ABSTRACT: 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.
In the absence of effective therapy, patients with chronic-phase chronic myeloid leukemia (CML) invariably progress to a more aggressive phase of the disease termed blastic phase, typically preceded by an accelerated phase of variable duration. The hallmark of the accelerated phase and particularly of the blastic phase is an unregulated overproduction of cells of myeloid origin with an increasing representation of immature forms as the disease progresses. Thus, patients in blastic phase present with a peripheral blood or bone marrow blast percentage of 30% or higher. The estimated risk of transformation to the blastic phase is 5% to 10% per year during the first 2 years after diagnosis and increases to up to 20%–25% per year thereafter.[1,2] Blastic-phase CML is usually resistant to standard chemotherapeutic agents. Prior to the introduction of targeted tyrosine kinase inhibitors (TKIs) for the treatment of CML, the median survival of patients in blastic phase was less than 6 months.
The hallmark genetic abnormality in CML is the balanced translocation t(9;22)(q34;q11.2), which results in the Philadelphia chromosome (Ph). The molecular surrogate of the Ph chromosome is the BCR-ABL hybrid oncogene,[3,4] which encodes for BCR-ABL, a tyrosine kinase with deregulated activity that has been shown to be both necessary and sufficient for the initiation and maintenance of CML.
The addition of imatinib mesylate (Gleevec) to the therapeutic armamentarium for CML has dramatically changed the management and prognostic outlook of patients with this disease. Imatinib is a phenylamino pyrimidine TKI that specifically targets BCR-ABL, KIT, and platelet-derived growth factor receptor (PDGFR) kinases, has proven to be highly active and safe in patients with CML, and has become standard frontline therapy for patients with this disorder. 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. The occurrence of BCR-ABL kinase point mutations is the most frequently identified mechanism responsible for resistance to imatinib and other TKIs. In smaller subsets of patients, other mechanisms have been identified as responsible for imatinib resistance.
Clinical Resistance to Imatinib
Resistance to imatinib therapy can be segregated into primary (or intrinsic), in which patients exhibit lack of efficacy to TKIs from the onset of therapy, and secondary (or acquired), in which patients experience an initial response to imatinib followed by loss of response after a period of time of variable length. Resistance can be further subdivided into hematologic (lack of normalization of peripheral blood counts), cytogenetic (persistence of Ph chromosome), and molecular resistance (persistence of BCR-ABL transcripts by reverse transcriptase polymerase chain reaction).
In 2006, on behalf of the European LeukemiaNet, a panel of experts put forth a set of recommendations for the definition of resistance to imatinib that has now become standard. According to this definition, the lack of achievement of a predefined level of response at specific temporal milestones or the loss of hematologic or cytogenetic response at any time defines imatinib failure (Table 1). Patients who meet these definitions of failure to imatinib have an inferior outcome that mirrors that of patients in the pre-imatinib era. Recognizing the importance of the time to achieve the therapeutic goals, this panel also included a group of patients who were defined as having a suboptimal response. These represent patients who cannot be considered to have failed therapy, but whose prognosis has been shown to be less favorable than that of patients with optimal response at the corresponding time points.
In addition, the panel issued a series of therapeutic recommendations for the management of patients who fail imatinib therapy. Although the definitions of imatinib failure provide a useful framework that facilitates the management of patients with CML, the proposals concerning therapeutic intervention have evolved significantly since the time of the issuance of the guidelines, particularly with the emergence of more data regarding the efficacy and safety of second-generation TKIs.
Causes and Consequences
Imatinib mesylate is an orally bioavailable TKI that inhibits the constitutively active BCR-ABL kinase with 50% inhibitory concentration (IC50) values ranging from 0.1 to 0.5 μM.[8-10] In the phase III, randomized International Randomized study of Interferon versus STI571 (IRIS) trial, the efficacy of imatinib was compared to the combination of interferon-alpha and low-dose cytarabine in patients with newly diagnosed CML in chronic phase. After a median follow-up of 60 months, the projected rates of complete hematologic response (CHR) and cytogenetic response (CCyR) were 98% and 87%, respectively. The estimated 5-year survival rate was approximately 90%.
Based on these results, imatinib has become the standard frontline therapy for CML. The initial enthusiasm brought about by the impressive results obtained with imatinib was partially attenuated by the fact that only a small fraction of patients receiving this TKI actually have their disease eradicated at the molecular level. However, nearly two-thirds of patients achieve a major molecular response (3-log reduction in BCR-ABL/ABL transcript levels), which has been associated with 100% survival free from transformation to accelerated or blastic phase when achieved within 12 months.
Still, approximately 20% to 30% of patients will eventually develop resistance to imatinib. In addition, the response rates observed in patients with CML in accelerated or blastic phase were low, and these responses were generally of brief duration. These shortcomings and the development of resistance in 20% to 30% of patients treated in chronic phase have fueled the study of mechanisms of resistance to TKI therapy in CML and the development of novel agents to overcome them.
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 distinct BCR-ABL mutations, currently in excess of 60, have been reported, with the frequency of detection among patients with imatinib-resistant CML ranging from 20% to 90%, depending upon the disease phase and the sensitivity of the detection methodology.[15-21] These mutations translate into single amino acid substitutions that tend to cluster on defined functional areas of the BCR-ABL kinase.
BCR-ABL kinase oscillates between an active (open) and an inactive (closed) conformation, depending upon the spatial position of the activation and the P-loops. In the inactive state, the activation loop swings inwardly toward the catalytic site of the enzyme, whereas in the active state, the activation loop flips outwardly to facilitate substrate binding. Another important domain in ABL kinase activation is the P-loop at the amino-terminal end that functions as a docking site for phosphate moieties of ATP. The P-loop region is home to some of the most common mutations found in patients after imatinib failure.[23-25]
Mutations can induce imatinib resistance by distorting the configuration of the BCR-ABL kinase, which results in the inability of the enzyme to adopt the inactive conformation necessary for imatinib binding.[16,22,26,27] Other mutations may affect necessary binding sites for imatinib, thereby preventing adequate attachment of the inhibitors. Different mutations confer different degrees of resistance. The mutation conferring the highest degree of resistance to imatinib and second-generation TKIs such as dasatinib (Sprycel) or nilotinib (Tasigna) is that involving the substitution of the threonine residue at the “gatekeeper” residue 315 for a bulkier isoleucine amino acid. This mutation is frequently identified in patients with imatinib-resistant advanced-phase CML. The threonine residue at position 315 controls access to the active site of the enzyme, thus causing steric clash with imatinib and other TKIs. For that reason, the BCR-ABL T315I mutation represents a formidable challenge for CML clinicians and researchers.
Other mechanisms of resistance have also been identified in CML, including overexpression or amplification of BCR-ABL, clonal evolution, and BCR-ABL–independent mechanisms such as overexpression of the SRC family of kinases (SFKs),[20,29] inhibition of imatinib influx into the cell, or increased efflux. Unlike BCR-ABL kinase mutations, these other mechanisms of resistance are less well characterized.
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