Abstract
Chronic myeloid leukemia (CML) is a chronic myeloproliferative disorder with leukemic cells featuring the Philadelphia (Ph1) chromosome comprising the reciprocal chromosomal translocation t(9;22)(q34;q22) and the resultant constitutive active Bcr-Abl tyrosine kinase (TK). The introduction of disease-specific molecular targeted agents, that is, TK inhibitors (TKIs) for Bcr-Abl TK, such as the first-in-class TKI imatinib mesylate (IM) or the secondgeneration TKIs (SGIs) nilotinib and dasatinib, has dramatically improved the long-term treatment outcome for CML in this century. In addition, several new SGIs, such as bosutinib or bafetinib, are under development, while ponatinib, which is active against CML refractory for all preceding TKIs, for example, CML with T315I Abl kinase domain mutation, is currently being evaluated in clinical trials. Because those TKIs have different sensitivity for Bcr- Abl mutation and profiles for adverse effects, a thorough understanding of the pharmacologic characteristics of TKIs is mandatory for their safe and effective clinical use. Recent studies have clearly shown the faster and deeper responses to SGIs, both nilotinib and dasatinib, compared with those to IM, indicating the need for a paradigm shift in approaches to TKI therapy for treatment-naive CML. In addition, evidence accumulated during the past decade has indicated optimal methodologies for monitoring the treatment effect of TKIs, selecting the appropriate therapeutic strategies, and predicting the outcome for treatment with TKIs for individual patients with CML. In this article, we review the principles and current knowledge and topics of the various uses of TKIs for CML. We also touch upon the reason why the faster and the deeper responses to TKIs is the prerequisite for their safer use and longer-lasting positive treatment outcome for CML.
Highlights
Chronic myeloid leukemia (CML) is a subtype of chronic myeloproliferative disorders with leukemic cells featuring the reciprocal chromosomal translocation t(9;22)(q34;q22), known as the Philadelphia (Ph1) chromosome, and its resultant Bcr-Abl fusion oncoprotein, which exerts constitutive tyrosine kinase (TK) activity which in turn stimulates various downstream signaling cascades for deregulated cell proliferation, cell survival, resistance to cytotoxic stimuli and genetic instability [1,2]
The IRIS (International Randomized Study of Interferon and STI571) study of chronic phase CML (CML-CP) patients which compared the effects of imatinib mesylate (IM) and IFN-α plus cytarabine as first-line therapy found that continuous IM treatment resulted in greater treatment success with an eight-year overall survival (OS) rate of 93% and cumulative complete cytogenetic response (CCyR) of 83%, demonstrating the apparent advantage of firstline IM therapy for better long-term outcomes for CML patients [3,4]
The apparently better OS rate and the notably fewer short-term lifethreatening adverse events attained with IM in comparison with allogeneic hematopoietic stem cell transplantation (HSCT), the former has come to be regarded as the first-line treatment for CML, especially in the chronic phase (CP)
Summary
Chronic myeloid leukemia (CML) is a subtype of chronic myeloproliferative disorders with leukemic cells featuring the reciprocal chromosomal translocation t(9;22)(q34;q22), known as the Philadelphia (Ph1) chromosome, and its resultant Bcr-Abl fusion oncoprotein, which exerts constitutive tyrosine kinase (TK) activity which in turn stimulates various downstream signaling cascades for deregulated cell proliferation, cell survival, resistance to cytotoxic stimuli and genetic instability [1,2]. To overcome the major mechanisms for IM resistance, several SGIs with more flexiblity in response to Abl KD conformational changes, higher affinity for more abundant Bcr-Abl and ability to block various leukemogenic kinases have been developed for or introduced to the treatment for CML As of this writing, nilotinib and dasatinib have been approved for clinical use as second-line and as first-line treatment, while bosutinib, bafetinib and ponatinib are undergoing clinical trials. The CCyR rates after 24 months of treatment with nilotinib for IM-resistant and IM-intolerant CML-CP patients were reportedly 41% and 51%, respectively, while the MMR rate obtained with nilotinib for these patients was as high as 28% [55] These results imply that there is a need for predictors for response to second-line SGIs for the development of alternative treatment strategies. The 7 sections deal with several topics regarding the use of TKIs based on a decade of experience
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