Mutant BCR-ABL clones in chronic myeloid leukemia

The management of chronic myeloid leukemia (CML) has been revolutionized by the availability of small molecule tyrosine kinase inhibitors (TKI), such as imatinib (formerly STI571), dasatinib, and nilotinib. These agents work by competing with adenosine triphosphate (ATP) at its binding site on the ABL kinase, leading to inhibition of tyrosine phosphorylation of proteins involved in signal transduction. 1 The updated results of the International Randomized Study of Interferon and STI571 (IRIS) have confirmed high rates of durable cytogenetic remission coupled with a very low risk of progression to advanced disease VSports. 2 At the 6-year follow up, progression-free survival and overall survival rates were 93% and 88%, respectively, for patients treated with imatinib. Nevertheless, some patients never respond to imatinib while some others have an initial response which is then followed by disease progression. Primary resistance refers to a lack of any relevant hematologic or cytogenetic response. Secondary resistance is acquired, and is defined as the achievement of hematologic or cytogenetic response followed by subsequent loss of disease control. Acquired resistance was documented in 24% of the patients in the 5-year follow up of the IRIS data. 3 There appears to be a peak of imatinib resistance in the second and third years of therapy, underscoring the need for second-line options or improved front-line strategies. 4.

A number of factors may be implicated in patients who eventually lose their response to imatinib. The mechanisms may involve BCR-ABL gene amplification, BCR-ABL over-expression, aberrations in other signaling pathways, and a host of others. 5 Point mutations in the BCR-ABL kinase domain are a major cause of imatinib resistance, and may be identified in approximately 50% or more of the cases. Mutations in the kinase domain have the ability to impair the binding of imatinib, leading to drug resistance. Many more than 100 different mutations have so far been identified, with varying degrees of clinical relevance. 6 The particular mutation identified may have therapeutic implications in terms of second- or third-line therapy. 7 One of the most notable mutations is the threonine to isoleucine mutation at codon 315 (T315I), which is known to be resistant to all currently available TKI. Jabbour et al. evaluated whether scoring a mutation based on the in vitro 50% inhibitory concentration (IC50) at the time of imatinib failure had an impact on outcome in the context of treatment with other TKI VSports app下载. 8 The study demonstrated that patients in chronic phase disease with mutations demonstrating intermediate IC50 values had a shorter duration of response to second-line therapy, and inferior survival overall. It is, therefore, important to obtain a mutational analysis for all patients failing to meet pre-specified therapeutic benchmarks. 9.

Dasatinib and nilotinib are second generation TKI that were initially developed to treat patients who could not tolerate, or did not respond adequately to imatinib. Recently, the results of large phase III trials comparing these agents to imatinib in treatment-naïve patients have been published, establishing both dasatinib and nilotinib as potentially viable front-line therapeutic options. 10,11 It has previously been shown that most mutations that confer resistance to imatinib retain sensitivity to both dasatinib and nilotinib V体育官网. 12,13.

Investigators have evaluated the influence of BCR-ABL mutations on treatment with dasatinib. Of 805 patients who had suboptimal response or resistance to imatinib, 48% were found to have a BCR-ABL mutation. 12 Despite the high prevalence of mutations, relevant outcomes in patients with mutations were similar to those without baseline mutations (complete cytogenetic response 40% versus 41%, respectively). However, there were specific mutations identified according to the IC50 that appear to predict an inferior outcome in dasatinib-treated patients; these mutations included the phenylalanine to leucine mutation at codon 317 (F317L) and valine to lysine mutation at codon 299 (V299L). These mutations have been consistently associated with lower rates of cytogenetic remission under treatment with dasatinib, making alternative treatments more attractive when faced with this scenario VSports手机版.

Similarly, nilotinib has been shown to be active against most known BCR-ABL mutations leading to failure of imatinib treatment. 13 When evaluating data from one of the phase II trials evaluating the use of nilotinib in CML, patients were stratified into three groups based on their mutation status at the time of failure of imatinib treatment: no mutations, sensitive mutations, and those with less sensitive mutations according to the IC50. Rates of response, including major cytogenetic response, complete cytogenetic response, and major molecular response, were all similar between the three groups. However, further evaluation did isolate several low sensitivity mutations that influenced the response to nilotinib V体育安卓版. These included the glutamic acid to valine or lysine mutation at codon 255 (E255V/K), the tyrosine to histidine mutation at codon 253 (Y253H), and the phenylalanine to cysteine or valine mutations at codon 359 (F359C/V).

Mutational status should not be the sole factor determining how to treat a patient in whom imatinib treatment has failed or who has disease progression V体育ios版. The patient’s medical history must be considered and placed in the context of the known toxicity profile of a given treatment. Apart from displaying different patterns of activity and resistance to various BCR-ABL mutations, the currently available TKI also have distinct adverse event profiles. Any patient with uncontrolled diabetes, or a past history of pancreatitis should be followed very closely if nilotinib is prescribed, as the drug has been associated with grade 3/4 elevations of serum glucose and lipase. Likewise, if dasatinib treatment is being considered, caution must be exercised in individuals with a history of gastrointestinal bleeding, asthma, chronic obstructive pulmonary disease, or congestive heart failure, given the high risk of hemorrhage and pleural or pericardial effusions. 14 These pieces of information coupled with the mutational status of a patient may help to optimally tailor and monitor further therapy.

There is also the issue of what happens to the BCR-ABL genotype over time, and how it might be influenced by the most recent therapy. The concept of clonal selection, or cytogenetic evolution in CML has been described previously. 15 Small populations of mutated cells have been shown to exist at baseline, and therapy with a TKI may offer these cells a growth advantage, eventually leading to their predominance. Baseline mutations, however, did not have an effect on response to therapy. One question that remains to be thoroughly explored is what happens to the BCR-ABL genotype once the selective pressure of TKI therapy is removed. In this issue of Haematologica, Hanfstein et al. report on the dynamics of BCR-ABL mutations in 19 patients after therapy with a TKI was stopped. 16 These patients were switched to non-TKI based therapy upon imatinib failure deemed secondary to the emergence of a well-characterized mutation. Patients were followed over time using highly sensitive methods to determine the size of the mutant clone after cessation of the TKI. The investigators were able to demonstrate consistent regression of most BCR-ABL mutations over a period of months, and overall described an 86% relative decline of the size of the mutant clones after cessation of the TKI VSports最新版本. Importantly, they were also able to document the complete disappearance of the T315I mutation in two patients, though more commonly this mutation persisted despite manipulation of the therapeutic strategy. The authors also found evidence of repeated deselection and reselection of mutant clones in patients who resumed therapy with TKI after periods of cessation.

There are several points to be made regarding the above findings. First, clinicians should no longer consider the mutational status of a patient as a static event, and screening for BCR-ABL mutations should always be placed in the context of where the patient is in terms of therapy. This has implications for the monitoring of the mutational status as patients are switched to an alternative TKI or non-TKI based therapy V体育平台登录. One important question that remains concerns the resumption of currently available TKI therapy after the disappearance of the selected mutation. In particular, for patients with the T315I mutation, therapeutic options are limited, and it would be helpful to know whether such patients could safely and effectively resume a TKI. Potentially, non-cross resistant chemotherapy combined with a TKI may be an option for these patients if the mutant clone regresses appreciably. The authors noted that resurgence of the mutant clone after resumption of TKI therapy was possible. Indeed, the patterns of deselection and reselection of mutant clones in a number of the patients described in the report indicate that the clones may not be completely eradicated. It is uncertain whether TKI withdrawal or the effects of non-specific chemotherapy were principally responsible for the disappearance of some mutations. The phenomenon may be multifactorial.

The treatment landscape of CML continues to evolve, as does the capability to characterize and quantify minimal residual disease. Second generation TKI are now moving to the frontline, and it will be important to monitor the impact that this paradigm shift has on BCR-ABL mutants. Indeed, the emergence of novel BCR-ABL mutants was noted shortly after the introduction of dasatinib and nilotinib into clinical practice as second-line options. 17 Regression of mutations conferring imatinib resistance was also noted in this report, but it was not as pronounced or predictable as described in the present study. Novel TKI, such as bosutinib and ponatinib (formerly AP24534), are now entering into advanced stages of clinical development for the management of CML. 18,19 Soon, mutational information will have to be placed in the context of the availability of these newer options. Innovative strategies, which may include non-TKI-based regimens or a combination approach, continue to be necessary for patients who develop mutations that are resistant to current therapy. More intensive monitoring of the mutational status should be considered for patients who develop mutations, but who subsequently receive therapy that may allow for deselection over time by relieving clonal pressure VSports注册入口.

"VSports在线直播" Footnotes

• Michael S. Mathisen, Pharm.D., is Clinical Pharmacy Specialist at the Departments of Leukemia and Pharmacy, M. D. Anderson Cancer Center. He is very active in both patient care and research missions of the Department of Leukemia. Hagop M. Kantarjian, M.D. is Professor and Chairman of the Department of Leukemia, M. D. Anderson Cancer Center. He has been a major investigator in clinical trials that have led to the approval of several new drugs for leukemia patients and has published more than 1,000 peer-reviewed articles. Jorge Cortes, M.D., is Professor of Medicine in the Department of Leukemia, M. D. Anderson Cancer Center. He serves as the Chief of the Chronic Myeloid Leukemia section within the department. He is currently leading several trials investigating the uses of both novel and established drugs for patients diagnosed with CML. Elias Jabbour, M.D. is Assistant Professor in the Department of Leukemia, M. D. Anderson Cancer Center. He is active in the field of myeloid disorders and, in particular, mechanisms of resistance to tyrosine kinase inhibitors. He is also an investigator of numerous novel therapies for the treatment of CML and myelodysplastic syndromes.
• Related Original Article on page 360
• Financial and other disclosures provided by the author using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are available with the full text of this paper at www.haematologica.org.