Spotlight on Imatinib Mesylate in Chronic Myeloid Leukemia

Imatinib mesylate (Gleevec, Glivec) is an orally administered competitive inhibitor of the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukemia (CML). In patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in the chronic phase, imatinib mesylate 400 mg/day, compared with interferon-alpha (IFNalpha) plus cytarabine, resulted in higher hematologic response (HR) and cytogenetic response (CR) rates and fewer patients progressing to the accelerated phase or blast crisis in a large comparative trial. Preliminary results indicate that, compared with IFNalpha plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life (HR-QOL). Imatinib mesylate was also effective in patients with chronic-phase CML refractory to or intolerant of treatment with IFNalpha (as 400 mg/day) and in those with blast-crisis or accelerated-phase CML (600 mg/day). In the latter groups, HR and CR rates were lower than those in patients with chronic-phase CML. Imatinib mesylate-associated adverse events were common in clinical trials, but were mostly mild to moderate in severity. The most frequently reported adverse events were superficial edema, nausea, muscle cramps, diarrhea, vomiting, and skin rash. Myelosuppression (thrombocytopenia and neutropenia) was also reported, especially in patients with advanced disease. In patients with previously untreated chronic-phase CML, serious adverse events (both hematologic and nonhematologic) were less common with imatinib mesylate than with IFNalpha plus cytarabine treatment. CONCLUSION: Imatinib mesylate is a valuable therapy for patients with newly diagnosed Ph+ chronic-phase CML. It is better tolerated and produces higher HR, CR and freedom from progressive disease rates than conventional therapy with IFNalpha plus cytarabine. Preliminary results indicate that, compared with IFNalpha plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher HR-QOL. Imatinib mesylate is also effective in patients with accelerated-phase and blast-crisis CML, and patients with chronic-phase CML who have failed IFNalpha therapy. Given its efficacy and generally manageable adverse event profile, imatinib mesylate offers an important early treatment option for patients with CML.     

Pathology of gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. It was found that most GIST expressed KIT, a receptor tyrosine kinase encoded by protooncogene c-kit. In normal gastrointestinal wall, KIT is expressed by interstitial cells of Cajal (ICC), which are a pacemaker for autonomous gastrointestinal movement. Because both GIST and ICC are double-positive for KIT and CD34, and because familial and multiple GIST appear to develop from diffuse hyperplasia of ICC, GIST are considered to originate from ICC or their precursor cells. It was also found that approximately 90% of the sporadic GIST have somatic gain-of-function mutations of the c-kit gene, and that the patients with familial and multiple GIST have germline gain-of-function mutations of the c-kit gene. These facts strongly suggest that the c-kit gene mutations are a cause of GIST. Approximately half of the sporadic GIST without c-kit gene mutations were demonstrated to have gain-of-function mutations in platelet-derived growth factor receptor-alpha (PDGFRA) gene that encodes another receptor tyrosine kinase. Because KIT is immunohistochemically negative in a minority of GIST, especially in PDGFRA gene mutation-harboring GIST, mutational analyses of c-kit and PDGFRA genes may be required to diagnose such GIST definitely. Imatinib mesylate was developed as a selective tyrosine kinase inhibitor. It inhibits constitutive activation of mutated KIT and PDGFRA, and is now being used for KIT-positive metastatic or unresectable GIST as a molecular target drug. Confirmation of KIT expression by immunohistochemistry is necessary for application of the drug. The effect of imatinib mesylate is different in various types of c-kit and PDGFRA gene mutations, and the secondary resistance against imatinib mesylate is often acquired by the second mutation of the identical genes. Mutational analyses of c-kit and PDGFRA genes are also significant for prediction of effectiveness of drugs including newly developed agents.     

Molecular targeted treatment--new treatment strategy for patients with chronic myeloid leukemia

Imatinib mesylate is a new drug that can inhibit the tyrosine kinase activity of Bcr-Abl, the receptors for platelet-derived growth factor receptor(PDGF) and stem cell factor, or c-kit. Chronic myeloid leukemia (CML) is distinguished by the presence of a reciprocal translocation between chromosomes 9 and 22 that results in a shortened chromosome 22, termed the Philadelphia(Ph) chromosome. As a result of the translocation, a fusion gene called the Bcr-Abl gene is created from two normal cellular genes, encoding a chimeric Bcr-Abl protein with a deregulated tyrosine kinase activity. The expression of Bcr-Abl tyrosine kinase has been shown to be necessary and sufficient for the transformed phenotype of CML cells. Imatinib can block the kinase activity of Bcr-Abl, thus inhibiting the proliferation of Ph-positive progenitors, and has shown activity against all phases of CML, though responses are most substantial and durable in patients in the chronic phase. An international phase III study which compared the efficacy of imatinib with that of interferon alpha combined with low-dose cytarabine in newly diagnosed chronic-phase CML showed the rate of major cytogenetic response at 24 months was 90%, including 82% of complete cytogenetic response. These results indicated that imatinib was superior to interferon-containing treatment as a first-line therapy. More than 10,000 patients worldwide, including those in Japan, have been treated with imatinib in clinical trials, and a lot of information has been accumulated on the use of this drug. The aim of this article is to review the use of this drug and the practical management of patients with chronic myeloid leukemia.     

Clonal chromosome aberrations in Philadelphia-negative cells from chronic myelocytic leukemia patients treated with imatinib mesylate: report of two cases

Imatinib mesylate (tested as STI571), an abl kinase inhibitor, induces sustained, complete hematologic and cytogenetic responses in chronic myelocytic leukemia (CML) patients; however, emergence of clonal chromosomal aberrations in Philadelphia-negative (Ph-) cells during treatment has been reported. We describe two CML patients in chronic phase who presented with complete cytogenetic responses during imatinib mesylate therapy but developed new clonal chromosomal rearrangements in Ph- cells. The first patient presented with a duplication of chromosome 1, dup(1)(q21q42), and the second showed two new clonal aberrations consisting of inv(1)(q12q32) and del(7)(q22) in the same clone.     

Advanced gastrointestinal stromal tumors successfully treated with imatinib mesylate: a report of two cases

Activation of kit-receptor tyrosine kinase occurs in all cases of gastrointestinal stromal tumors, regardless of the mutation status of kit. Imatinib mesylate (STI 571,Gleevec) is a selective inhibitor of certain protein tyrosine kinases. It has been shown in preclinical models and clinical studies to have activity against such tumors. The aim of the present study was to report the efficacy of imatinib mesylate in the treatment of advanced gastrointestinal stromal tumors. Two adults with histologically confirmed, unresectable, and metastatic gastrointestinal stromal tumors that expressed CD117 (a marker of kit-receptor tyrosine kinase) were identified at our institution during 2000-2002. As the diseases were advanced and not amenable to surgery, chemotherapy, or radiation therapy, imatinib mesylate was used, because this targeted inhibitor has been shown to be active against advanced gastrointestinal stromal tumors and has a mild toxicity profile. Imatinib mesylate induced a sustained response in both patients with advanced unresectable or metastatic gastrointestinal stromal tumors. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.     

Current and emerging tests for the laboratory monitoring of chronic myeloid leukaemia and related disorders

Chronic myeloid leukaemia (CML) is a molecularly defined disease. The BCR-ABL fusion occurs in all cases of classical CML and leukaemic cells express a constitutively activated BCR-ABL tyrosine kinase. Other fusion oncogenes involving tyrosine kinases, including ABL and PDGFRA/B, have been identified, and are associated with leukaemic syndromes that may resemble CML. The discovery and treatment of these related disorders has been facilitated by our detailed understanding of CML. Imatinib mesylate has significantly improved the outcome of patients with CML, but there remains a significant minority of chronic phase CML patients for whom the response to treatment with standard dose imatinib is suboptimal. Cytogenetic and molecular monitoring of the response to treatment provides important prognostic information. Achievement of a major molecular response (MMR) in chronic phase patients treated de novo with imatinib confers near 100% freedom from progression to advanced phase, and MMR is now an important goal of therapy. Standardisation of BCR-ABL molecular monitoring is under way and should enable the accurate and reproducible identification of MMR in laboratories around the world. Point mutations in the kinase domain of BCR-ABL are the most common cause of acquired resistance to imatinib treatment. The susceptibility of a mutation to imatinib, nilotinib, or dasatinib may help to guide changes in therapy in a patient with resistance. In addition to these established methods of monitoring, there are new tests in development that may assist in determining prognosis and optimising therapy. Among patients receiving the same dose of imatinib, the plasma level of imatinib shows considerable inter-patient variation, and there is emerging evidence that higher levels may be associated with improved response to treatment. The intracellular concentration of imatinib also shows considerable variation, most likely related to differences in influx and efflux transport mechanisms. We discuss how these established and emerging assays might be used to optimise the treatment of CML patients.     

Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications

Neoplastic expansion of myeloid cells is associated with specific genetic changes that lead to chronic activation of signaling pathways, as well as altered metabolism. It has become increasingly evident that transformation relies on the interdependency of both events. Among the various genetic changes, the oncogenic BCR-ABL tyrosine kinase in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) has been a focus of extensive research. Transformation by this oncogene is associated with elevated levels of intracellular reactive oxygen species (ROS). ROS have been implicated in processes that promote viability, cell growth, and regulation of other biological functions such as migration of cells or gene expression. Currently, the BCR-ABL inhibitor imatinib mesylate (Gleevec) is being used as a first-line therapy for the treatment of CML. However, BCR-ABL transformation is associated with genomic instability, and disease progression or resistance to imatinib can occur. Imatinib resistance is not known to cause or significantly alter signaling requirements in transformed cells. Elevated ROS are crucial for transformation, making them an ideal additional target for therapeutic intervention. The underlying mechanisms leading to elevated oxidative stress are reviewed, and signaling mechanisms that may serve as novel targeted approaches to overcome ROS-dependent cell growth are discussed.     

Random aneuploidy in CML patients at diagnosis and under imatinib treatment

Chronic myeloid leukemia (CML) is characterized by the presence of a BCR-ABL fusion gene, which is the result of a reciprocal translocation between chromosomes 9 and 22, and is cytogenetically visible as a shortened chromosome 22 (Philadelphia). Research during the past two decades has established that BCR-ABL is probably the pathogenetic pathway leading to CML, and that constitutive tyrosine kinase activity is central to BCR-ABL capacity to transform hematopoietic cells in vitro and in vivo. The tyrosine kinase inhibitor imatinib mesylate was introduced into the treatment regimen for CML in 1998. During the last few years, reports on chromosomal changes during imatinib treatment have been described. In this study, we evaluated the random aneuploidy rate with chromosomes 9 and 18 in bone marrow from treated and untreated patients. We found higher aneuploidy rates in both treated and untreated patients compared to the control group. In three patients who were treated with imatinib mesylate for more than 1.5 years, triploidy also appeared in some nuclei. To our knowledge, this is the first report on new chromosomal changes such as random aneuploidy and triploidy under imatinib treatment, but more studies are needed to investigate the long-term effect of the imatinib treatment on genetic instability.     

BCR/ABL amplification in chronic myelocytic leukemia blast crisis following imatinib mesylate administration

The onset of accelerated phase or blast crisis of chronic myelocytic leukemia (CML) is usually associated with the acquisition of new chromosome abnormalities in addition to the t(9;22)(q34;q11) that is characteristic of the chronic phase CML. We describe the cytogenetic and molecular genetic findings in two cases of myelocytic blast crisis of CML, one occurring 6 months after commencing treatment with the ABL-specific tyrosine kinase inhibitor imatinib mesylate (STI571, Glivec, or Gleevec) and the second treated with imatinib mesylate for established blast crisis. In both cases, multiple secondary cytogenetic abnormalities were observed at transformation, with homogeneously staining regions that were shown to contain BCR/ABL amplification by fluorescence in situ hybridization appearing after imatinib mesylate administration. BCR/ABL amplification is emerging as an important mechanism of acquired resistance to imatinib mesylate.     

Chronic myeloid leukemia: "Archetype" of the impact of targeted therapies

Chronic myeloid leukemia (CML) is a chronic blood disorder characterized by a reciprocal translocation between chromosomes 9 and 22, leading to the creation of a chimeric gene encoding the BCR-ABL fusion protein with a constitutive tyrosine kinase activity. Although long known as a disease with an inexorable progression to acute leukemia, CML history has been significantly improved by the use of imatinib, a tyrosine kinase inhibitor. Imatinib has revolutionized the treatment of CML by transforming it from an invariably fatal disease to a chronic but manageable condition. In fact, the discovery of this class of targeted therapy had an impact not only on the survival of CML patients but also on other scientific and medical fields. This review illustrates the impact of imatinib, the first example of tyrosine kinase inhibitors on the treatment of CML, on the treatment of other cancers, the impact on health systems and on the scientific research in general.     

Mechanisms of resistance to imatinib mesylate in KIT-positive metastatic uveal melanoma

Imatinib mesylate is used in targeted therapy of cancer to inhibit type III tyrosine kinase receptors, such as KIT and platelet-derived growth factor receptors (PDGFRs). Expression of KIT in uveal melanoma (UM) suggests that this receptor may be the target of imatinib mesylate therapy. However, phase II multicenter clinical studies have shown no effect of imatinib mesylate in patients with unresectable liver metastases of UM. We therefore investigated which molecular mechanisms promote imatinib mesylate-resistance in metastatic UM. Expression of KIT, stem cell factor (SCF), PDGFRα and PDGFRβ, was analyzed by RT-PCR, immunostaining, and Western blot in twenty-four samples of UM liver metastases, as well as UM primary tumor and metastatic cell lines. Soluble SCF was quantified in UM cell lines using enzyme-linked immunosorbent assay. Cell viability of UM cell lines treated with imatinib mesylate and grown in SCF-supplemented medium or in microvascular endothelial cells-conditioned medium was studied by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays. UM liver metastases and cell lines expressed KIT and SCF, but not the PDGFRs. Ninety-five percent of liver metastases expressed KIT at the protein level, but PDGFRs were not detected in these samples. Imatinib mesylate reduced the viability of UM metastatic cell lines in a concentration-dependent manner, but an increased resistance to this drug was observed when cells were incubated in SCF-supplemented or microvascular endothelial cells-conditioned medium. This study provides evidence that tumor microenvironment cytokines such as SCF may promote resistance to imatinib mesylate in metastatic UM.     

Hämatologische Nebenwirkungen der Tyrosinkinaseinhibition mit Imatinib

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones.Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare.Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.     

Imatinib mesylate (STI 571)--a new oral target therapy for chronic myelogenous leukemia (CML)

The publication provides an up-to-date review of the significance of cytogenetic abnormalities in chronic myelogenous leukemia (CML) and the development of a promising agent with specific molecular target against tyrosine kinase, product of the BCR-ABL fusion gene, namely imatinib mesylate (STI 571, Glivec). The publication summarizes the achieved results with this compound in the chronic phase CML (in patients resistant to interferon and in newly diagnosed patients) further in patients in the accelerated phase and in blast crisis and in patients in relapse after allogeneic stem cells transplantations for CML. The results in Ph+ acute lymphoblastic leukemia are also presented. The mechanisms of resistance to imatinib mesylate and the possibilities how to overcome or circumvent it are mentioned (escalation of the dosage, combination of imatinib with some other treatment modalities as immunotherapy, interferon or convention chemotherapy and development of new drugs).     

Desensitization to imatinib in patients with leukemia.

BACKGROUND: Imatinib mesylate is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia and hypereosinophilic syndrome. Imatinib is associated with a variety of adverse cutaneous reactions, including urticaria, maculopapular exanthem, generalized exanthematous pustulosis, exfoliative dermatitis, and Stevens-Johnson syndrome. OBJECTIVE: To evaluate the safety and efficacy of oral desensitization by administering incremental dosages of imatinib mesylate to patients with leukemia who have had rashes associated with prior exposure. METHODS: Ten patients with leukemia and imatinib-associated recurrent rash underwent a 4-hour outpatient oral desensitization procedure. Beginning with 10 ng, we administered oral imatinib elixir in increasing dosages every 15 minutes. Patient outcomes were monitored by a return clinic visit and by telephone follow-up for a median of approximately 3 years. RESULTS: No episodes of anaphylaxis or serious adverse effects occurred during or immediately after desensitization. Four patients (all with urticaria) had no recurrence of rash after desensitization, and 4 had recurrent rash that resolved after temporary glucocorticosteroid and antihistamine administration. Two patients developed a recurrent rash 5 hours and several days after the procedure and were unable to resume therapy. CONCLUSION: This oral desensitization protocol appears to help some leukemic patients with recurrent rash tolerate imatinib mesylate, thus permitting continuation of this life-prolonging therapy. These findings suggest that some adverse cutaneous reactions to imatinib may be due to a hypersensitivity mechanism rather than a pharmacologic effect.     

ST1571 (imatinib mesylate) reduces bone marrow cellularity and normalizes morphologic features irrespective of cytogenetic response

The tyrosine kinase inhibitor STI571 (imatinib mesylate, Gleevec) is an effective treatment for chronic myeloid leukemia (CML). We examined bone marrow samples from 53 patients with CML who were receiving STI571 in 3 multicenter phase 2 trials to assess morphologic changes and cytogenetic response to this drug. In most patients with initially increased blasts, the bone marrow blast count rapidly decreased during STI571 therapy. Reductions in cellularity, the myeloid/erythroid ratio (commonly with relative erythroid hyperplasia), and reticulin fibrosis (if present pretreatment) also were seen in most patients, resulting in an appearance resembling normal marrow in many cases. Eighteen patients (34%) had some degree of cytogenetic response. Surprisingly, these striking morphologic changes occurred irrespective of any cytogenetic response to STI571. Thus, STI571 seems to affect the differentiation of CML cells in vivo, causing even extensively Philadelphia chromosome-positive hematopoiesis to exhibitfeatures resembling normal hematopoiesis.     

胃肠道间质瘤患者伊马替尼血药浓度的监测及意义

胃肠间质瘤（GIST）是消化道常见的间叶源性肿瘤,多发生于胃部,其免疫组化CD117及DOG-1常表达阳性,介导Kit基因突变是导致该病的主要机制。伊马替尼是一种酪氨酸酶抑制剂,可以很好的抑制c-Kit的活性,作为复发、不可切除或者晚期的GIGT患者一线用药甲磺酸伊马替尼,它已被证实是治疗中晚期GIST患者最有效的药物,可以显著改善预后。在常规的治疗过程中,伊马替尼的血药浓度在不同的GIST患者中存在很大差异,既有血药浓度不足导致疗效较差,也有血药浓度过高导致不良反应太大,血药浓度的监测对于提高患者的依从性及预后具有重要的意义。同时我们也可以通过马替尼血药浓度的检测去探究疾病的原因,然而对于甲磺酸伊马替尼血药浓度的监测主要集中在国外,国内相关研究甚少。本文从伊马替尼的药代动力学、伊马替尼血药浓度的现状及问题、监测的意义等方面进行综述,探讨伊马替尼血药浓度的监测对GIST患者的意义。     

Imatinib Plasma Monitoring-Guided Dose Modification for Managing Imatinib-Related Toxicities in Gastrointestinal Stromal Tumor Patients

Imatinib, the first-line treatment in patients with advanced gastrointestinal stromal tumors (GIST), is generally well tolerated, although some patients have difficulty tolerating the standard dose of 400 mg/day. Adjusting imatinib dosage by plasma level monitoring may facilitate management of patients who experience intolerable toxicities due to overexposure to the drug. We present two cases of advanced GIST patients in whom we managed imatinib-related toxicities through dose modifications guided by imatinib plasma level monitoring. Imatinib blood level testing may be a promising approach for fine-tuning imatinib dosage for better tolerability and optimal clinical outcomes in patients with advanced GIST.     

Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha ( PDGFRA ) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13–17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.