Chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) represents about 14% of all leukemias and occurs with a frequency of about 1 in 100,000. It is rare in children. Symptoms include fatigue, weight loss, sweating, and abdominal discomfort from an enlarged spleen. The white blood cell count can range from 100-600 ul. CML has three phases: the chronic phase, accelerated phase, and blast phase. Most patients are diagnosed during the chronic phase. Ionizing radiation has been implicated in some cases of CML, but in most individuals no cause is known. The Philadelphia chromosome, an acquired genetic mutation represented by a translocation of chromosome 22 and chromosome 9, drives the leukemic changes in CML. Imatinib mesylate, a tyrosine kinase inhibitor, was approved in 2002 for the treatment of all phases of CML. Because of its effectiveness, imatinib has become the treatment of choice for most patients with CML. Stem cell transplantation also is an option for eligible patients. It is the only curative treatment for CML. Two drugs under study for patients who cannot tolerate or who become resistant to imatinib are BMS-354825 and AMN107. Oncology nurses who are knowledgeable about new therapies for CML can be effective resources for their patients.     

Chronic myelogenous leukemia: an overview

Important advances have been made in the treatment of chronic myelogenous leukemia (CML). In the past two decades, treatment of this disease has changed and now includes the use of hydroxyurea, interferon, tyrosine kinase inhibitors, and high-dose chemotherapy followed by hematopoietic stem cell transplantation. Because several relatively effective forms of therapy now exist, the care and management of patients with CML has become more complex. Through continued research and drug development, additional therapies are expected to emerge offering new hope and expanded treatment options for patients with CML.     

Hypokalemia in acute myelogenous leukemia

Forty-two patients with acute myelogenous leukemia or one of its variants were studied at diagnosis to determine the incidence and cause(s) of hypokalemia. Forty-three percent of patients were hypokalemic, and an inappropriate renal loss of potassium was noted. This potassium wastage could not be explained by antibiotic-induced renal tubular dysfunction, lysozymuria, or alterations in renin-aldosterone secretion.     

Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells

We have shown that cytotoxic T lymphocytes specific for PR1, an HLA-A2-restricted nonopeptide derived from proteinase 3, kill leukemia cells and may contribute to the elimination of chronic myelogenous leukemia (CML) after treatment with IFN or allogeneic bone marrow transplant. Some patients with persistent disease also have circulating PR1-specific T cells, however, suggesting the likelihood of immune tolerance. Here we show that both high- and low-avidity PR1-specific T cells from the peripheral blood of healthy donors can be identified and selectively expanded in vitro. Although high-avidity PR1-specific T cells killed CML more effectively than low-avidity T cells, only high-avidity T cells underwent apoptosis when stimulated with high PR1 peptide concentration or when exposed to leukemia that overexpressed proteinase 3. No high-avidity PR1-specific T cells could be identified or expanded from newly diagnosed leukemia patients, whereas low-avidity T cells were readily expanded. Circulating high-avidity PR1-specific T cells were identified in IFN-sensitive patients in cytogenetic remission, however. These results provide evidence that CML shapes the host immune response and that leukemia outgrowth may result in part from leukemia-induced selective deletion of high-avidity PR1-specific T cells.     

Blastic phase of chronic myelogenous leukemia

Chronic myeloid leukemia (CML), a clonal stem cell disorder, inevitably evolves into a blastic phase that is very resistant to treatment. Recent developments of a better understanding of molecular changes in CML have led to highly effective targeted therapy that can induce molecular remissions, many of which are long-lasting. It is expected that these approaches will eventually improve treatment of the blastic phase of this disease, the molecular changes during its evolution to blastic phase, and the potential for therapeutic interventions. We review the molecular biology and evolution of treatment of the blastic phase of CML.     

Kinase inhibitors in chronic myelogenous leukemia

The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate launched the era of molecular targeted therapy and constitutes a milestone in oncology history. However, despite impressive cytogenetic response rates achieved with this agent in patients with chronic myelogenous leukemia (CML) in chronic phase, those with advanced-stage CML frequently obtain more modest responses that are in many instances of short duration. Several mechanisms of resistance to imatinib have been described among patients that develop clinical resistance to imatinib. Point mutations in the Bcr-Abl kinase domain that impair the ability of imatinib to inhibit the kinase activity represent the leading cause of resistance. Several approaches are being pursued to overcome these mutations. In addition, many other protein kinases implicated in signaling transduction downstream Bcr-Abl play critical roles in the pathogenesis of CML, thus representing potential therapeutic targets. Multiple compounds are being screened to identify inhibitors of these kinases. This article focuses on the current state of development of new kinase inhibitors for the therapy of CML.     

慢性粒细胞白血病的治疗进展

慢性粒细胞白血病(CML)是一种造血干细胞克隆性骨髓增殖性肿瘤.尽管酪氨酸激酶抑制剂(TKI)可抑制Bcr/Abl激酶活性,并在慢性期CML治疗中取得了很好的疗效,而且耐受性良好,但TKI有很多的不良反应.目前对于CML患者和社会而言,TKI的治疗已成为一个沉重的负担.因此,迫切需要探索清除来源于Ph+恶性干细胞克隆的CML微小残留病灶有望获得CML永久治愈和长期无病生存的方法,现就其治疗进展作一综述.     

儿童急性髓系白血病临床研究

目的：了解儿童急性髓系白血病的临床特点、治疗疗效及预后因素。方法：对１９７８年８月～１９９５年１２月２７４例儿童急性髓系白血病进行临床总结和分析。结果和结论：中位确诊年龄７岁３个月，男∶女＝１．６３∶１，Ｍ２、Ｍ３型占８０％，高白细胞血症２０例，髓外白血病２４例，有Ａｕｅｒ小体者占３２．９％。治疗２４４例，分别以三种方案进行治疗，完全缓解（ＣＲ）率５５．８８％～９２．３１％，证明采用ＤＡ或ＤＡ＋Ｖｍ２６或Ｖｐ１６是提高ＣＲ的关键。影响诱导缓解因素为病初白细胞计数和肝脾肿大程度。通过ＳＰＳＳ统计学软件分析，ＡＭＬ亚型、Ａｕｅｒ小体、诱导缓解时间、髓外白血病等因素对远期预后有影响。     

Chronic myelogenous leukemia: in vitro studies of hematopoietic regulation in a patient undergoing intensive chemotherapy.

A patient heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase and with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) was treated with combination chemotherapy and had a partial loss of Philadelphia chromosome accompanied by partial restoration of nonclonal hematopoiesis as determined by glucose-6-phosphate dehydrogenase. Studies of in vitro hematopoiesis were performed after chemotherapy to evaluate the influences of neoplastic stem cells on normal cells and to determine whether there were physical and cell kinetic differences between leukemic stem cells and their normal counterparts. The data revealed the following: (a) The frequencies of normal committed granulocytic stem cells (CFU-C) and erythroid stem cells (BFU-E) in blood did not differ from the frequencies in marrow. (b) Normal late erythroid progenitors (CFU-E) were found at a significantly lower frequency that the more primitive BFU-E. Calculations indicated that not only was there a decrease in CFU-E production by normal BFU-E, but there was also abnormal clonal expansion of CML BFU-E (CFU-E:BFU-E ratio for normal progenitors was 1.1, whereas for the CML clone it was 11.5). (c) No increase in frequency of normal CFU-C was found after marrow cells were exposed to high specific activity tritiated thymidine. (d) Normal CFU-C and those from the CML clone were not separable on the basis of density. (e) The frequency of normal BFU-E was consistently greater than that of CFU-C, suggesting that regulatory differences influence the commitment of normal progenitors to the two pathways.     

格列卫治疗54例Ph阳性慢性髓细胞白血病

目的评价甲磺酸伊马替尼(商品名格列卫)治疗Ph阳性慢性髓细胞白血病慢性期(CML-CP)的有效性及安全性。方法54例对α干扰素(IFN-α)耐药或不能耐受及异基因干细胞移植(allo—SCT)后复发的CMI-CP患口服格列卫400mg／d，持续6-11个月。结果全部患于服药后7～28天达到血液学完全缓解。1例服药后7个月复发，很快进展为加速期。观察截止时，血液学完全缓解为52例(98％)。发生主要遗传学效应为37例(70％)，其中遗传学完全缓解为27例(51％)。37例中29例(78％)患达到主要遗传学缓解的时间为3个月。约10％患出现Ⅲ级白细胞和(或)血小板减少，多可控制或耐受。Ⅲ～Ⅳ级非血液学不良反应很少发生。仅1例患因药物不良反应退出。结论①格列卫对经IFN—α治疗失败的CMI-CP有较高的血液学及遗传学缓解率，且起效迅速；②格列卫服用方便，不良反应轻微、多可耐受或自行消失。