硼替佐米为基础的联合化疗方案及细胞遗传学特性与多发性骨髓瘤治疗反应及预后的回顾性研究
发布时间：2018-07-20 19:51
【摘要】：目的：本研究为探究以硼替佐米为基础的多药联合化疗方案治疗初发多发性骨髓瘤患者的疗效；分析患者骨髓异常浆细胞细胞遗传学异常对该组患者疗效、生存的影响。 方法：2006年1月至2014年3月在本单位就诊的初发的多发性骨髓瘤患者共212例,采用以硼替佐米(Bortezomib, B)为基础的联合化疗,其中BDT方案34例、BD方案44例、BCD方案76例、BAD方案58例；其中76例用原位免疫荧光(FISH)技术进行细胞遗传学检测,采用探针包括13q14.3(DS13S319)/17p13(P53).1q21/13q14(RB1)双探针和14q32(IGH)双色探针。并观察疗效及生存情况。所有212例患者中位随访时间为23个月(2-81个月)。BAD组患者中位随访时间21月(3-81个月),BCD组患者中位随访时间20.5月(3-72个月),BD组患者中位随访时间23月(2-72个月),BDT组中位随访时间37.5月(12-64个月)。 结果：(1)所有患者完成中位疗程数3疗程(1-8个疗程),总体疗效有反应者(疗效评价PR及以上)有196例,ORR为91.2%,其中达到PR的有77例(36.3%),获得VGPR及以上的有119例(55.3%),获得CR/nCR的60例(27.9%)。BAD, BCD, BD, BDT四组的ORR分别为96.6%,94.7%,77.8%,90.9%(X2=10.949,P=0.008)；VGPR以上的比例为60.3%,57.9%,42.1%,57.6%(χ2=3.937,P=0.263)；CR/nCR率为32.8%,28.9%,13.3%,33.3%(χ2=6.397,P=0.093)。提示三药联合方案总体疗效显著优于两药联合方案。 (2)所有患者中一疗程后总体有反应者(ORR)为166例,有效率77.2%,其中达到PR者134例(63.2%),达到VGPR及以上者32例(14.9%)。BAD,BCD,BD,BDT组的ORR分别为82.8%,80.3%,53.3%,90.9%(χ2=17.444,P=0.000)。四组疗效达到VGPR以上比例分别为31.0%,10.5%,8.9%,6.1%(χ2=13.926,P=0.003)。提示在一疗程治疗后治疗反应性三药联合方案即显著优于两药联合方案。 (3)212例患者总体中位PFS为23个月(95%CI：18.9-27.1个月)。其中BAD组患者中位PFS为16个月(95%CI：2.4-29.6个月)；BCD组患者中位PFS为23个月(95%CI：13.3-32.7个月)；BD组患者中位PFS为16个月(95%CI：11.2-20.8个月)；BDT组患者中位PFS为36个月。各组PFS差异统计学边缘显著(χ2=7.415,P=0.064)。高龄患者(年龄65岁及以上)的中位PFS为12个月(95%CI：9.7-14.3个月),低龄组患者(年龄小于65岁)的中位PFS为29个月(95%CI：24.2-33.8个月)。二者差异有统计学意义(χ2=15.077,P=0.000)。BCD组中位OS为57个月(95%CI：17.7-96.3个月),BDT组中位OS为36个月,其余治疗组均未达到中位生存时间,组间差异不显著(χ2=2.315,P=0.545)(图4C)。在不同年龄组患者中,高龄患者(65岁及以上)的中位OS为31个月(95%CI：24.3-37.7个月),低龄组患者(65岁以下)的中位OS未达到。二者差异有统计学意义(212.979,P=0.000)。化疗方案对PFS有显著性影响,低龄组患者的PFS和OS亦显著高于高龄组患者。 (4)FISH检测17p13位点异常33例(43.4%),13q14位点异常26例(34.2%),1q21位点异常15例(19.7%),14q32位点异常21例(27.6%),13q14.3位点异常36例(47.4%)。存在同时有两种或多种位点异常的患者37例,总阳性率为77.6%。(5)17p13异常与血红蛋白水平负相关(P0.05),1q21异常与Alb负相关(P0.05),13q14异常与LDH水平正相关(P0.05),与PFS负相关(P0.05),14q32异常与PFS负相关(P0.05)。 (6)当17p13位点正常时,三药方案比两药方案有显著OS优势(均未达到)(χ2=3.583,P=0.012),而异常时,二者差异无统计学意义(P0.05)。当17p13与1q21两位点均正常时,三药方案比两药方案有显著OS优势(均未达到)(χ2=5.095,P=0.024),而两位点中至少存在一个异常时,三药方案与两药方案无差异(P0.05)。 结论：使用以硼替佐米为基础的联合化疗方案治疗初发多发性骨髓瘤患者,不同治疗组之间疗效存在显著性差异,三药联合方案(BAD. BCD及BDT方案)的反应率显著优于两药方案(BD方案)。三药联合方案的PFS显著优于两药方案,OS不存在显著性差异；年轻患者的PFS和OS均高于高龄患者。在17p13和1q21均正常的患者中,三药联合化疗较两药化疗有OS优势,而17p13或1q21异常的患者中,则没有这种优势。提示FISH检测结果可能预测耐药。
[Abstract]:Objective: To investigate the efficacy of bortezomizomi based multidrug combined chemotherapy in the treatment of patients with primary multiple myeloma, and to analyze the effects of abnormal cytogenetic abnormalities on the survival of the patients.
Methods: 212 patients with primary multiple myeloma from January 2006 to March 2014 were treated with combined chemotherapy based on Bortezomib (Bortezomib, B), of which 34 cases of BDT, 44 cases of BD, 76 BCD regimen, 58 cases of BAD, 76 cases were detected by in situ immunofluorescence (FISH). The probe included 13q14.3 (DS13S319) /17p13 (P53).1q21/13q14 (RB1) double probe and 14q32 (IGH) dual probe. The efficacy and survival were observed. The median follow-up time of all 212 patients was 23 months (2-81 months) for 21 months (3-81 months), and the median follow-up time of the BCD group was 20.5 months (3-72 months), and the BD group The median follow-up time was 23 months (2-72 months). The median follow-up time in group BDT was 37.5 months (12-64 months).
Results: (1) all patients completed a course of 3 courses of treatment (1-8 courses), 196 cases (PR and above) and 77 cases (36.3%) to PR, 119 cases (55.3%), 60 cases (27.9%).BAD, BCD, BD, BDT four group ORR respectively, 96.6%, 94.7%, BDT four, respectively. (X2=10.949, P=0.008); the proportion above VGPR was 60.3%, 57.9%, 42.1%, 57.6% (x 2=3.937, P=0.263), and the CR/nCR rate was 32.8%, 28.9%, 13.3%, 33.3% (x 2=6.397, P=0.093). The overall efficacy of the three drug combination scheme was significantly better than the two drug combination regimen.
(2) in all patients, the overall response (ORR) was 166 cases after one course of treatment, the effective rate was 77.2%, of which 134 cases (63.2%) reached PR, 32 cases (14.9%), BCD, BD, and BDT in the group of VGPR and above, 82.8%, 80.3%, 53.3%, 90.9% (chi 2=17.444, P= 0). .003). It is suggested that after a course of treatment, the three drug combination regimen is superior to the two drug combination regimen.
(3) the total median PFS of the 212 patients was 23 months (95%CI:18.9-27.1 months). The median PFS of the group BAD was 16 months (95%CI:2.4-29.6 months); the median PFS of the group BCD was 23 months (95%CI:13.3-32.7 months); the median PFS of the group BD was 16 months (95%CI:11.2-20.8 month); the median of the BDT group was 36 months. The difference between the groups was 36 months. The statistical margin was significant (x 2=7.415, P=0.064). The median PFS of the elderly patients (age 65 years and above) was 12 months (95%CI:9.7-14.3 months), and the middle PFS of the lower age group (age less than 65 years old) was 29 months (95%CI:24.2-33.8 months). The two difference was statistically significant (x 2=15.077, P=0.000).BCD middle OS for 57 months (95%CI:17.7-96.) 3 months), the median OS in the BDT group was 36 months, and the rest of the treatment groups did not reach the median survival time. The difference between the groups was not significant (x 2=2.315, P=0.545). In the different age groups, the middle OS of the elderly patients (65 years and above) was 31 months (95%CI:24.3-37.7 months), and the middle OS of the lower age group (under 65 years of age) was not reached. There were two differences. Statistical significance (212.979, P=0.000). Chemotherapy regimen had a significant effect on PFS, and PFS and OS in younger age group were also significantly higher than those in elderly group.
(4) FISH detected abnormal 17p13 loci (43.4%), 26 13q14 loci (34.2%), 15 1q21 loci (19.7%), 21 14q32 loci (27.6%), and 36 13q14.3 loci (47.4%). The total positive rate was 77.6%. (5) 17p13 abnormality and hemoglobin level negative correlation (P0.05), 1q21. Abnormality is negatively correlated with Alb (P0.05), 13q14 anomaly is positively correlated with LDH level (P0.05), negatively correlated with PFS (P0.05), 14q32 anomaly is negatively correlated with PFS (P0.05).
(6) when the 17p13 locus was normal, the three drug regimen had a significant OS advantage over the two drug (x 2=3.583, P=0.012), but the difference was not statistically significant (P0.05). When 17p13 and 1q21 two were all normal, the three drug regimen had a significant OS advantage over the two regimen (x 2=5.095, P=0.024), while at least the two loci existed. In one case, there was no difference between the three drug regimens and the two drug regimens (P0.05).
Conclusion: there is a significant difference in the curative effect between different treatment groups with bortezomizomi based combined chemotherapy regimen in the treatment of primary multiple myeloma. The response rate of the three drug combination regimen (BAD. BCD and BDT scheme) is significantly better than that of the two drug regimen (BD scheme). The PFS of the three drug combination scheme is significantly better than the two drug regimen, and the OS does not exist significantly. Sex differences; both PFS and OS in young patients were higher than those in older patients. In patients with normal 17p13 and 1q21, combined chemotherapy with three drugs had a OS advantage compared with two drug chemotherapy, but there was no such advantage in patients with 17p13 or 1q21 abnormalities suggesting that the results of FISH test may predict drug resistance.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R733.3
本文编号：2134590
[Abstract]:Objective: To investigate the efficacy of bortezomizomi based multidrug combined chemotherapy in the treatment of patients with primary multiple myeloma, and to analyze the effects of abnormal cytogenetic abnormalities on the survival of the patients.
Methods: 212 patients with primary multiple myeloma from January 2006 to March 2014 were treated with combined chemotherapy based on Bortezomib (Bortezomib, B), of which 34 cases of BDT, 44 cases of BD, 76 BCD regimen, 58 cases of BAD, 76 cases were detected by in situ immunofluorescence (FISH). The probe included 13q14.3 (DS13S319) /17p13 (P53).1q21/13q14 (RB1) double probe and 14q32 (IGH) dual probe. The efficacy and survival were observed. The median follow-up time of all 212 patients was 23 months (2-81 months) for 21 months (3-81 months), and the median follow-up time of the BCD group was 20.5 months (3-72 months), and the BD group The median follow-up time was 23 months (2-72 months). The median follow-up time in group BDT was 37.5 months (12-64 months).
Results: (1) all patients completed a course of 3 courses of treatment (1-8 courses), 196 cases (PR and above) and 77 cases (36.3%) to PR, 119 cases (55.3%), 60 cases (27.9%).BAD, BCD, BD, BDT four group ORR respectively, 96.6%, 94.7%, BDT four, respectively. (X2=10.949, P=0.008); the proportion above VGPR was 60.3%, 57.9%, 42.1%, 57.6% (x 2=3.937, P=0.263), and the CR/nCR rate was 32.8%, 28.9%, 13.3%, 33.3% (x 2=6.397, P=0.093). The overall efficacy of the three drug combination scheme was significantly better than the two drug combination regimen.
(2) in all patients, the overall response (ORR) was 166 cases after one course of treatment, the effective rate was 77.2%, of which 134 cases (63.2%) reached PR, 32 cases (14.9%), BCD, BD, and BDT in the group of VGPR and above, 82.8%, 80.3%, 53.3%, 90.9% (chi 2=17.444, P= 0). .003). It is suggested that after a course of treatment, the three drug combination regimen is superior to the two drug combination regimen.
(3) the total median PFS of the 212 patients was 23 months (95%CI:18.9-27.1 months). The median PFS of the group BAD was 16 months (95%CI:2.4-29.6 months); the median PFS of the group BCD was 23 months (95%CI:13.3-32.7 months); the median PFS of the group BD was 16 months (95%CI:11.2-20.8 month); the median of the BDT group was 36 months. The difference between the groups was 36 months. The statistical margin was significant (x 2=7.415, P=0.064). The median PFS of the elderly patients (age 65 years and above) was 12 months (95%CI:9.7-14.3 months), and the middle PFS of the lower age group (age less than 65 years old) was 29 months (95%CI:24.2-33.8 months). The two difference was statistically significant (x 2=15.077, P=0.000).BCD middle OS for 57 months (95%CI:17.7-96.) 3 months), the median OS in the BDT group was 36 months, and the rest of the treatment groups did not reach the median survival time. The difference between the groups was not significant (x 2=2.315, P=0.545). In the different age groups, the middle OS of the elderly patients (65 years and above) was 31 months (95%CI:24.3-37.7 months), and the middle OS of the lower age group (under 65 years of age) was not reached. There were two differences. Statistical significance (212.979, P=0.000). Chemotherapy regimen had a significant effect on PFS, and PFS and OS in younger age group were also significantly higher than those in elderly group.
(4) FISH detected abnormal 17p13 loci (43.4%), 26 13q14 loci (34.2%), 15 1q21 loci (19.7%), 21 14q32 loci (27.6%), and 36 13q14.3 loci (47.4%). The total positive rate was 77.6%. (5) 17p13 abnormality and hemoglobin level negative correlation (P0.05), 1q21. Abnormality is negatively correlated with Alb (P0.05), 13q14 anomaly is positively correlated with LDH level (P0.05), negatively correlated with PFS (P0.05), 14q32 anomaly is negatively correlated with PFS (P0.05).
(6) when the 17p13 locus was normal, the three drug regimen had a significant OS advantage over the two drug (x 2=3.583, P=0.012), but the difference was not statistically significant (P0.05). When 17p13 and 1q21 two were all normal, the three drug regimen had a significant OS advantage over the two regimen (x 2=5.095, P=0.024), while at least the two loci existed. In one case, there was no difference between the three drug regimens and the two drug regimens (P0.05).
Conclusion: there is a significant difference in the curative effect between different treatment groups with bortezomizomi based combined chemotherapy regimen in the treatment of primary multiple myeloma. The response rate of the three drug combination regimen (BAD. BCD and BDT scheme) is significantly better than that of the two drug regimen (BD scheme). The PFS of the three drug combination scheme is significantly better than the two drug regimen, and the OS does not exist significantly. Sex differences; both PFS and OS in young patients were higher than those in older patients. In patients with normal 17p13 and 1q21, combined chemotherapy with three drugs had a OS advantage compared with two drug chemotherapy, but there was no such advantage in patients with 17p13 or 1q21 abnormalities suggesting that the results of FISH test may predict drug resistance.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R733.3
【参考文献】
相关期刊论文 前1条
1 Roberto Ria;Antonia Reale;Angelo Vacca;;Novel agents and new therapeutic approaches for treatment of multiple myeloma[J];World Journal of Methodology;2014年02期
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