伊马替尼一线治疗慢性粒细胞白血病慢性期患者- 单中心十年回顾性分析*

目的:总结以伊马替尼为一线治疗的慢性粒细胞白血病（chroni cmyeloid leukemia,CML ）初治患者的疗效和生存。方法:回顾性分析南昌大学第一附属医院2003年1 月至2013年12月间收治的295 例CML 初治患者的临床资料,其中185 例为入组格列卫全球患者援助项目（GIPAP）行伊马替尼治疗、30例为干扰素（IFN-α）治疗、50例为羟基脲单药治疗和30例为异基因外周血造血干细胞移植（allogeneic hematopoietic stem cell transplantation ,Allo-HSCT）治疗的患者,分析各组患者的治疗疗效和生存情况。结果:伊马替尼治疗组和Allo-HSCT 治疗组患者完全血液学缓解率（complete hematologic remission ,CHR ）均为96.7% ,完全细胞遗传学缓解率（complete cytogenetic remission,CCyR）为89.7% 和93.3% ,完全分子学缓解率（complete molecular remission ,CMoR）为49.7% 和83.3%（P = 0.001）;而干扰素和羟基脲治疗组CHR 、CCyR和CMoR 均明显低于伊马替尼治疗组和Allo-HSCT 治疗组。伊马替尼组患者的总生存时间（overall survival,OS）明显优于其他组（P < 0.001）,甚至优于Allo-HSCT 治疗组（10年OS为89.0% vs .67.0% ,P < 0.001）。 Cox 多因素分析显示接受伊马替尼治疗（HR= 5.267,95%CI 为1.054～1.940,P = 0.022）和获得CCyR（HR= 9.541,95%CI 为1.692～10.513,P = 0.002）是影响本组患者预后良好的独立因素。结论:CML 初治患者接受伊马替尼治疗可以获得更高的CHR 和CCyR,且OS更优,伊马替尼适合作为中国初治CML 患者的一线治疗。      

伊马替尼治疗中miRNA在慢性粒细胞白血病患者中的表达

目的:探讨miRNA在服用伊马替尼治疗慢性粒细胞性白血病（CML）患者中的表达水平以及与CML患者服用伊马替尼后病情进展的关系。方法:收集慢性粒细胞白血病初诊敏感患者和病情进展患者的骨髓标本共35例。制备骨髓单个核细胞并提取总RNA,利用紫外分光光度仪检测RNA提取液的浓度和纯度,最后利用real-time PCR技术检测microRNA-21、microRNA-10a、microRNA-31、microRNA-34a、microRNA-155在敏感组和进展组中的相对表达水平。结果:慢性粒细胞白血病患者服用伊马替尼后进展组白血病细胞中microRNA-21（miR-21）的表达明显高于敏感组,miR-10a、miR-31、miR-34a、miR-155在两组患者骨髓单个核细胞中的表达水平无显著统计学意义（P＞0.05）。结论:miR-21的高表达可能与慢性粒细胞性白血病患者服用伊马替尼后病情进展有关。     

伊马替尼对慢性粒细胞白血病患者生育及生殖的影响

伊马替尼对慢性粒细胞白血病的分子靶向性治疗获得了极大的成功,病人的生存时间延长,生活质量接近正常人。由于伊马替尼可能导致畸形,通常建议患者服药治疗期间避免妊娠。近年来,伊马替尼治疗的患者中选择妊娠及合并妊娠、成功分娩的个案多有报告,但尚无流行病学的大样本研究结果支持伊马替尼治疗的患者可以选择生育,对伊马替尼治疗影响生育和生殖的研究也仅停留于动物实验。本文就伊马替尼对慢性粒细胞白血病患者生育和生殖的影响作一综述。     

伊马替尼联合造血干细胞移植或化疗治疗bcr-abl+急性淋巴细胞白血病

 目的　探讨伊马替尼联合异基因造血干细胞移植（allo-HSCT）或化疗治疗bcr-abl+融合基因成年人急性淋巴细胞白血病（ALL）（以下简称成年人ALL）的疗效。方法　12例成年人ALL经骨髓细胞学、细胞化学、免疫学表型、bcr-abl融合基因检测确诊为bcr-abl+ ALL（B细胞型）。初治时接受伊马替尼联合化疗诱导治疗,伊马替尼剂量为400 mg／d。完全缓解（CR）后8例接受allo-HSCT治疗,移植后bcr-abl融合基因转为阳性者给予伊马替尼（400～600 mg／d）治疗,3例接受伊马替尼与化疗交替巩固治疗。结果　11例获得CR,CR率91.7 %;诱导治疗2个疗程时bcr-abl融合基因转阴率为41.7 %;8例接受移植患者3例复发,3例化疗与伊马替尼交替巩固治疗的患者2例复发,伊马替尼联合造血干细胞移植组与伊马替尼联合化疗组患者的中位缓解期分别为16个月与10个月（P＜0.01）;中位生存期为18个月与12个月（P＜0.01）。结论　伊马替尼联合化疗诱导治疗bcr-abl+成年人ALL有较高的血液学和分子生物学缓解率,伊马替尼联合allo-HSCT的疗效优于伊马替尼联合化疗。     

咖啡酸治疗伊马替尼致慢性粒细胞白血病患者血小板、白细胞减少的临床观察

 【摘要】　目的　观察咖啡酸（CFA）对伊马替尼致慢性粒细胞白血病（CML）患者血小板、白细胞减少的临床疗效和患者不良反应。方法　对42例应用伊马替尼治疗后出现血小板、白细胞减少的CML患者,血小板和（或）白细胞减少时即开始应用CFA,0.2 g／次,3次／d,口服,观察治疗过程中血小板、白细胞变化情况和患者不良反应。结果　治疗血小板减少42例,其中显效21例,良效13例,无效8例,总有效率81.0 %（34／42）;治疗白细胞减少28例,其中显效15例,良效8例,无效5例,总有效率82.1 %（23／28）;治疗第2周时血小板、白细胞计数与治疗前相比差异有统计学意义（t＝2.015,P＝0.023;t＝1.913,P＝0.035 ）;CFA治疗有效患者的平均起效时间为2周。未发现治疗相关不良反应。结论　CFA治疗伊马替尼所致的CML患者血小板、白细胞减少疗效确切,无明显不良反应,是CML治疗过程中安全有效的辅助治疗药物。     

伊马替尼联合HAG方案治疗慢性粒细胞白血病急变期临床观察

 目的　探讨使干扰素治疗失败的慢性粒细胞白血病（CML）急变期达完全缓解的有效方法。方法　CML急变期患者8例,Ph染色体、bcr-abl融合基因均阳性。2例出现附加染色体。每例患者急变前除应用羟基脲外,均应用过3个月以上干扰素,5例患者曾用含阿糖胞苷（Ara-C）的不同方案化疗,均未服用伊马替尼。8例急变期患者均服用伊马替尼600 mg／d,联合HAG方案[高三尖杉酯碱（HH）1～2 mg／d,Ara-C 15～25 mg每12 h 1次,粒细胞集落刺激因子（G-CSF）200 μg／m2]。根据患者年龄、血常规、骨髓象决定用药剂量及时间长短。结果　2例达血液学部分缓解,6例达血液学完全缓解,继续服用伊马替尼600 mg／d。6例血液学完全缓解者达遗传学缓解,生存时间6（3～9）个月,均未达分子生物学缓解。中位血液学复发时间10（3～26）个月,伊马替尼联合HAG方案治疗中位生存时间17（8～28）个月。结论　伊马替尼联合HAG方案治疗CML急变期患者安全有效。     

干扰素、亚砷酸联合酪氨酸激酶抑制剂治疗原发T315I突变慢性粒细胞白血病一例并文献复习

目的 探讨干扰素、亚砷酸联合酪氨酸激酶抑制剂(TKI)治疗原发T315I突变慢性粒细胞白血病(CML)的效果.方法 应用干扰素、亚砷酸联合TKI(伊马替尼)治疗1例原发T315I突变的CML患者,并进行文献复习.结果 CML加速期患者应用亚砷酸联合伊马替尼治疗1周后达完全血液学缓解;更换为干扰素联合尼洛替尼治疗6个月后,达部分细胞遗传学缓解,T315I突变消失.结论 干扰素、亚砷酸联合TKI可作为原发T315I突变CML的有效治疗手段.     

伊马替尼联合HAG方案治疗慢性粒细胞白血病急变期临床观察

目的 探讨使干扰素治疗失败的慢性粒细胞白血病(CML)急变期达完全缓解的有效方法.方法 CML急变期患者8例,Ph染色体、bcr-abl融合基因均阳性.2例出现附加染色体.每例患者急变前除应用羟基脲外,均应用过3个月以上干扰素,5例患者曾用含阿糖胞苷(Ara-C)的不同方案化疗,均未服用伊马替尼.8例急变期患者均服用伊马替尼600 mg/d,联合HAG方案[高三尖杉酯碱(HH)1～2mg/d,Ara-C 15～25mg每12h 1次,粒细胞集落刺激因子(G-CSF)200μg/m2].根据患者年龄、血常规、骨髓象决定用药剂量及时间长短.结果 2例达血液学部分缓解,6例达血液学完全缓解,继续服用伊马替尼600mg/d.6例血液学完全缓解者达遗传学缓解,生存时间6(3～9)个月,均未达分子生物学缓解.中位血液学复发时间10(3～26)个月,伊马替尼联合HAG方案治疗中位生存时间17(8～28)个月.结论 伊马替尼联合HAG方案治疗CML急变期患者安全有效.     

伊马替尼联合HAG方案治疗慢性粒细胞白血病急变期临床观察

目的 探讨使干扰素治疗失败的慢性粒细胞白血病(CML)急变期达完全缓解的有效方法.方法 CML急变期患者8例,Ph染色体、bcr-abl融合基因均阳性.2例出现附加染色体.每例患者急变前除应用羟基脲外,均应用过3个月以上干扰素,5例患者曾用含阿糖胞苷(Ara-C)的不同方案化疗,均未服用伊马替尼.8例急变期患者均服用伊马替尼600 mg/d,联合HAG方案[高三尖杉酯碱(HH)1～2mg/d,Ara-C 15～25mg每12h 1次,粒细胞集落刺激因子(G-CSF)200μg/m2].根据患者年龄、血常规、骨髓象决定用药剂量及时间长短.结果 2例达血液学部分缓解,6例达血液学完全缓解,继续服用伊马替尼600mg/d.6例血液学完全缓解者达遗传学缓解,生存时间6(3～9)个月,均未达分子生物学缓解.中位血液学复发时间10(3～26)个月,伊马替尼联合HAG方案治疗中位生存时间17(8～28)个月.结论 伊马替尼联合HAG方案治疗CML急变期患者安全有效.     

干扰素联合化疗与伊马替尼治疗慢性粒细胞白血病的疗效比较分析

目的比较分析干扰素联合化疗与伊马替尼治疗慢性粒细胞白血病(CML)的临床疗效。方法 72例新诊断的Ph染色体阳性CML慢性期患者根据治疗方案的不同随机分为干扰素联合化疗组和伊马替尼组,并比较2组临床疗效。结果 2组总有效率比较差异无统计学意义(P>0.05);伊马替尼组完全血液学缓解率、完全细胞遗传学缓解率、完全分子学效应率、5 a总生存率均明显高于干扰素联合化疗组(P<0.05)。结论干扰素联合化疗和伊马替尼均可作为CML慢性期的有效治疗方法。     

Successful Completion of Pregnancy in a Patient With Chronic Myeloid Leukemia Without Active Intervention: A Case Report and Review of the Literature

The management of patients with chronic myeloid leukemia (CML) during pregnancy is a matter of continued debate. We present a 21-year-old woman in whom CML was diagnosed during early pregnancy. Because the patient was asymptomatic and desired to carry the pregnancy to term while minimizing fetal exposure to medication, she was observed with no therapy for the duration of her pregnancy. The white blood cell count showed a slow downward trend throughout her pregnancy. She delivered a healthy baby and breast fed for a time before initiating therapy for CML. We reviewed the published case reports of women who had a pregnancy occur in the setting of treatment with imatinib. Given the adverse effects of fetal exposure to imatinib as treatment for the mother with CML, close observation might be an option for selected patients who are diagnosed with CML while pregnant and who have minimal clinical manifestations of CML.     

Response to treatment in women with chronic myeloid leukemia during pregnancy and after delivery

Here we report response to treatment of chronic myeloid leukemia (CML) of five pregnant women during and after pregnancy. CML was diagnosed during pregnancy in three patients. Pregnancy was confirmed during CML in two patients: in one in the 21st week of pregnancy while on imatinib, in another in the 12th week during the interferon treatment. Interferon with leukapheresis when needed was applied in the 2nd and 3rd trimester. All patients except one achieved complete hematological response during pregnancy. After delivery four patients achieved partial cytogenetic response on imatinib and two patients achieved major molecular response after crossover to dasatinib.     

Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia

BACKGROUND: Imatinib mesylate administration has become standard treatment for patients with chronic myelogenous leukemia (CML). Although the safety profile of imatinib is favorable, Grade > or = 3 neutropenia (according to the National Cancer Institute Common Toxicity Criteria) occurs in 35-45% of patients with CML in chronic phase who receive standard-dose imatinib. Myelosuppression results in treatment interruptions, which may compromise responses to imatinib. The authors investigated the ability of granulocyte-colony-stimulating factor (filgrastim) to reverse imatinib-associated neutropenia, thereby allowing for more continuous imatinib administration. METHODS: Thirteen patients with chronic-phase CML and Grade > or = 3, imatinib-induced neutropenia were treated with filgrastim. Treatment with filgrastim was initiated after a median of 22 months from the start of imatinib. Eleven patients received filgrastim 5 microg/kg 1-3 times weekly, and 2 patients received filgrastim 5 microg/kg daily; doses were titrated to maintain an absolute neutrophil count (ANC) > or = 10(9)/L. RESULTS: Seven of 11 patients (64%) who began treatment with an ANC < 1.5 x 10(9)/L had responses (i.e., their ANC improved to > or = 2 x 10(9)/L within 21 days); the other 4 patients experienced slower recovery but were able to continue receiving imatinib uninterrupted. Before filgrastim administration was initiated, patients did not receive imatinib (due to neutropenia-related treatment interruptions) for an average of 21% of the total time since the start of imatinib. This figure decreased to 6% after the start of filgrastim treatment (P = 0.0008). Before filgrastim treatment was initiated, only one patient had achieved a major (partial) cytogenetic response. After the start of filgrastim treatment, five patients had major cytogenetic responses (including two complete responses). CONCLUSIONS: The authors concluded that filgrastim may overcome imatinib-associated neutropenia and allow improved delivery of imatinib. Some patients may experience improvements in their responses to therapy as a result.     

Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML). Outcome of discontinuation of imatinib therapy after achieving a molecular remission

Because of the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy. We describe successful pregnancy and delivery, without any congenital anomaly, in a patient with CML under treatment of imatinib. The fetus had been exposed to imatinib for 8 weeks. The patient remained off treatment during gestation and cytogenetic relapse of CML (5 months after discontinuation of imatinib therapy) developed at seventh month of gestation.     

Quality of life in patients with newly diagnosed chronic phase chronic myeloid leukemia on imatinib versus interferon alfa plus low-dose cytarabine: results from the IRIS Study.

PURPOSE: Quality of life (QOL) outcomes in patients with chronic myeloid leukemia (CML) were evaluated in an international phase III study. PATIENTS AND METHODS: Newly diagnosed patients with chronic phase CML were randomly assigned to imatinib or interferon alfa plus subcutaneous low-dose cytarabine (IFN+LDAC). Cross-over to the other treatment was permitted because of intolerance or lack of efficacy. Patients completed cancer-specific QOL (Functional Assessment of Cancer Therapy-Biologic Response Modifiers) and utility (Euro QoL-5D) questionnaires at baseline and during treatment (n = 1,049). The primary QOL end point was the Trial Outcome Index (TOI; a measure of physical function and well-being). Secondary end points included social and family well-being (SFWB), emotional well-being (EWB), and the utility score. Primary analyses were intention to treat with secondary analyses accounting for cross-over. RESULTS: Patients receiving IFN+LDAC experienced a large decline in the TOI, whereas those receiving imatinib maintained their baseline level. Treatment differences at each visit were significant (P <.001) and clinically relevant in favor of imatinib. Mean SFWB, EWB, and utility scores were also significantly better for those patients taking imatinib. Patients who crossed over to imatinib experienced a large increase in TOI; significant (P <.001) differences were observed between patients who did and did not cross over in favor of imatinib. CONCLUSION: Imatinib offers clear QOL advantages compared with IFN+LDAC as first-line treatment of chronic phase CML. In addition, patients who cross over to imatinib from IFN+LDAC experience a significant improvement in QOL compared with patients who continue to take IFN+LDAC.     

Summary of 615 patients of chronic myeloid leukemia in Shanghai from 2001 to 2006

Background

To retrospectively review the incidence, treatment efficacy, we followed up newly diagnosed chronic myelogenous leukemia (CML) patients residing in Shanghai during 2001-2006.

Methods

All eligible cases were reviewed with the data of efficacy responses as well as overall survival (OS) and progression-free survival (PFS) time.

Results

A total of 615 cases entered the study. CML mainly afflicted those aged 40-60 years old and was slightly more frequent in males than females. More than 85% of the patients were in chronic phase (CP) when diagnosed. All patients were divided into four groups based on the main regimens - hydroxyurea, interferon alpha (IFN-α), imatinib, and hemopoietic stem cell transplantation (HSCT). With the median follow-up of 18 months, imatinib treatment induced 92.2% complete hematologic responses, and 64.3% complete cytogenetic responses among CML-CP patients. Overall the therapeutic efficacy in the imatinib group was higher than that in the hydroxyurea or IFN-α group. Meanwhile, in the imatinib group, all response rates of patients in CP were significantly greater than that in accelerated or blastic crisis phase. The patients treated with imatinib also showed the most promising results regarding OS and PFS. Patients receiving HSCT decreased markedly in number with the introduction of imatinib.

Conclusions

The number of new patients arising in Shanghai increased from 2001 to 2006. There were still patients receiving hydroxyurea and IFN-α. As the first-line regime for CML, imatinib was less administered in Shanghai before, but has received considerable development and great responses since 2003.     

Changes in the activity of the GPx-1 anti-oxidant selenoenzyme in mononuclear cells following imatinib treatment

Imatinib inhibits the ABL tyrosine kinase and is effective for the treatment of chronic myeloid leukemia (CML). ABL activates GPx-1, an enzyme associated with protection against oxidative DNA damage and disease. Enzyme activity was assessed in sample pairs consisting of mononuclear cells obtained from patients before and after imatinib therapy. Control sample sets obtained from patients not receiving imatinib showed little change in GPx activity over a several month interval. Five of 7 sample sets obtained from imatinib-receiving patients showed changes in GPx activity greater than 30%. One sample decreased 42% while 4 others increased 33-208%. Patients with the largest increase in activity were female and had the lowest baseline levels of GPx activity. Changes in GPx activity may influence the clinical outcome of patients being treated for CML.     

Development of Varicella-Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate.

PURPOSE: Infection with Varicella-Zoster virus (VZV) is an exceptionally rare complication of chronic myelogenous leukemia (CML) without stem cell transplantation. We report 16 patients with CML who developed VZV infection during imatinib mesylate therapy. PATIENTS AND METHODS: From July 1998 until February 2002, 771 patients were included in 11 imatinib mesylate studies for all CML phases in the Departments of Leukemia and Bioimmunotherapy at The University of Texas M. D. Anderson Cancer Center. Sixteen patients developed VZV infection. Charts and follow-up information of were reviewed and analyzed. RESULTS: Sixteen patients (2%) developed a VZV infection [15 episodes of herpes zoster (HZ), 1 varicella]. The baseline characteristics of the 16 patients with infection do not differ significantly from those who did not develop VZV infection, except for time from diagnosis of CML to imatinib (median: 55 versus 25 months, P = 0.0056) and the number of prior therapies (3 versus 1, P < 0.001). All patients received therapy with antiviral agents with good response. Six patients developed postherpetic neuralgia. CONCLUSIONS: Our results suggest that imatinib therapy in CML is associated with low incidence of HZ infection. VZV infection is more frequent with longer duration of CML disease and with prior therapy, does not disseminate, responds well to therapy, and does not mandate a recommendation for HZ prophylaxis in such patients.     

Ever-advancing chronic myeloid leukemia treatment

Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines.