Association between C1236T Genetic Variant of ABCB1 Gene and Molecular Response to Imatinib in Indonesian Chronic Myeloid Patients

Objective: Imatinib is the first-line drug used for the treatment of chronic myeloid leukemia (CML) patients due to high molecular response and overall survival rate. However, some patients develop resistance to imatinib even after attaining a response. Mutation in ABCB1 efflux transporters is one of the known mechanisms of resistance to imatinib in chronic myeloid leukemia patients. This study was aimed to investigate the association of ABCB1 C1236T polymorphism in Indonesian chronic myeloid patients with molecular response to imatinib treatment. Methods: We analyzed 120 samples from chronic myeloid leukemia patients in the chronic phase, who had been on imatinib treatment for at least 12 months. We analyzed the C1236T variant of the ABCB1 gene using PCR, followed by direct sequencing, and associate them with the achievement of major molecular response (MMR). Results: The major molecular response was achieved in 28% of patients. The frequencies of the SNPs were CC (40%), CT (46%), and TT (14%). Our result showed that there was a lack of association between polymorphism of ABCB1 C1236T and imatinib response in Indonesian patients, with OR = 0.646 (95% CI: 0.283, 1.471; p>0.05). Conclusion: There was no association between ABCB1 C1236T variants with the major molecular response in Indonesian chronic myeloid leukemia patients receiving imatinib treatment.     

Treatment of generalized infantile myofibromatosis with sorafenib and imatinib: A case report

Infantile myofibromatosis (IM) is characterized by solitary musculoskeletal nodules presenting during infancy but can manifest as multiple lesions with visceral involvement. Multicentric IM with visceral involvement carries a high risk of mortality and there is no consensus on treatment. We present a case of a patient with multicentric IM and pulmonary involvement who progressed on several chemotherapeutic regimens and subsequently had a complete response to sorafenib and later imatinib. This report describes the novel use of sorafenib and imatinib to treat generalized IM and the role of continued tyrosine kinase inhibitor therapy to maintain remission.     

A 4-month-old boy with gastrointestinal stromal tumor of mesocolon

Gastrointestinal stromal tumors (GISTs) are very uncommon in pediatric patients, and they are distinct clinical-pathological and molecular deviations from their adult counterparts. Most pediatric GISTs lack the c-kit or platelet-derived growth factor receptor alpha (PDGFRA) genes mutations. To date, there is no published standard guidelines available for the best treatment of pediatric GISTs, especially for infant GIST. Therefore, we report a case of 4-month-old infant with GIST of mesocolon without KIT/PDGFRA mutation. We also review the clinical, biological, and genetic features of pediatric GISTs and re-think several questions that could affect clinical practice.     

国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期临床观察

目的 甲磺酸伊马替尼作为治疗慢性粒细胞白血病(chronic myelogenous leukemia,CML)-慢性期(chronic phase,CP)患者的一线治疗药物,国产药物应用的安全性和有效性尚缺乏系统评价参考.本研究探讨国产甲磺酸伊马替尼治疗初诊CML-CP患者的早期血液学、细胞遗传学、分子学反应与安全性.方法 收集2014-03-01-2015-10-31就诊于新疆自治区人民医院血液科的43例初诊CML-CP患者,给予国产甲磺酸伊马替尼(昕维?R)400 mg/d口服,治疗3、6、12个月时进行骨髓细胞学、染色体、FISH与骨髓BCR-ABL融合基因转录本水平评估,观察评估患者血液学反应、细胞遗传学反应和分子学反应及安全性.结果 43例患者治疗满3个月时,42例(97.7%)达完全血液学反应(complete hematologic response,CHR);35例(81.4%)达主要细胞遗传学反应(major cytogenetic response,MCyR),其中11例(25.6%)达完全细胞遗传学反应(complete cytogenetic response,CCyR);30例(69.8%)达国际标准化BCR-ABL转录本水平(BCR-ABLIS)≤10%,4例(9.3%)达BCR-ABLIS≤0.1%.17例患者治疗满6个月时,均达CHR(100.0%);11例(64.7%)达CCyR;12例(70.6%)达BCR-ABLIS≤1%,其中4例(23.5%)达BCR-ABLIS≤0.1%.5例患者治疗满12个月,4例达CCyR;2例BCR-ABLIS≤1%,2例BCR-ABLIS≤0.1%,1例BCR-ABLIS>10%.血液学不良反应:3/4级白细胞减少、血小板减少和贫血发生率分别为20.9%、23.3%和16.3%.非血液学不良反应发生率分别为水肿76.7%,恶心呕吐51.2%,骨关节肌肉酸痛39.5%),皮疹20.9%,发热11.6%,腹泻11.6%,肝功能损害2.3%.无4/4级血液学与非血液学不良反应.结论 国产甲磺酸伊马替尼治疗初诊CML-CP患者的近期疗效肯定,不良反应可耐受,但仍需长期观察研究.     

Liposomal cytarabine for treatment of myeloid central nervous system relapse in chronic myeloid leukaemia occurring during imatinib therapy

BACKGROUND: Central nervous system (CNS) relapse in chronic myeloid leukaemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation. The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood-brain barrier. PATIENTS AND METHODS: We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukaemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations were found. Both patients received intrathecal liposomal cytarabine (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other, consecutive treatment with dasatinib (70 mg per os twice daily) was started. RESULTS: In response to therapy, the clinical symptoms resolved, and the leukaemic cells in the CSF disappeared in both cases. After three months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse. CONCLUSIONS: 'Anatomic' resistance against imatinib in the CNS can lead to a myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For systemic treatment and prophylaxis, BCR/ABL kinase inhibitors crossing the blood-brain barrier such as dasatinib should be considered in patients with CNS relapse.     

In vivo effects of imatinib mesylate on human haematopoietic progenitor cells

BACKGROUND: Imatinib mesylate has considerable antineoplastic activity in patients with chronic myeloid leukaemia (CML) and some solid tumours. Although originally regarded as nontoxic for normal haematopoiesis, mild to moderate myelosuppression is a commonly observed side-effect of this treatment. Recently, this molecule has been shown to suppress normal haematopoietic progenitor cells in vitro. This is the first study that has investigated the effect of imatinib on haematopoietic progenitor cells in vivo. MATERIALS AND METHODS: We investigated the number of circulating haematopoietic progenitor cells in 79 patients with CML and five patients with solid tumours who were treated with imatinib for at least 3 months. Bone marrow progenitor cells were assessed in a subgroup of 18 patients with CML after 12 months of imatinib treatment. Results were compared with haematopoietic progenitor cell numbers of normal controls. RESULTS: Circulating progenitors of all classes were significantly decreased in CML up to 24 months of imatinib therapy compared with healthy controls (median progenitor cells in CML after 12 months: CFU-GM 62, range 0-2543; BFU-E 216, range 0-3259; CFU-GEMM 0, range 0-139; versus controls: CFU-GM 208, range 50-936; BFU-E 690, range 120-1862; CFU-GEMM 20, range 4-77; P < 0.001). Similar reductions in the number of progenitor cells derived from bone marrow were found in a subgroup of 18 patients with CML. In patients with solid tumours the number of circulating progenitor cells was significantly lower under treatment with imatinib when compared with the controls. Withdrawal of imatinib in a patient with a malignant brain tumour resulted in a prompt normalization of circulating progenitors. CONCLUSIONS: This study suggests that imatinib exerts myelosuppressive effects through inhibition of haematopoietic progenitor cells.     

甲磺酸伊马替尼治疗晚期胃肠间质瘤的护理体会

目的:探讨甲磺酸伊马替尼治疗无法手术完全切除、术后复发和(或)转移性晚期胃肠间质瘤的临床疗效。方法:对某院2011年1月~2014年2月住院并已经在外院确诊晚期胃肠间质瘤(并在外院证实术中无法完全切除病灶或术后复发、转移,失去手术机会)患者86例,分为2组,治疗组给予甲磺酸伊马替尼治疗400~600mg/d口服的患者34例;对照组给于环磷酰胺注射,疗程为8个月,结果:治疗组患者获益率(85.7%),1年、2年生存率分别为100%、83.3%。对照组获益率(86.04%),1年、2年治疗组及对照组生存率分别为100%、83.3%。结论:甲磺酸伊马替尼治疗胃肠间质瘤疗效肯定,不良反应相对轻,毒性可耐受。     

Human hepatocyte assessment of imatinib drug–drug interactions – complexities in clinical translation

Aim

Inducers and inhibitors of CYP3A, such as ritonavir and efavirenz, may be used as part of the highly active antiretroviral therapy (HAART) to treat HIV patients. HIV patients with chronic myeloid leukemia or gastrointestinal stromal tumour may need imatinib, a CYP3A4 substrate with known exposure response–relationships. Administration of imatinib to patients on ritonavir or efavirenz may result in altered imatinib exposure leading to increased toxicity or failure of therapy, respectively. We used primary human hepatocyte cultures to evaluate the magnitude of interaction between imatinib and ritonavir/efavirenz.

Methods

Hepatocytes were pre-treated with vehicle, ritonavir, ketoconazole, efavirenz or rifampicin, and the metabolism of imatinib was characterized over time. Concentrations of imatinib and metabolite were quantitated in combined lysate and medium, using LC-MS.

Results

The predicted changes in imatinib CL_oral (95% CI) with ketoconazole, ritonavir, rifampicin and efavirenz were 4.0-fold (0, 9.2) lower, 2.8-fold (0.04, 5.5) lower, 2.9-fold (2.2, 3.5) higher and 2.0-fold (0.42, 3.5) higher, respectively. These predictions were in good agreement with clinical single dose drug–drug interaction studies, but not with reports of imatinib interactions at steady-state. Alterations in metabolism were similar after acute or chronic imatinib exposure.

Conclusions

In vitro human hepatocytes predicted increased clearance of imatinib with inducers and decreased clearance with inhibitors of CYP enzymes. The impact of HAART on imatinib may depend on whether it is being initiated or has already been dosed chronically in patients. Therapeutic drug monitoring may have a role in optimizing imatinib therapy in this patient population.     

伊马替尼耐药或不耐受的 CML 患者更换二代 TKI治疗的疗效观察及相关因素分析

目的：观察伊马替尼耐药或不耐受的慢性髓性白血病(CML)患者更换二代酪氨酸激酶抑制剂(TKI)后的疗效,分析相关因素对疗效的影响。方法随机选取伊马替尼耐药或不耐受而转用二代 TKI(达沙替尼和尼洛替尼)的患者各25例,监测患者3个月或6个月时 BCR/ ABL 融合基因定量结果,分析患者在6个月达到 BCR/ ABL≤10%这一“最佳”疗效与换药原因、换药时分期、换药时血液学缓解状态、换药后依从性之间的关系。结果因耐药或不耐受而换用二代 TKI 的患者6个月达到 BCR/ ABL≤10%分别有16例(41．0%)和9例(81．8%);转用二代 TKI 时处于慢性期和进展期的患者6个月达到 BCR/ ABL≤10%分别有23例(76．7%)和2例(10．0%);转用二代 TKI 时未丧失完全血液学缓解(CHR)和丧失 CHR 的患者6个月达到 BCR/ ABL≤10%分别有16例(72．7%)和9例(32．1%);转用二代TKI 后依从性好和依从性差的患者6个月达到 BCR/ ABL≤10%分别有23例(74．2%)和2例10．5%)。结论伊马替尼耐药或不耐受的 CML 患者改用二代 TKI 药物可取得一定的疗效,且两种二代 TKI 药物(达沙替尼、尼洛替尼)疗效差异无统计学意义。因不耐受而换药的患者的疗效要优于因耐药而换药的患者;换药时处于慢性期的患者的疗效要优于换药时处于进展期的患者;换药时未丧失 CHR 的患者的疗效要优于丧失 CHR 的患者;服用二代 TKI 药物依从性好的患者的疗效要优于依从性差的患者。