硼替佐米為基礎(chǔ)的聯(lián)合化療方案及細(xì)胞遺傳學(xué)特性與多發(fā)性骨髓瘤治療反應(yīng)及預(yù)后的回顧性研究
發(fā)布時(shí)間：2018-07-20 19:51
【摘要】：目的：本研究為探究以硼替佐米為基礎(chǔ)的多藥聯(lián)合化療方案治療初發(fā)多發(fā)性骨髓瘤患者的療效；分析患者骨髓異常漿細(xì)胞細(xì)胞遺傳學(xué)異常對(duì)該組患者療效、生存的影響。 方法：2006年1月至2014年3月在本單位就診的初發(fā)的多發(fā)性骨髓瘤患者共212例,采用以硼替佐米(Bortezomib, B)為基礎(chǔ)的聯(lián)合化療,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例用原位免疫熒光(FISH)技術(shù)進(jìn)行細(xì)胞遺傳學(xué)檢測(cè),采用探針包括13q14.3(DS13S319)/17p13(P53).1q21/13q14(RB1)雙探針和14q32(IGH)雙色探針。并觀察療效及生存情況。所有212例患者中位隨訪時(shí)間為23個(gè)月(2-81個(gè)月)。BAD組患者中位隨訪時(shí)間21月(3-81個(gè)月),BCD組患者中位隨訪時(shí)間20.5月(3-72個(gè)月),BD組患者中位隨訪時(shí)間23月(2-72個(gè)月),BDT組中位隨訪時(shí)間37.5月(12-64個(gè)月)。 結(jié)果：(1)所有患者完成中位療程數(shù)3療程(1-8個(gè)療程),總體療效有反應(yīng)者(療效評(píng)價(jià)PR及以上)有196例,ORR為91.2%,其中達(dá)到PR的有77例(36.3%),獲得VGPR及以上的有119例(55.3%),獲得CR/nCR的60例(27.9%)。BAD, BCD, BD, BDT四組的ORR分別為96.6%,94.7%,77.8%,90.9%(X2=10.949,P=0.008)；VGPR以上的比例為60.3%,57.9%,42.1%,57.6%(χ2=3.937,P=0.263)；CR/nCR率為32.8%,28.9%,13.3%,33.3%(χ2=6.397,P=0.093)。提示三藥聯(lián)合方案總體療效顯著優(yōu)于兩藥聯(lián)合方案。 (2)所有患者中一療程后總體有反應(yīng)者(ORR)為166例,有效率77.2%,其中達(dá)到PR者134例(63.2%),達(dá)到VGPR及以上者32例(14.9%)。BAD,BCD,BD,BDT組的ORR分別為82.8%,80.3%,53.3%,90.9%(χ2=17.444,P=0.000)。四組療效達(dá)到VGPR以上比例分別為31.0%,10.5%,8.9%,6.1%(χ2=13.926,P=0.003)。提示在一療程治療后治療反應(yīng)性三藥聯(lián)合方案即顯著優(yōu)于兩藥聯(lián)合方案。 (3)212例患者總體中位PFS為23個(gè)月(95%CI：18.9-27.1個(gè)月)。其中BAD組患者中位PFS為16個(gè)月(95%CI：2.4-29.6個(gè)月)；BCD組患者中位PFS為23個(gè)月(95%CI：13.3-32.7個(gè)月)；BD組患者中位PFS為16個(gè)月(95%CI：11.2-20.8個(gè)月)；BDT組患者中位PFS為36個(gè)月。各組PFS差異統(tǒng)計(jì)學(xué)邊緣顯著(χ2=7.415,P=0.064)。高齡患者(年齡65歲及以上)的中位PFS為12個(gè)月(95%CI：9.7-14.3個(gè)月),低齡組患者(年齡小于65歲)的中位PFS為29個(gè)月(95%CI：24.2-33.8個(gè)月)。二者差異有統(tǒng)計(jì)學(xué)意義(χ2=15.077,P=0.000)。BCD組中位OS為57個(gè)月(95%CI：17.7-96.3個(gè)月),BDT組中位OS為36個(gè)月,其余治療組均未達(dá)到中位生存時(shí)間,組間差異不顯著(χ2=2.315,P=0.545)(圖4C)。在不同年齡組患者中,高齡患者(65歲及以上)的中位OS為31個(gè)月(95%CI：24.3-37.7個(gè)月),低齡組患者(65歲以下)的中位OS未達(dá)到。二者差異有統(tǒng)計(jì)學(xué)意義(212.979,P=0.000)�；煼桨笇�(duì)PFS有顯著性影響,低齡組患者的PFS和OS亦顯著高于高齡組患者。 (4)FISH檢測(cè)17p13位點(diǎn)異常33例(43.4%),13q14位點(diǎn)異常26例(34.2%),1q21位點(diǎn)異常15例(19.7%),14q32位點(diǎn)異常21例(27.6%),13q14.3位點(diǎn)異常36例(47.4%)。存在同時(shí)有兩種或多種位點(diǎn)異常的患者37例,總陽(yáng)性率為77.6%。(5)17p13異常與血紅蛋白水平負(fù)相關(guān)(P0.05),1q21異常與Alb負(fù)相關(guān)(P0.05),13q14異常與LDH水平正相關(guān)(P0.05),與PFS負(fù)相關(guān)(P0.05),14q32異常與PFS負(fù)相關(guān)(P0.05)。 (6)當(dāng)17p13位點(diǎn)正常時(shí),三藥方案比兩藥方案有顯著OS優(yōu)勢(shì)(均未達(dá)到)(χ2=3.583,P=0.012),而異常時(shí),二者差異無(wú)統(tǒng)計(jì)學(xué)意義(P0.05)。當(dāng)17p13與1q21兩位點(diǎn)均正常時(shí),三藥方案比兩藥方案有顯著OS優(yōu)勢(shì)(均未達(dá)到)(χ2=5.095,P=0.024),而兩位點(diǎn)中至少存在一個(gè)異常時(shí),三藥方案與兩藥方案無(wú)差異(P0.05)。 結(jié)論：使用以硼替佐米為基礎(chǔ)的聯(lián)合化療方案治療初發(fā)多發(fā)性骨髓瘤患者,不同治療組之間療效存在顯著性差異,三藥聯(lián)合方案(BAD. BCD及BDT方案)的反應(yīng)率顯著優(yōu)于兩藥方案(BD方案)。三藥聯(lián)合方案的PFS顯著優(yōu)于兩藥方案,OS不存在顯著性差異；年輕患者的PFS和OS均高于高齡患者。在17p13和1q21均正常的患者中,三藥聯(lián)合化療較兩藥化療有OS優(yōu)勢(shì),而17p13或1q21異常的患者中,則沒有這種優(yōu)勢(shì)。提示FISH檢測(cè)結(jié)果可能預(yù)測(cè)耐藥。
[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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R733.3
本文編號(hào)：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.
【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R733.3
【參考文獻(xiàn)】
相關(guān)期刊論文 前1條
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
，本文編號(hào)：2134590
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