Update on practical aspects of the treatment of chronic myeloid leukemia with imatinib mesylate

Imatinib (imatinib mesylate, Gleevec? [formerly known as STI571], Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for patients with all phases of chronic myeloid leukemia (CML). Imatinib is remarkably effective as treatment for CML in the chronic phase (at a dosage of 400 mg/d) and the accelerated phase (at 600 mg/d). At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently in some patients so that they are functionally "cured," and also whether the increased rate of major molecular response induced by doses of imatinib higher than 400 mg/d will further improve overall survival of patients with CML in the chronic phase. The value of molecular monitoring of response in patients with CML in the chronic phase is examined. Although imatinib 800 mg/d can induce dramatic responses in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the responses are usually incomplete and of short duration. We discuss the role of imatinib in relation to allogeneic stem cell transplantation (particularly in younger patients), recognizing that the data upon which any decisions can be made are relatively immature. Finally, recent data on new tyrosine kinase inhibitors capable of overcoming primary or acquired resistance to imatinib are reviewed.     

Update on practical aspects of the treatment of chronic myeloid leukemia with imatinib mesylate

Imatinib (imatinib mesylate, Gleevec® [formerly known as STI571], Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for patients with all phases of chronic myeloid leukemia (CML). Imatinib is remarkably effective as treatment for CML in the chronic phase (at a dosage of 400 mg/d) and the accelerated phase (at 600 mg/d). At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently in some patients so that they are functionally "cured," and also whether the increased rate of major molecular response induced by doses of imatinib higher than 400 mg/d will further improve overall survival of patients with CML in the chronic phase. The value of molecular monitoring of response in patients with CML in the chronic phase is examined. Although imatinib 800 mg/d can induce dramatic responses in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the responses are usually incomplete and of short duration. We discuss the role of imatinib in relation to allogeneic stem cell transplantation (particularly in younger patients), recognizing that the data upon which any decisions can be made are relatively immature. Finally, recent data on new tyrosine kinase inhibitors capable of overcoming primary or acquired resistance to imatinib are reviewed.     

The role of allogeneic stem cell transplantation for CML in the tyrosine kinase inhibitor era

Allogeneic stem cell transplantation is an accepted standard therapy for chronic myeloid leukemia (CML). In recent years, however, the use of transplantation has diminished, largely because of the introduction of the novel tyrosine kinase inhibitor, imatinib mesylate. Despite the introduction of imatinib and the other new tyrosine kinase inhibitors, a rational role for transplantation remains. This review focuses on the indications for transplantation in the tyrosine kinase inhibitor era.     

The role of allogeneic stem cell transplantation for CML in the tyrosine kinase inhibitor era

Allogeneic stem cell transplantation is an accepted standard therapy for chronic myeloid leukemia (CML). In recent years, however, the use of transplantation has diminished, largely because of the introduction of the novel tyrosine kinase inhibitor, imatinib mesylate. Despite the introduction of imatinib and the other new tyrosine kinase inhibitors, a rational role for transplantation remains. This review focuses on the indications for transplantation in the tyrosine kinase inhibitor era.     

Chronic myeloid leukemia in the tyrosine kinase inhibitor era: What is the best therapy?

Imatinib mesylate, 400 mg/d, is considered standard therapy for managing patients with chronic myeloid leukemia (CML) in chronic phase, yielding high rates of cytogenetic responses that translate into favorable long-term outcomes. However, some patients do not achieve adequate levels of response, lose a previously acquired response, or are forced to discontinue imatinib therapy because of safety reasons. To avoid these outcomes, several approaches are being tested in the frontline setting, including the use of higher imatinib doses or second-generation tyrosine kinase inhibitors such as nilotinib or dasatinib, the latter of which is approved only for managing patients who have imatinib therapy failure. Newer multikinase inhibitors active against multiple ABL1 mutations are also under development for patients in any CML phase who have therapy failure on sequential imatinib and a second-generation tyrosine kinase inhibitor or carry the highly resistant T315I mutation and are not candidates for allogeneic stem cell transplantation. Some of these approaches are expected to improve the outcomes of patients with CML.     

New Strategies for the First-Line Treatment of Chronic Myeloid Leukemia: Can Resistance Be Avoided?

Imatinib is well established as a safe, effective therapy for patients with chronic myeloid leukemia (CML). However, point mutations in the kinase domain of Bcr-Abl can lead to imatinib resistance and reactivation of kinase activity. The second-generation Abl kinase inhibitors nilotinib and dasatinib were developed to reestablish disease control. A rising clinical challenge is using imatinib and novel Abl kinase inhibitors with the aim of completely preempting resistance. Fortunately, relapse on imatinib therapy so far has affected a minority of patients commencing treatment in the chronic phase of CML, and relapse rates continue to decline with treatment duration. In contrast, nearly all patients with CML have molecularly detectable disease. Thus, even among the best responders to imatinib, disease eradication is not achieved within a timeframe of years. Herein, we review current and emerging paradigms for using Abl kinase inhibitors to achieve maximal disease control and strategies to eradicate disease by targeting leukemic stem cells.     

Tyrosine Kinase Inhibitors: The First Decade

The treatment of chronic myeloid leukemia (CML) drastically changed with the introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), in 1998. By directly targeting this leukemogenic protein kinase, imatinib affords patients with CML sustained chromosomal remissions, which translate into prolonged survival. However, there has been concern over the emergence of resistance to imatinib, and some patients fail to respond or are intolerant of imatinib therapy because of untoward toxicity. This has spurred interest in developing novel TKIs to overcome the mechanisms of resistance that lead to treatment failure—most importantly, Bcr-Abl1 kinase domain mutations. Two of these second-generation TKIs, nilotinib and dasatinib, are approved worldwide for the treatment of CML after imatinib failure or intolerance. Although these agents are active, they fail in many patients because of the development of highly resistant mutations such as the T315I, against which several novel agents are currently being tested in clinical trials. This review provides an account of the progress made in the field of TKI therapy for CML over the past decade.     

Monitoring patients with chronic myeloid leukemia receiving Abl tyrosine kinase inhibitor therapy

The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of chronic myeloid leukemia (CML). Complete cytogenetic remissions are standard for patients treated in chronic phase; however, treatment outcomes in advanced-phase disease are far less promising. Because hematopoietic cell transplantation is potentially curative in CML and newer TKIs are now available, the use of imatinib necessitates careful monitoring in order to identify cases in which transplantation or alternative TKI therapy might be indicated. Monitoring CML with cytogenetics and molecular methods such as the polymerase chain reaction can define subsets of patients at low or high risk of relapse and progression. In this review, we define the types of tests used to monitor the disease, provide clinically relevant endpoints, and outline guidelines for monitoring patients with CML receiving imatinib therapy.     

Imatinib has the potential to exert its antileukemia effects by down-regulating hERG1 K+ channels in chronic myelogenous leukemia

Imatinib is a powerful protein tyrosine kinase (PTK) inhibitor that specifically targets BCR-ABL, KIT, and PDGFR kinases, has become the current first-line therapy for all newly diagnosed chronic myeloid leukemia (CML). Beside PTKs, PTK inhibitors alter the activity of a large number of voltage-dependent ion channels. hERG1 K(+) channels are highly expressed in leukemia cells and appear of exceptional importance in favoring leukemogenesis. The present study explored a possible regulatory effect of imatinib upon hERG1 K(+) channels as a means to uncover new molecular events involved in the antileukemic activity of this PTK inhibitor in CML. The results demonstrated that hERG1 was highly detected in K562 cells and primary CML cells, and down-regulated by imatinib at mRNA and protein levels. Furthermore, imatinib markedly reduced hERG currents in HEK293T-hERG cells, this effect was accompanied by inhibition of CML cell proliferation and apoptosis, as well as suppression of vascular endothelial growth factor (VEGF) secretion. Moreover, these antileukemia effects of imatinib were potentiated by E-4031, a specific hERG1 inhibitor. Together, these results provide evidence of a novel potential molecular mechanism of antileukemic activities by imatinib which, independent of targeting tyrosine kinase, highlight hERG1 K(+) channels as a therapeutic target for CML treatment.     

Bcr-Abl kinase domain mutations and the unsettled problem of Bcr-AblT315I: looking into the future of controlling drug resistance in chronic myeloid leukemia

In 2006, most newly diagnosed patients with chronic myeloid leukemia (CML) underwent first-line, molecular-targeted therapy with the Bcr-Abl tyrosine kinase inhibitor, imatinib. The expectation was that the vast majority of these patients would exhibit a complete cytogenetic response on imatinib alone. Studies of patients with acquired imatinib resistance revealed that Bcr-Abl signaling is reactivated at the time of resistance, predominantly because of mutations that interfere with drug binding in the kinase domain of Bcr-Abl. The knowledge that Bcr-Abl remains the optimal target for treating imatinib-refractory CML has driven an already highly successful search for alternative approaches to restore target inhibition. Here, we review the current state of affairs in the realm of controlling drug resistance in CML, including cutting-edge strategies to reign in Bcr-AblT315I, which is cross resistant to imatinib, as well as the "next generation" Bcr-Abl inhibitors, nilotinib and dasatinib. We also critically assess the role of combined Abl kinase inhibitor therapy in overcoming resistance and provide recommendations for monitoring patients for kinase domain mutations.     

Uncommon or delayed adverse events associated with imatinib treatment for chronic myeloid leukemia

Imatinib, a tyrosine kinase inhibitor, is the first-line therapy for chronic myeloid leukemia (CML). The majority of patients continue treatment for their lifespan because discontinuation generally results in relapse. Many patients treated with imatinib experience adverse events (AEs) at some time during their treatment. Commonly encountered AEs and their management are well known. However, in addition to the common AEs with imatinib, there is a significant number of patients who display either uncommon or delayed AEs. These events can involve cardiac, renal, or dermatologic problems, and fluid retention. Herein, we review these less-than-common side effects and the hazard of administering imatinib during pregnancy. While chronic treatment with imatinib has revolutionized CML prognosis, physicians should be aware of both the common and uncommon adverse reactions.     

Granulocyte-macrophage colony stimulating factor (GM-CSF) enhances the clinical responses to interferon-α (IFN) in newly diagnosed chronic myeloid leukemia (CML)

The majority of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) remain with residual disease. In contrast to TKIs, interferon (IFN) is directly toxic to CML progenitor cells, and myeloid growth factors such as GM-CSF may enhance IFN's cytotoxicity. We performed a phase 2 study of IFN + GM-CSF in 58 newly diagnosed CML patients before imatinib approval. Short-term clinical responses included: 60% major cytogenetic response, 28% complete cytogenetic response and 19% complete molecular response. Six patients remain off all therapy for CML (range: 15 months–12 years) after IFN + GM-CSF treatment. IFN + GM-CSF shows promise as an adjunctive therapy for CML.     

Acute myeloid leukemia developing during imatinib mesylate therapy for chronic myeloid leukemia in the absence of new cytogenetic abnormalities

The BCR/ABL tyrosine kinase inhibitor imatinib mesylate produces a high rate of cytogenetic responses in patients with Philadelphia (Ph)-positive chronic myeloid leukemia (CML), but secondary clonal chromosome abnormalities may develop in Ph-negative cells, and acute myeloid leukemia (AML) has been reported in patients with secondary chromosome abnormalities. We report a patient who developed AML during imatinib treatment of Ph-positive CML despite a cytogenetic response and absence of secondary chromosome abnormalities. Thus, development of AML as a rare event in CML patients with cytogenetic responses to imatinib therapy does not depend on the development of secondary cytogenetic abnormalities.     

How Much and How Long: Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia

As the first clinically successful tyrosine kinase inhibitor (TKI), imatinib pioneered a new approach to treating patients with cancer. Dramatic results from chronic myeloid leukemia (CML) clinical trials spurred the development of TKIs for other malignancies such as acute myeloid leukemia as well as kidney and lung cancer. In CML, imatinib resistance led to the rapid development of dasatinib and nilotinib, more potent second-generation ABL kinase inhibitors that can often overcome imatinib resistance. While the clinical efficacy of TKIs in CML is well established, a number of important questions remain about the optimal dose and duration of therapy. Even the best initial dose for imatinib is still under investigation. Although laboratory and clinical studies had led to the prevailing view that continual inhibition of the BCR-ABL kinase was required for optimal efficacy, recent data on dasatinib have upended this notion and have led to a change in the recommended dosing schedule. The availability of dasatinib and nilotinib also begs the question of whether they might be superior to imatinib as first-line agents. Finally, the question of whether it may be possible to stop TKI therapy at least in some patients with CML has attracted considerable attention. More than 10 years after the introduction of imatinib, optimization of TKI therapy for CML continues.     

Current and emerging treatment options in chronic myeloid leukemia

Treatments for chronic myeloid leukemia (CML) represent a success story in molecular medicine. The development of imatinib, a tyrosine kinase inhibitor (TKI) targeted against the causative Bcr-Abl oncoprotein in CML, has resulted in hematologic and cytogenetic remissions in all phases of CML. A significant proportion of patients are resistant to imatinib or develop resistance during treatment. This is often a result of mutated forms of the Bcr-Abl oncoprotein to which imatinib is unable to bind. Several strategies have been developed to overcome the problem of imatinib resistance, including high-dose imatinib, novel targeted agents, and combination treatments. Novel agents include dasatinib, a potent TKI that inhibits several critical oncogenic proteins and which has recently been approved for patients with CML who are resistant or intolerant to imatinib; and nilotinib, a potent selective Bcr-Abl kinase inhibitor currently in clinical development. Other agents in development include SKI-606 and INNO-406. Stem cell transplantation remains a useful option, although it is not generally used as first-line treatment. Overall, there are an increasing number of treatment options available for patients with CML.     

Diagnosis and management of chronic myeloid leukemia: a survey of American and European practice patterns

BACKGROUND: The success of imatinib therapy for chronic myeloid leukemia (CML) has brought new challenges; these include optimizing disease monitoring, imatinib resistance, and use of novel, more potent tyrosine kinase inhibitors. Thus, there is a need to establish new best practices for CML management in the post-imatinib era. METHODS: An internet-based questionnaire, consisting of 26 multiple choice questions, was developed to assess hematologists' and oncologists' self-reported treatment strategies for CML. RESULTS: Between November 2005 and January 2006, 956 eligible physicians responded to the survey; 727 from the US and 229 from Europe. Most US respondents (60%) practiced in the community setting, whereas European respondents were primarily academic (44%) and hospital-based (40%). Physicians' responses were generally in line with current recommendations, although differences were identified. Confusion existed among respondents over optimal timing of treatment decisions, with a notable proportion of physicians focusing on a single timepoint rather than consistent monitoring, as currently advocated. Some respondents were unaware of new molecular monitoring techniques, when to monitor for BCR-ABL mutations (and the impact on treatment decisions), and the benefit of new tyrosine kinase inhibitors. CONCLUSIONS: Responses to the survey suggest that treatment practices in some areas of CML management are not in line with current recommendations. Identified areas of need should be targeted in future educational activities for the CML community.     

Management of the New Patient with CML in Chronic Phase

Imatinib has been the preferred initial therapy for newly diagnosed chronic myeloid leukemia (CML) patients for the last 10 years. Today, other tyrosine kinase inhibitors (TKIs) are licensed for first-line use. In this paper we analyze the pros and cons of the various alternatives to imatinib and try to give some advice on the management of the newly diagnosed patient.     

Genetic Mechanisms of Chronic Myeloid Leukemia Blastic Transformation

The BCR-ABL1 oncogenic tyrosine kinase can transform pluripotent hematopoietic stem cells and initiate chronic myeloid leukemia in chronic phase (CML-CP), a myeloproliferative disorder characterized by excessive accumulation of mature myeloid cells. Patients in CML-CP usually respond to treatment with ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib, though some patients who respond initially may become resistant later. CML-CP leukemia stem cells (LSCs) are intrinsically insensitive to TKIs and thus survive in the long term. These LSCs or their progeny may at some stage acquire additional genetic changes that cause the leukemia to transform further, from CML-CP to a more advanced phase, which has been subclassified as either accelerated phase (CML-AP) or blastic phase (CML-BP). CML-BP is characterized by a major clonal expansion of immature progenitors, which have either myeloid or lymphoid features. CML-BP responds poorly to treatment and is usually fatal. This review discusses the role of genomic instability leading to blastic transformation of CML and proposes some novel therapeutic approaches.     

Nilotinib: a phenylamino-pyrimidine derivative with activity against BCR-ABL, KIT and PDGFR kinases

The BCR-ABL kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia (CML). However, mutations within the ABL kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib. Multiple distinct BCR-ABL kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported. Nilotinib is a tyrosine kinase inhibitor 30-fold more potent than imatinib against BCR-ABL kinase. Nilotinib is active against a wide range of imatinib-resistant BCR-ABL mutant isoforms, except for T315I. Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting. Studies addressing the activity of nilotinib in newly-diagnosed patients with CML are underway. Furthermore, nilotinib is a potent inhibitor of KIT and PDGFR kinases. Here, we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by KIT and/or PDGFR mutant kinases, such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia.     

Management of patients with resistant or refractory chronic myelogenous leukemia

The introduction of imatinib mesylate (Gleevec) has dramatically changed the management and prognostic outlook of patients with chronic myeloid leukemia (CML). Despite the outstanding results achieved with imatinib, approximately 20% to 30% of patients may either not respond to therapy or eventually develop resistance or intolerance to the drug. Resistance to imatinib is mediated to a great extent by the emergence of mutations within the tyrosine kinase domain of the BCR-ABL oncogene. A growing number of tyrosine kinase inhibitors (TKIs) with different pharmacokinetic and pharmacodynamic profiles are currently being investigated in clinical trials to determine their efficacy against CML resistant to imatinib therapy. The leading examples of this group of second-generation TKIs are nilotinib (Tasigna) and dasatinib (Sprycel). This review addresses the causes and consequences of imatinib resistance and current management of refractory CML with the second-generation TKIs.