程等基线资料均衡可比。②疗效结果显示,两组完全缓解(CR)病例分别为26例、占39.4%(治疗组)与15例、占24.6%(对照组);部分缓解(PR)病例分别为24例,占36.4%(治疗组)与17例,占27.9%(对照组);未缓解病例(NR)病例分别为16例,占24.2%(治疗组)与29例,占47.5%(对照组)。两组病例疗效整体比较,经秩和检验,有统计学意义(P<0.05),治疗组优于对照组;两组病例有效性(CR+PR)比较,经χ2检验,具有显著统计学意义(P<0.01),治疗组有效率显著高于对照组(75.8%>52.5%)。③疾病分型与疗效关系分析结果,两组间ALL患者有效性(CR+PR)比较,经χ2检验,具有统计学意义(P<0.05),治疗组高于对照组(92%>60%)。④性别与疗效关系分析结果,治疗组男性患者疗效与对照组相比,经秩和检验,有统计学意义(P<0.05),治疗组疗效优于对照组。⑤病程与疗效关系分析结果,治疗组病程<6个更多还原

【Abstract】 There are about 30% adults who suffer from AL are difficult to initial treatment. After receiving CR, 60% of the patients will recur and become difficult to treat ultimately, even after transplantation of haemopoietic stem cell. Bad reaction to treatment, low induced relieving rate, high recurrence rate, and short survival period are tough problem in the treatment of refractory acute leukemia (RAL). So combined chemotherapy is still the main treatment method. MDR is the main reason which causes its refractoriness. Studying the mechanism of the cause and resolving method of MDR is one of the main means of enhancing the curative effect of leukemia. It has been proved that many compounds, biological preparations and Chinese herbs have the effect of reversing MDR of tumor or leukemia cells. However, the apply of these preparations are greatly limited due to its great side effect and bad clinical curative effect, not to say the study is still at the stage of out-of-body.Previous study on MDR in our department shows that the alkaloid of Fritillary Bulb has the biological activity of reversing MDR of leukemia cells. It can also enhance the anti-tumor drug concentration in AL cells. Clinical preliminary experiment shows that the totally relieving rate of treatment group is significantly higher than that of control group. Its ascendancy is more significant for refractory and recurrent leukemia patients. It can also enhance the curative effect on patients with high Pgp expression. On this base, we run a prospective, double-blind-method, and multi-center clinical study first time to interfere in RAL ambi-chemotherapy mainly treated with Chinese herbs in domestic. We strictly observe the randomized allocation and double blind method principle in clinical study, institute coincident clinical research program and CRF, divide treat group and control group according to random arrangement created by computer. In addition to applying standard chemotherapy, drug granules is prescribed 3 days before chemotherapy. Ten grams of Fritillary Bulb and malt, three times a day, were given to the treatment group and control group respectively. Any other drugs which can reverse MRD in leukemia were ruled out. All the patients had their drugs 14 days continuously, with the standard chemotherapy period being a treatment cycle. If it was ineffective after a course of treatment, the patient could continue to have these drug granules and be observed for another course of treatment as another man-time. The research staff must attend a certain training so that they will know well the clinical research plan, and strictly note down every index (including primitive granulocyte counts in both marrow and peripheral blood, peripheral blood counts, MDR relative protein, safety index, etc.) and untoward affairs before and after chemotherapy. They should also judge the clinical curative effect. In the end, the result will be uncovered by two steps before statistical analysis.All the cases are from 12 hospitals through the country, and were all in-patients between January, 2004 and April, 2006. There were 66 cases in treatment group and 61cases in control更多还原