伊马替尼治疗慢性髓细胞白血病患者耐药基因分析及伊马替尼血药浓度临床相关性研究
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摘要
目的探讨甲磺酸伊马替尼(格列卫,IM)治疗的慢性粒细胞性白血病(CML)耐药患者ABL激酶区点突变发生情况及在患者并发耐药中的意义；探讨伊马替尼血药浓度检测在指导CML治疗中的意义。
方法1、应用巢式RT-PCR对28例伊马替尼治疗效果欠佳及10例初诊慢性期CML患者不同时期的51份骨髓标本进行ABL激酶区扩增,对产物进行纯化、测序以及序列同源性比对,确定点突变的存在及类型。2、利用液相色谱-质谱联用法(LC-MS/MS)对153例正规服用伊马替尼治疗CML患者进行伊马替尼血浆浓度检测,分析血药浓度与患者一般特征及疗效等之间的关系。
结果1、38例患者共12例患者检出点突变(31.6%),分别为M351T2例,Q252H7例,E279K2例,E255V及E356G各1例；慢性期、加速期和急变期的突变发生率分别为17.6%(3／17)、41.7%(5／12)和44.4%(4／9)；血液学和遗传学耐药患者的突变发生率分别为50%(5／10)和44.4%(8／18),95%可信区间分别为12.3%-87.7%和19%-69.9%；发现点突变的12例患者疗效均欠佳,经过加量至600mg,随访3-24个月,均在治疗过程中出现疾病进展或死亡。2、伊马替尼血药浓度水平与患者性别(t=0.9988,P>0.05)、年龄(r=-0.09687)、身高(r=-0.0663)、体重(r=-0.1881)、体表面积(r=-0.1427)以及服用IM时间(r=0.0023)之间无显著相关性。3、111例标准剂量伊马替尼治疗CML患者中86例获得完全细胞遗传学缓解(CCyR),在Q1、Q2-3和Q4组分别为18例(67.7%,18／27)、50例(87.7%,50／57)和18例(67.7%,18／27),三组间χ2=7.04,P<0.05；86例获得CCyR患者的血浆谷浓度水平[(1643.45±594.10)ng/ml]高于25例未获得CCyR的患者血浆谷浓度水平[(830.48±117.35)ng／ml](P<0.05,t=6.78)；106例进行分子生物学评估的患者中,63例获得分子生物学缓解(MMR),IM血浆谷浓度水平[(1671.3±349.38)ng／ml]高于未获得MMR的43例患者IM血浆谷浓度水平[(925.49±147.47)ng／ml](t=13.202,P<0.05)。
结论
1、ABL激酶区点突变是伊马替尼治疗CML失败的重要原因之一。发生伊马替尼耐药的患者BCR/ABL基因ABL激酶区存在高频率的点突变,定期监测ABL激酶区点突变有助于早期采取干预措施,提高治疗水平,对避免丧失治疗时机具有重要意义。
2、加速、急变期CML患者突变检出率较高,出现突变提示预后不佳,应缩短观察时间,及时调整治疗方案；晚慢性期患者突变检出率高于标准慢性期患者,应定期进行基因突变检测并密切观察患者病情变化以便能及早采取措施进行干预。
3、伊马替尼血药浓度水平与患者性别、年龄、身高、体重、体表面积等一般特征无关。
4、服用400mg标准剂量进行治疗的慢性期CML患者中,Q2-3组患者中获得CCyR患者例数明显多于Q1及Q4组,获得CCyR患者IM血浆谷浓度水平均高于未获得CCyR的患者,提示一定范围内较高的血药浓度水平有助于提高CCyR率,取得更好治疗效果,但过高的血药浓度水平可能对患者治疗产生不利影响。
5、服用400mg标准剂量进行治疗的慢性期CML患者中,三组间分子生物学缓解率(MMR)无明显差异,但获得MMR患者IM血浆谷浓度水平高于未获得MMR的患者,提示较高的血药浓度可能有利于患者获得MMR,但最适浓度范围尚有待于进一步明确。
Objective To explore the occurrence of ABL kinase domain mutation in chronic myelogenous leukemia (CML) patients with resistant to imatinib (Gleevec, IM); Detecting the imatinib plasma concentrations of CML patients, further exploring its clinical significance.
Method 1.51 bone marrow samples of CML patients were collected including 28 cases with imatinib resistant and 10 cases with newly diagnosed during Different periods. ABL kinase domain of BCR-ABL allele was amplified by reverse tmnscription polymerase chain reaction(RT-PCR), followed by direct sequencing and sequence homology analysis to determine the existance of mutation.
2. Imatinib plasma concentrations of the 153 CML patients taking regular treatment of imatinib were detected with liquid chromatography-mass-spectrometry (LC-MS/MS), and the correlation between imatinib plasma concentrations and general characteristics of patients were analyzed.
Results 1.The point mutations were found in 12 of 38 patients, and all the 12 ones progressed to advanced disease or death.2 patients showed Met351Thr mutation,7 Glu252His and 2 Glu279Lys, the other types were Glu255Val and Glu356Gly, each of which was tested in one patient. The incidence of the point mutation was 17.6%,45.5% and 44.4% in chronic,accelerated and blast phase, respectively. The incidence of hematologically and genetically resistant patients is 50%(5/10) and 44.4%(8/18) and the 95%CI was 12.3%-87.7% and 19%-69.9%.
2. Imatinib in patients with plasma concentration levels and gender (t=0.9988, P> 0.05), age (r=-0.09687), height (r=-0.0663), body weight (r=-0.1881), body surface area (r =-0.1427), and taking IM time (r=0.0023) There was no significant correlation between the.
3. 111 cases of standard-dose imatinib in treatment of CML patients,86 cases achieved complete cytogenetic response (CCyR), In Q1, Q2-3, and Q4 group were 18 cases (67.7%,18/27),50 cases (87.7%,50/57) and 18 cases (67.7%,18/27),χ2= 7.04 among the three groups, P<0.05; 86 cases received CCyR plasma trough concentrations in patients with the level of [(1643.45±594.10) ng/ml] than 25 cases of patients without the CCyR Valley plasma concentrations [(830.48±117.35) ng/ml] (P<0.05, t=6.78); 86 cases received CCyR plasma trough concentrations in patients with the level of [(1643.45±594.10) ng/ml] than 25 cases of patients without the CCyR Valley plasma concentrations [(830.48±117.35) ng/ml] (P<0.05, t=6.78);
Conclusion 1.ABL kinase point mutation is an important mechanism of imatinib resistance, monitoring of the ABL kinase domain point mutation is helpful to estimate the prognosis and for therapeutic strategy adjustment. ABL kinase domain point mutations in imatinib treatment of CML is a major reason for failure. Occurs in patients with imatinib-resistant BCR/ABL gene ABL kinase domain point mutations with high frequency, regular monitoring of ABL kinase domain point mutations contribute to the early intervention measures to raise the treatment level, to avoid the loss of great significance to the treatment time.
2. Accelerated, blastic phase CML patients with a higher detection rate of mutation, there mutation prompted poor prognosis, should shorten the observation period, and promptly adjust treatment programs; late mutation detection rate in patients with chronic phase chronic phase in patients with higher than the standard should be regularly carried out mutation test and to closely observe the patient's condition changes in order to be able to take early steps to intervene.
3. Imatinib plasma concentration levels and patient sex, age, height, weight, body surface area independent of the general characteristics.
4. Taking standard dose (400mg) treatment of chronic phase CML patients, Q2-3 group of patients was significantly more than the number of cases of CCyR patients with Ql and Q4 group, access to CCyR plasma trough concentrations in patients with IM were higher than that without the CCyR patients with Tip within a certain range the higher the level of blood concentration help improve CCyR rate, to achieve better therapeutic effect, but the high blood concentration level may be a negative impact on patient care.
5. Taking standard dose (400mg) of IM for the treatment of chronic phase CML patients, among the three groups of molecular biology remission rate (MMR) no significant difference, but access to MMR in patients with IM of plasma trough concentrations higher than those of patients without the MMR, suggesting that the higher the blood drug concentration may be beneficial to patients with access to MMR, but the optimal concentration range of yet to be further clarified.
方法1、应用巢式RT-PCR对28例伊马替尼治疗效果欠佳及10例初诊慢性期CML患者不同时期的51份骨髓标本进行ABL激酶区扩增,对产物进行纯化、测序以及序列同源性比对,确定点突变的存在及类型。2、利用液相色谱-质谱联用法(LC-MS/MS)对153例正规服用伊马替尼治疗CML患者进行伊马替尼血浆浓度检测,分析血药浓度与患者一般特征及疗效等之间的关系。
结果1、38例患者共12例患者检出点突变(31.6%),分别为M351T2例,Q252H7例,E279K2例,E255V及E356G各1例；慢性期、加速期和急变期的突变发生率分别为17.6%(3／17)、41.7%(5／12)和44.4%(4／9)；血液学和遗传学耐药患者的突变发生率分别为50%(5／10)和44.4%(8／18),95%可信区间分别为12.3%-87.7%和19%-69.9%；发现点突变的12例患者疗效均欠佳,经过加量至600mg,随访3-24个月,均在治疗过程中出现疾病进展或死亡。2、伊马替尼血药浓度水平与患者性别(t=0.9988,P>0.05)、年龄(r=-0.09687)、身高(r=-0.0663)、体重(r=-0.1881)、体表面积(r=-0.1427)以及服用IM时间(r=0.0023)之间无显著相关性。3、111例标准剂量伊马替尼治疗CML患者中86例获得完全细胞遗传学缓解(CCyR),在Q1、Q2-3和Q4组分别为18例(67.7%,18／27)、50例(87.7%,50／57)和18例(67.7%,18／27),三组间χ2=7.04,P<0.05；86例获得CCyR患者的血浆谷浓度水平[(1643.45±594.10)ng/ml]高于25例未获得CCyR的患者血浆谷浓度水平[(830.48±117.35)ng／ml](P<0.05,t=6.78)；106例进行分子生物学评估的患者中,63例获得分子生物学缓解(MMR),IM血浆谷浓度水平[(1671.3±349.38)ng／ml]高于未获得MMR的43例患者IM血浆谷浓度水平[(925.49±147.47)ng／ml](t=13.202,P<0.05)。
结论
1、ABL激酶区点突变是伊马替尼治疗CML失败的重要原因之一。发生伊马替尼耐药的患者BCR/ABL基因ABL激酶区存在高频率的点突变,定期监测ABL激酶区点突变有助于早期采取干预措施,提高治疗水平,对避免丧失治疗时机具有重要意义。
2、加速、急变期CML患者突变检出率较高,出现突变提示预后不佳,应缩短观察时间,及时调整治疗方案；晚慢性期患者突变检出率高于标准慢性期患者,应定期进行基因突变检测并密切观察患者病情变化以便能及早采取措施进行干预。
3、伊马替尼血药浓度水平与患者性别、年龄、身高、体重、体表面积等一般特征无关。
4、服用400mg标准剂量进行治疗的慢性期CML患者中,Q2-3组患者中获得CCyR患者例数明显多于Q1及Q4组,获得CCyR患者IM血浆谷浓度水平均高于未获得CCyR的患者,提示一定范围内较高的血药浓度水平有助于提高CCyR率,取得更好治疗效果,但过高的血药浓度水平可能对患者治疗产生不利影响。
5、服用400mg标准剂量进行治疗的慢性期CML患者中,三组间分子生物学缓解率(MMR)无明显差异,但获得MMR患者IM血浆谷浓度水平高于未获得MMR的患者,提示较高的血药浓度可能有利于患者获得MMR,但最适浓度范围尚有待于进一步明确。
Objective To explore the occurrence of ABL kinase domain mutation in chronic myelogenous leukemia (CML) patients with resistant to imatinib (Gleevec, IM); Detecting the imatinib plasma concentrations of CML patients, further exploring its clinical significance.
Method 1.51 bone marrow samples of CML patients were collected including 28 cases with imatinib resistant and 10 cases with newly diagnosed during Different periods. ABL kinase domain of BCR-ABL allele was amplified by reverse tmnscription polymerase chain reaction(RT-PCR), followed by direct sequencing and sequence homology analysis to determine the existance of mutation.
2. Imatinib plasma concentrations of the 153 CML patients taking regular treatment of imatinib were detected with liquid chromatography-mass-spectrometry (LC-MS/MS), and the correlation between imatinib plasma concentrations and general characteristics of patients were analyzed.
Results 1.The point mutations were found in 12 of 38 patients, and all the 12 ones progressed to advanced disease or death.2 patients showed Met351Thr mutation,7 Glu252His and 2 Glu279Lys, the other types were Glu255Val and Glu356Gly, each of which was tested in one patient. The incidence of the point mutation was 17.6%,45.5% and 44.4% in chronic,accelerated and blast phase, respectively. The incidence of hematologically and genetically resistant patients is 50%(5/10) and 44.4%(8/18) and the 95%CI was 12.3%-87.7% and 19%-69.9%.
2. Imatinib in patients with plasma concentration levels and gender (t=0.9988, P> 0.05), age (r=-0.09687), height (r=-0.0663), body weight (r=-0.1881), body surface area (r =-0.1427), and taking IM time (r=0.0023) There was no significant correlation between the.
3. 111 cases of standard-dose imatinib in treatment of CML patients,86 cases achieved complete cytogenetic response (CCyR), In Q1, Q2-3, and Q4 group were 18 cases (67.7%,18/27),50 cases (87.7%,50/57) and 18 cases (67.7%,18/27),χ2= 7.04 among the three groups, P<0.05; 86 cases received CCyR plasma trough concentrations in patients with the level of [(1643.45±594.10) ng/ml] than 25 cases of patients without the CCyR Valley plasma concentrations [(830.48±117.35) ng/ml] (P<0.05, t=6.78); 86 cases received CCyR plasma trough concentrations in patients with the level of [(1643.45±594.10) ng/ml] than 25 cases of patients without the CCyR Valley plasma concentrations [(830.48±117.35) ng/ml] (P<0.05, t=6.78);
Conclusion 1.ABL kinase point mutation is an important mechanism of imatinib resistance, monitoring of the ABL kinase domain point mutation is helpful to estimate the prognosis and for therapeutic strategy adjustment. ABL kinase domain point mutations in imatinib treatment of CML is a major reason for failure. Occurs in patients with imatinib-resistant BCR/ABL gene ABL kinase domain point mutations with high frequency, regular monitoring of ABL kinase domain point mutations contribute to the early intervention measures to raise the treatment level, to avoid the loss of great significance to the treatment time.
2. Accelerated, blastic phase CML patients with a higher detection rate of mutation, there mutation prompted poor prognosis, should shorten the observation period, and promptly adjust treatment programs; late mutation detection rate in patients with chronic phase chronic phase in patients with higher than the standard should be regularly carried out mutation test and to closely observe the patient's condition changes in order to be able to take early steps to intervene.
3. Imatinib plasma concentration levels and patient sex, age, height, weight, body surface area independent of the general characteristics.
4. Taking standard dose (400mg) treatment of chronic phase CML patients, Q2-3 group of patients was significantly more than the number of cases of CCyR patients with Ql and Q4 group, access to CCyR plasma trough concentrations in patients with IM were higher than that without the CCyR patients with Tip within a certain range the higher the level of blood concentration help improve CCyR rate, to achieve better therapeutic effect, but the high blood concentration level may be a negative impact on patient care.
5. Taking standard dose (400mg) of IM for the treatment of chronic phase CML patients, among the three groups of molecular biology remission rate (MMR) no significant difference, but access to MMR in patients with IM of plasma trough concentrations higher than those of patients without the MMR, suggesting that the higher the blood drug concentration may be beneficial to patients with access to MMR, but the optimal concentration range of yet to be further clarified.
引文
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17. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and-intolerant chronic-phase chronic myeloid leukemia. JClin Oncol. 2008 Jul 1;26(19):3204-3212.
18. O'Srien S, GilesF, TalpazM,etal.Results of triple therapy with interferon-alpha, cytarabine, and homoharringtonine, and the impactof adding imatinib to the treatment sequence in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in early chronic phase. Cancer,2003; 98:888-893.
19. Chen R, Benaissa S, PlunkettW. A sequential blockade strategy to target the Bcr/Abl oncoprotein in chronicmyelogenous leukemia with STI571 and the protein synthesis inhibitor homoharringtonine. Proc Am Assoc CancerRes,2003; 44:34.
20.卢润章,邱林等.三氧化二砷对伊马替尼耐药bcr-abl基因突变细胞株生长抑制作用的研究.中华血液学杂志.2009,30(1)：13-17.
21. Peters DG. Hoover RR, Gerlach MJ, et al. Activity of the farnesyl protein transferase inhibitor SCH66336 against BCR/ABL-induced murine leukemia and primary cells from patients with chronic myeloid leukemia.Blood,2001,97(5):1404-12.
22.Nakajilna A, Tauctli T, sumi M, et al.Emcacy of sCH66336, afarnesyl transferase inhibitor, in conjunction with imatinib against BCR-ABL-positive cells. M01 Cancer Ther,2003;2:219-224.
23. Combined treatment depends on the underlying mechanism of resistance in imatinib-resistant Bcr-Abl positive cell lines. Blood,2004; 103:208-215.
24.NimmanapalliR, Fuino L, Stobaugh C,etal.Cotreatmentwith the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl positivehuman acute leukemia cells. Blood,2003; 101,3236-3239.
25. Yu C, Rahmani M, Almenara J,et al.Histone deacetylase inhibitors promote STI571-mediated apoptosis in STI571-sensitive and resistantBcr/Abl+humanmyeloid leukemia cells.CancerRes,2003; 63:2118-2126.