本文選題：POEMS綜合征 + 來那度胺��； 參考：《北京協(xié)和醫(yī)學院》2015年博士論文

【摘要】：背景及目的：POEMS綜合征是一種高致殘性的克隆性漿細胞病,尚無標準治療。近年來,來那度胺在治療POEMS綜合征方面取得了較好的療效,但個體間差異較大,一部分患者可以獲得完全緩解,而另一部分患者則無效。既往針對多發(fā)性骨髓瘤的研究已經(jīng)證實cereblon (CRBN)是來那度胺作用的直接靶點分子,cereblon基因高表達的患者往往具有更好的藥物敏感性及療效。同時研究還發(fā)現(xiàn)cereblon下游靶基因IKZF1和IKZF3在來那度胺抗骨髓瘤方面也起到了重要作用。但在對不伴5q-的骨髓增生異常綜合征患者的研究中并未發(fā)現(xiàn)cereblon基因表達水平與來那度胺療效的相關(guān)性,提示來那度胺在不同疾病的治療中可能存在不同的作用機制。目前尚無關(guān)于cereblon基因表達水平與來那度胺治療POEMS綜合征療效相關(guān)性的研究。因此,本研究擬通過比較來那度胺治療有效組和無效組POEMS綜合征患者的骨髓漿細胞中基線cereblon、IKZF1、 IKZF3基因的mRNA及蛋白表達水平的差異,揭示出上述基因及蛋白與來那度胺治療POEMS綜合征療效的相關(guān)性。方法：通過對入組臨床試驗(一項單中心、開放性II期臨床試驗：評價來那度胺聯(lián)合地塞米松方案治療初治POEMS綜合征患者的有效性和安全性)的初治POEMS綜合征患者進行基線數(shù)據(jù)采集和隨訪,評價來那度胺治療POEMS綜合征的有效性、安全性及預后分析。收集北京協(xié)和醫(yī)院自2014年3月至2015年4月期間確診為POEMS綜合征的患者骨髓液和骨髓活檢組織,CD138免疫磁珠分選得到純化的CD138+漿細胞,采用real-time PCR的方法檢測所有患者CD138+漿細胞中cereblon, IKZF1, IKZF3基因的mRNA表達水平；采用連續(xù)切片免疫組化法檢測骨髓活檢組織的漿細胞中上述基因蛋白產(chǎn)物的水平。通過比較來那度胺治療有效組與無效組之間上述基因及蛋白表達的差異來探索上述基因及蛋白與來那度胺治療療效的相關(guān)性。結(jié)果：臨床試驗共入組41例初治POEMS綜合征患者,中位總體神經(jīng)功能限制評分(ONLS)為4分(1-10分),所有患者均接受來那度胺聯(lián)合地塞米松方案的治療。在中位隨訪時間10個月(2-14個月)后,血液學、神經(jīng)癥狀、血清VEGF水平、和臨床水負荷的總有效率分別達70%、90.2%、77.5%、和100%。治療期間無1例藥物相關(guān)死亡,僅1例患者出現(xiàn)3級皮疹。2例(4.9%)患者在治療期間因疾病進展而死亡,另1例(2.5%)因疾病進展轉(zhuǎn)行自體干細胞移植。1年疾病無進展生存(PFS)和疾病總生存(OS)分別為92.7%和95.1%。治療有效組和無效組POEMS綜合征患者其1年P(guān)FS分別為100%和62.5%(p=0.0006)；1年OS分別為100%和73%(p=0.0055)。我們通過進一步的研究發(fā)現(xiàn),治療有效的POEMS綜合征患者骨髓漿細胞中的基線cereblon基因的平均nRNA表達水平為2.51%,無效組為0.44%(P=0.005)。兩組IKZF1基因的表達分別為1.51%和0.18%(p=0.002)；IKZF3基因的平均表達水平為2.07%和0.51%(p=0.076)。在蛋白層面上,我們僅發(fā)現(xiàn)cereblon蛋白產(chǎn)物(CRBN)與來那度胺療效相關(guān)(p=0.029)。此外,我們還發(fā)現(xiàn)IKZF1基因的mRNA表達水平與疾病預后密切相關(guān),IKZF1低表達的患者具有更短的PFS(p= 0.02),臨床預后較差,但其對OS并無影響。結(jié)論：來那度胺對初治POEMS綜合征具有很好的療效,但是存在較大的個體差異,而患者骨髓CD138+漿細胞中基線cereblon, IKZF1的mRNA表達水平與來那度胺的療效密切相關(guān),上述基因高表達的患者具有更好的藥物療效；此外研究還發(fā)現(xiàn)IKZF1基因高表達的患者具有更長的PFS。
[Abstract]:Background and purpose: POEMS syndrome is a highly crippled cloned plasma cell disease. There is no standard treatment yet. In recent years, amido has achieved good results in the treatment of POEMS syndrome, but there is a large difference among individuals, some patients can get complete remission, and the other part of the patients are invalid. The study has confirmed that cereblon (CRBN) is a direct target molecule to the action of amines. The patients with high expression of cereblon gene often have better drug sensitivity and efficacy. Meanwhile, the study also found that the downstream target gene of cereblon, IKZF1 and IKZF3, also plays an important role in the anti myeloma of the amines, but in the bone marrow that does not accompany 5q-. In the study of patients with hyperplastic syndrome, there was no correlation between the cereblon gene expression level and the effect of amido, suggesting that amines may have different mechanisms of action in the treatment of different diseases. There is no study on the correlation between the expression level of cereblon gene and the effect of the treatment of POEMS syndrome on the treatment with amido. This study is to compare the differences in the mRNA and protein expression levels of the baseline cereblon, IKZF1, and IKZF3 genes in the myeloma cells of the effective and ineffective group POEMS syndrome, and to reveal the correlation between the gene and protein and the therapeutic effect of nalamines on the treatment of POEMS syndrome. (a single center, open II phase clinical trial: baseline data collection and follow-up for patients with primary POEMS syndrome treated with amidomide combined with dexamethasone regimen for patients with initial POEMS syndrome) to evaluate the efficacy, safety, and prognosis of the amines in the treatment of POEMS syndrome. Collection of Beijing Association The bone marrow fluid and bone marrow biopsy tissue of the patients with POEMS syndrome from March 2014 to April 2015 were selected and the purified CD138+ plasma cells were separated by CD138 immunomagnetic beads. The expression level of cereblon, IKZF1, IKZF3 gene in CD138+ plasma cells in all patients was detected by real-time PCR; continuous slice immunization was used. The level of the above gene protein products in the plasma cells of bone marrow biopsy tissue was detected by histochemical method. The correlation between the gene and protein expression of the above gene and protein was explored by comparing the difference of the expression of the above gene and protein between the effective group and the ineffective group. Results: 41 cases of POEMS synthesis in the clinical trial group were enrolled. The total median nerve function limit score (ONLS) was 4 (1-10). All patients received treatment with amido combined with dexamethasone. After a median follow-up period of 10 months (2-14 months), the total effective rate of Hematology, neurologic, serum VEGF, and clinical water load was 70%, 90.2%, 77.5%, and 100%., respectively. No 1 cases of drug-related death were found, only 1 patients had 3 rash.2 cases (4.9%) in.2 cases (4.9%), and 1 (2.5%) underwent autologous stem cell transplantation for.1 years of disease progression free survival (PFS) and disease total survival (OS), 92.7% and 95.1%., respectively, and the 1 year PF in the ineffective group of patients with POEMS syndrome. S was 100% and 62.5% (p=0.0006), and 1 years OS were 100% and 73% (p=0.0055). We found that the average nRNA expression level of the baseline cereblon gene in the myeloelt cells of the patients with effective POEMS syndrome was 2.51%, and the ineffective group was 0.44% (P= 0.005). The expression of the IKZF1 gene in the two group was 1.51% and 0.18% (p=0.0), respectively. 02); the average expression level of the IKZF3 gene was 2.07% and 0.51% (p=0.076). At the protein level, we only found that the cereblon protein product (CRBN) was associated with the therapeutic effect of amido (p=0.029). In addition, we also found that the mRNA expression of the IKZF1 gene was closely related to the prognosis of the disease, and the patients with low expression of IKZF1 had a shorter PFS (p= 0.02), and the clinical value of IKZF1 was shorter (p= 0.02). The prognosis is poor, but it has no effect on OS. Conclusion: amido has a good effect on the initial treatment of POEMS syndrome, but there is a large individual difference, while the baseline cereblon in the CD138+ plasma cell of the patient's bone marrow, the mRNA expression level of IKZF1 is closely related to the effect of the amines, and the above gene is better for the patients with the high expression of the gene. In addition, the study also found that patients with high IKZF1 expression had longer PFS..
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R597

【共引文獻】

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本文編號：2111810