Optimizing the Selection of Kinase Inhibitors for Chronic Myeloid Leukemia Patients

Devendra K Hiwase; David T Yeung; Deborah L White

Disclosures

Expert Rev Hematol. 2011;4(3):285-299. 

In This Article

Abstract and Introduction

Abstract

Long-term follow-up of clinical studies has demonstrated the efficacy of imatinib therapy in newly diagnosed chronic phase-chronic myeloid leukemia patients (CML). However, recent updates of two separate randomized Phase III studies demonstrated higher complete cytogenetic and major molecular response rates with dasatinib and nilotinib compared with imatinib 400 mg/day. Hence, for newly diagnosed chronic phase-CML patients there are multiple treatment options, including standard-dose imatinib, high-dose imatinib, and combination therapy of imatinib and interferon, dasatinib and nilotinib. This article critically analyzes the current literature and provides guidelines for the management of newly diagnosed CML. Disease and therapy-related prognostic factors, which may aid in the selection of therapeutic strategies to enable optimal treatment outcomes, are discussed. In addition, we provide commentary on the therapeutic options for patients who fail imatinib therapy.

Introduction

Chronic myeloid leukemia (CML) has become a model disease in cancer medicine. The understanding of the underlying biology of CML has led to the characterization of therapeutic targets and the development of rationally designed targeted therapies with unprecedented potency and specificity. These same targets can also be used effectively as molecular markers for diagnosis and, more importantly, monitoring of the patient's response to targeted therapy. CML is characterized by the Philadelphia chromosome (Ph),[1] which results from reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11).[2] The resultant chimeric BCR–ABL1 oncogene translates a Bcr–Abl oncoprotein with constitutively active tyrosine kinase activity. Imatinib (Glivec™, formerly STI571; Novartis Pharmaceuticals, Basel, Switzerland) has dramatically improved the treatment of CML and has led to important changes in management of this disease. With the widespread use of imatinib and increasing experience with nilotinib (formerly AMN107; Novartis Pharmaceuticals, Basel, Switzerland) and dasatinib (formerly BMS-35482; Bristol-Myers Squibb, NJ, USA), the current challenge is to use these drugs rationally to maximize efficacy and minimize toxicity.

Most patients diagnosed with CML in chronic phase (CP) can expect excellent disease control with remarkable improvement in survival compared with the pre-imatinib era. For a minority of patients who appear to be either intolerant or resistant to one or more tyrosine kinase inhibitors (TKIs), management is less straightforward.

In this article, we aim to summarize the current evidence regarding pertinent questions in contemporary CML management. In turn, we also address the following questions: what are the therapeutic goals for newly diagnosed CML patients? Can we predict poor responders to imatinib therapy and how can we optimize therapy in these patients? How do we monitor patients treated with imatinib therapy? With the more recent development of second-generation, more potent inhibitors such as nilotinib and dasatinib, and the demonstration of their effectiveness as front-line therapy, what is the best strategy in the de novo CP-CML patient?

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