甲磺酸伊马替尼治疗慢性粒细胞白血病需注意的问题

甲磺酸伊马替尼（Imatinib mesylate，简称Im）的问世是一个多世纪以来慢性粒细胞白血病（CML）治疗的重大突破。它是当今惟一可以使CML达到分子效应的药物。20世纪末，国际多中心Ⅱ期临床试验共1000余例证明Im对干扰素α（IFN-α）治疗失效或不能耐受的CML慢性期（CP）、加速期（AP）、急变期（BP）的完全血液学缓解（CHR）率分别为95％、34％和8％，完全遗传学缓解（CCyR）率分别为41％、17％和7％，进展率分别为11％，40％和80％。不良反应多可耐受或可控制。严重不良反应发生率在各期为1％、2％和5％。证明了Im的安全性和有效性。它对CML各期均有效但疗效随疾病进展递减，对BP患者的疗效维持时问不长。由于Im的突出疗效，2001年5月美国FDA经快通道批准了该药用于治疗对IFN-α失效或不能耐受的CML—CP、AP和BP患者。     

亲缘异基因造血干细胞移植联合甲磺酸伊马替尼治疗Ph阳性白血病

背景：造血干细胞移植是可以治愈Ph＋白血病有效方法,甲磺酸伊马替尼是一种高度特异的酪氨酸激酶抑制剂,能抑制BCR/ABL酪氨酸激酶活性,在Ph＋白血病中的应用越来越多。目的：探讨甲磺酸伊马替尼联合亲缘异基因造血干细胞移植治疗Ph＋白血病的临床疗效。方法：回顾性分析2011年1月至2012年10月采用亲缘异基因造血干细胞移植联合甲磺酸伊马替尼治疗12例Ph＋白血病的疗效并文献复习。结果与结论：12例患者移植后均获得造血重建,移植后中性粒细胞和血小板植活的中位时间分别为15 d和18 d;发生Ⅱ度急性移植物抗宿主病7例,Ⅲ度急性移植物抗宿主病1例,局限型慢性移植物抗宿主病7例,广泛型慢性移植物抗宿主病3例;无白血病存活率为67%,移植相关死亡率为25%。行HLA匹配亲缘造血干细胞移植者的总体存活率为75.0%。平均无病生存8.5个月（7-17个月）,BCR/ABL转阴时间2-5个月。亲缘异基因造血干细胞移植前、后联合甲磺酸伊马替尼治疗Ph＋白血病,具有降低移植前白血病细胞负荷,抑制残留白血病细胞增殖,促进供者完全嵌合状态的转变,是一种安全有效的治疗方法。     

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.     

Acute renal failure secondary to imatinib mesylate treatment in prostate cancer

OBJECTIVE: To report a case of acute renal failure associated with the administration of imatinib mesylate. CASE SUMMARY: A 64-year-old man diagnosed with prostate cancer was enrolled in a Phase I trial of imatinib mesylate plus taxotere on a protocol that required a run-in period of imatinib mesylate alone. During therapy with imatinib mesylate, the patient developed acute renal failure, requiring hemodialysis. A renal biopsy revealed tubular vacuolization. Renal failure resolved with cessation of imatinib mesylate. DISCUSSION: Imatinib mesylate is a protein tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the receptor tyrosine kinases for platelet-derived growth factor, and stem cell factor c-kit. Prostate cancer has been identified as a target for therapy with imatinib mesylate. This patient had no other confounding factors for the cause of the renal failure. An objective causality assessment determined that imatinib mesylate was the probable cause of the acute renal failure. The presence of a primary glomerular disease was excluded by biopsy. CONCLUSIONS: Imatinib mesylate-induced acute renal failure has now been linked to toxic effects on renal tubular cells in 3 cases. Renal function should be closely monitored during imatinib mesylate therapy.     

Cost-utility analysis of imatinib mesylate for the treatment of chronic myelogenous leukemia in the chronic phase

BACKGROUND: Imatinib mesylate is a targeted therapy for the treatment of chronic myeloid leukemia (CML). OBJECTIVE: The aim of this study was to estimate the incremental cost-utility of imatinib mesylate compared with hydroxyurea in patients with chronic-phase CML for whom first-line treatment with interferon-alpha failed to produce a response. METHODS: A Markov model was developed to simulate disease progression for hypothetical patients receiving imatinib mesylate or hydroxyurea, who had not previously responded to interferon-a therapy, to determine outcomes in terms of quality-adjusted life-years (QALYs). Costs were estimated from the perspective of the United Kingdom National Health Service. Patient data were derived from previously published trials. RESULTS: The Markov model simulated the transitions of a hypothetical sample of 1000 chronic-phase CML patients using 1 monthly cycle over the lifetime of the patient sample. Median survival rates were estimated to be 77 months for imatinib mesylate-treated patients and 56 months for hydroxyurea-treated patients. Patients receiving imatinib mesylate accrued 5.95 QALYs, whereas hydroxyurea-treated patients accrued 3.49 QALYs. The estimated per-patient lifetime costs were 110,103 pound sterlings for patients in the imatinib mesylate group and 15,566 pound sterlings for patients in the hydroxyurea group (year-2001 values). The estimated year-2001 incremental cost per QALY gained from using imatinib mesylate compared with hydroxyurea in chronic phase CML was 38,468 pound sterlings. CONCLUSIONS: In the present model analysis, imatinib mesylate as a second-line treatment for patients with chronic phase CML was found to offer considerable health benefits to patients, but at a cost to the payer. The incremental cost-effectiveness ratio was 38,468 pound sterlings (year-2001 values).     

Effect of St John's wort on imatinib mesylate pharmacokinetics

OBJECTIVE: Imatinib is a potent inhibitor of the Bcr-Abl and c- kit tyrosine kinases and is approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Because imatinib is predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it is coadministered with drugs or herbs (eg, St John's wort) that modulate CYP3A4 activity.Thus we examined the effects of St John's wort on imatinib pharmacokinetics. METHODS: This 2-period, open-label, fixed-sequence study was completed by 12 healthy subjects (6 men and 6 women) aged between 20 and 51 years. Each subject received 400 mg imatinib orally on study day 1, St John's wort (300 mg 3 times daily) on days 4 to 17, and 400 mg imatinib again on day 15. Serial blood samples were obtained over a 72-hour period after each imatinib dose. Imatinib and N -desmethyl-imatinib (CGP 74588) were quantified in plasma by liquid chromatography-mass spectrometry. RESULTS: St John's wort administration increased imatinib clearance by 43% ( P < .001), from 12.5 +/- 3.6 L/h to 17.9 +/- 5.6 L/h; imatinib area under the concentration versus time curve (AUC) extrapolated to infinity was decreased by 30%, from 34.5 +/- 9.5 microg . h/mL to 24.2 +/- 7.0 microg . h/mL ( P < .001). Imatinib half-life (12.8 hours versus 9.0 hours) and maximum concentration (C max ) (2.2 microg/mL versus 1.8 microg/mL) were also significantly decreased ( P < .005). N -desmethyl-imatinib C max was increased from 285 +/- 95 ng/mL to 318 +/- 95 ng/mL during St John's wort dosing, but the AUC from 0 to 72 hours was not altered. CONCLUSIONS: These data indicate that St John's wort increases imatinib clearance. Thus patients taking imatinib should avoid taking St John's wort. Concomitant use of enzyme inducers, including St John's wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.     

甲磺酸伊马替尼治疗慢性髓系白血病的临床研究及血药浓度监测

目的 观察甲磺酸伊马替尼(IM)治疗慢性髓系白血病(CML)的疗效,并分析血浆药物谷浓度水平与临床疗效及不良反应的关系.方法 观察101例CML患者接受IM治疗的疗效,并采用液相色谱-串联质谱法检测其中30例CML-慢性期(CP)患者IM血浆药物谷浓度.结果 ①89例CML-CP患者总的完全血液学缓解率(CHR)、主要细胞遗传学缓解率(MCyR)、完全细胞遗传学缓解率(CCyR)和BCR-ABL融合基因转阴率分别为96.6%、86.5%、77.5%和47.2%;12例CML进展期(加速期和急变期)患者的CHR、MCyR、CCyR、BCR-ABL转阴率分别为58.3%、25.0%、25.0%、8.3%.②服用IM 1年时获得CCyR患者的平均血浆药物谷浓度[(1472±482)μg/L]明显高于未获得CCyR者[(1067±373)μg/L],两者间差异有统计学意义(P＜0.05).服用IM 1年时获得主要分子学缓解(MMR)患者的平均血浆药物谷浓度[(1624 ±468)μg/L]也明显高于未获得MMR的患者[(1137±404)μg/L,P＜0.05].结论 IM明显提高CML患者细胞遗传学和分子学疗效.CML-CP期患者的疗效(1年时CCyR与MMR)与IM血浆药物谷浓度之间存在相关性.

Abstract：

Objective To analyze the clinical efficacy of imatinib mesylate (IM) for Ph-positive or BCR-ABL positive chronic myeloid leukemia( CML) to couple the trough plasma concentrations(Cmins) of IM with clinical responses and adverse events (AEs).Methods One hundred and one CML patients received IM therapy, and Cmins of IM were determmined in 30 patients.Results ①Cumulative complete hematological response( CHR) , major cytogenetic response ( MCyR ), complete cytogenetic response ( CCyR ) and negative BCR/ABL fusion gene rates were 96.6% , 86.5% ,77.5% and 47.2% , respectively, in CMLCP patients.In accelerated and blastic phases(AP and BC) patients, CHR, MCyR, CCyR and negative BCR-ABL fusion gene rates were 58.3% , 25.0% , 25.0% , 8.3%, respectively.②Mean Cmins of IM was significantly higher in the CCyR at 1 year[( 1472 ±482) μg/L]group than in the non-CCyR at 1 years group[(1067 ±373)μg/L](P＜0.05), and higher in the MMR at 1 year group than in the non-MMR at 1 years group[( 1624 ±468) μg/L as (1137 ±404) μg/L, P ＜0.05].Conclusion IM significantly improves cytogenetic and molecular response, envent-free survival, and overall survival for patients with Ph-positive CML.The Cmins of IM exerts a significant impact on clinical response (CCyR and MMR at 1 year).     

格列卫对博莱霉素致小鼠肺纤维化的干预作用

目的 观察酪氨酸激酶抑制剂格列卫对小鼠肺纤维化的干预作用，并探讨其作用机制。方法 120只C57BL／6小鼠被随机分为对照组、模型组、地塞米松组和格列卫组，每组30只。采用气管穿刺注入博莱霉素制备肺纤维化小鼠模型。分别于制模后7、14和21d处死动物，观察各组肺组织病理学变化、肺系数、肺组织羟脯氨酸（HYP）含量及血小板源性生长因子-BB（PDGF—BB）的表达。结果 与对照组比较，模型组动物术后不同时间点肺系数明显增加（P均〈0．05），肺泡炎分级和肺纤维化程度均明显增加（P均〈0．01），肺组织HYP含量明显升高（P均〈0．05），且随术后时间延长不断增加；而PDGF—BB含量也明显高于对照组（P均〈0．05），但随术后时间延长逐渐恢复降低。与模型组比较，格列卫组与地塞米松组的肺泡炎分级和肺纤维化程度均明显减轻，HYP含量和肺组织PDGF—BB表达均降低（P〈0．05或P〈0．01）；格列卫组上述各指标较地塞米松组稍好转；但两组间各指标比较差异均无显著性（P均〉0．05）。结论 格列卫能明显抑制博莱霉素诱导的小鼠肺纤维化过程。     

我国慢性髓系白血病患者服用伊马替尼血药浓度的初步分析

目的 评价我国慢性髓系白血病(CML)患者接受伊马替尼治疗的血浆谷浓度水平,以及伊马替尼血药浓度对临床个体化治疗的指导意义.方法 对全国6家综合性医院入组的416例CML患者进行伊马替尼治疗后血浆谷浓度检测,评价伊马替尼血浆谷浓度与患者年龄、体重、体表面积的相关性以及与剂量、疗效的关系.结果 ①伊马替尼血浆谷浓度与患者年龄、体重和体表面积均无明显相关性.②中位伊马替尼血浆谷浓度为1271( 109 ～4329) μg/L.伊马替尼血浆谷浓度与伊马替尼服用剂量有关,服用剂量＜400 mg/d、400 mg/d和＞400 mg/d组在伊马替尼血浆谷浓度分别为(969±585)、(1341±595)和(1740±748)μg/L(P ＜0.01).③获得完全细胞遗传学反应(CCyR)与未获得CCyR患者伊马替尼血浆谷浓度分别为(1337±571) μg/L和(1354±689) μg/L,差异无统计学意义(P =0.255).④伊马替尼血浆谷浓度对部分患者治疗具有指导意义.结论 我国CML患者服用伊马替尼后血药浓度的个体差异大;伊马替尼血浆谷浓度与其获得CCyR之间无明显相关性;增加伊马替尼剂量能提高伊马替尼血浆谷浓度,对于部分患者的治疗有一定的指导意义.     

Analysis of plasma trough level of imatinib in Chinese CML patients

OBJECTIVE: To evaluate the relationship between plasma trough level of imatinib and clinical outcomes in Chinese CML patients. Methods Plasma trough levels in 416 CML patients who received imatinib orally in six general hospitals were assessed. The correlations of imatinib plasma trough level with baseline characteristics including age, weight and BSA, and clinical response were evaluated. RESULTS: (1) Effects of age, body weight and BSA on imatinib plasma trough levels were not to be clinically significant. (2) Median imatinib plasma trough levels was 1271 (109-4329). Imatinib plasma trough level was related to dose of imatinib administration. Plasma trough levels at imatinib of dose < 400, 400 and > 400 mg were (969 ± 585), (1341 ± 595) and (1740 ± 748) μg/L (P < 0.01), respectively. (3) There was no statistic difference in imatinib plasma trough level with complete cytogenetic response [CCyR (1337 ± 571) μg/L vs no CCyR (1354 ± 689) μg/L, P = 0.255]. (4) Imatinib plasma trough level might be important for a good clinical response in some CML patients. Conclusion There was a large interpatient variability in imatinib plasma concentration in Chinese CML patients. No correlation of imatinib plasma trough level with CCyR was observed. However, higher doses of imatinib were shown to attain greater trough plasma concentration, suggesting that imatinib plasma trough level might be important for a good clinical response in some CML patients.     

低分级脑星形细胞瘤术后放疗或放化疗综合治疗的临床分析

目的　对50例低分级脑星形细胞瘤(kernohan分级法Ⅰ、Ⅱ期)术后单纯放疗或放化疗综合治疗的 患者进行回顾性生存分析。方法　1994年1月～1998年12月我科收住低分级脑星形细胞瘤50例,均有术后病理 证实,根据术后治疗方案不同分为两组,即单纯放疗组予术后放疗,总剂量为50～66Gy;放化疗综合组予术后放疗 结束后再静脉给药化疗。结果　单纯放疗组1、3、5年生存率分别为100%、75.0%、53.6%,放化疗综合组1、3、5 年生存率分别为95.5%、72.7%、45.5%,两者无显著差异P>0.05。结论　对低分级脑星形细胞瘤术后放疗后不 提倡加用化疗。     

伊马替尼治疗伴有嗜酸粒细胞增多的髓系肿瘤疗效观察

目的 评价伊马替尼治疗伴有嗜酸粒细胞增多的髓系肿瘤的疗效.方法 对8例有PDGFRα基因异常的伴嗜酸粒细胞增多的髓系肿瘤及1例慢性嗜酸粒细胞白血病,不另做分类(CEL,NOS)患者门服伊马替尼100 mg/d或400 mg/d进行疗效观察.结果 中位随访16(6～26)个月,血液学缓解率100%,其中完全血液学缓解(CHR)率87.5%,部分血液学缓解率12.5%.完全分子生物学缓解(CMR)率85.7%,FIP1L1-PDGFRα融合基因转阴中位时间4(1.5～8)个月.3例获得CMR后停药,停药后中位随访时间12(9～22)个月,均未复发.伊马替尼不良反应轻微,轻度骨髓抑制发生率37.5%,中位发生时间6(4～9)d.结论 伊马替尼治疗有PDGFRα基因异常的伴嗜酸粒细胞增多的髓系肿瘤有较高的CHR和CMR,起效迅速,不良反应轻微,患者易于耐受.     

Kaposi's sarcoma in a patient treated with imatinib mesylate for chronic myeloid leukemia

Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder primarily characterized by the presence of the Philadelphia chromosome resulting from a reciprocal translocation between the long arms of chromosomes 9 and 22. This translocation determines a fusion gene, bcr-abl, which encodes a constitutively active protein, tyrosine kinase, resulting in decreased apoptosis, defective adhesion, and genomic instability in transformed cells. The tyrosine kinase activity and its effects represent a potential pharmacologic target of tyrosine kinase inhibitors, such as imatinib. Flare of Kaposi's sarcoma (KS) is well described in immunosuppressed patients treated with corticosteroids and rituximab, but has not yet been reported during treatment with imatinib.Objective: We report a case of cutaneous KS lesions in a patient affected by CML treated with imatinib.Case summary: A 61-year-old white male patient (weight, 90 kg) was diagnosed with CML in March 2006 at the Division of Hematology, University of Rome “Tor Vergata,” Rome, Italy. He was treated with imatinib 400 mg/d, which improved his general condition with few adverse effects. After 12 months of treatment, molecular biology showed an important reduction in the peripheral blood of the fusion oncoprotein bcr-abl p210-b3a2. However, at the same time, multiple cutaneous violaceous papular-nodular lesions appeared on his left forearm. A punch biopsy showed the presence of KS, whereas a polymerase chain reaction assay documented the presence of human herpes virus type 8 (HHV8) DNA in the skin lesion. Serologic HIV was negative and HHV8 viremia was under the limit of quantitation of the assay. Total body computed tomography scan did not reveal any mucosal or visceral lesion.Conclusions: We present a case of a patient with CML who developed KS 12 months after starting treatment with imatinib 400 mg/d. The mechanism behind the development of the cutaneous lesions is unclear, and could have either a casual clinical association or be related to the study drug. According to the Naranjo adverse drug reaction probability scale, the development of KS in this case was probably associated with the imatinib treatment (score, 5–8).     

Treatment of rheumatoid arthritis with imatinib mesylate: clinical improvement in three refractory cases

BACKGROUND. Imatinib mesylate is an inhibitor of a few tyrosine kinases including KIT, which is an important growth factor receptor of mast cells. AIM. To study the efficacy and safety of imatinib in the treatment of rheumatoid arthritis. METHOD. Three patients with severe rheumatoid were treated with imatinib for 12 weeks. The number of tender and swollen joints, patient-assessed disease activity and pain as assessed by a visual analogue scale, a health assessment questionnaire (HAQ) score, serum C-reactive protein (CRP) and blood erythrocyte sedimentation rate (ESR) were used as the primary outcome measures. RESULTS. All outcome measures improved. The swollen joint count decreased in all patients, and the tender joint count in two of the three patients. The patients reported less pain and disease activity, and the HAQ scores improved. Serum CRP and blood ESR improved in two patients. One patient interrupted therapy due to a rash. CONCLUSIONS. Imatinib mesylate may have considerable anti-rheumatic efficacy. The mechanism of action is not known, but one possible target for the action of imatinib is inhibition of the KIT receptor on mast cells.