Practical advice for determining the role of BCR-ABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia

Abstract

Data demonstrating the superiority of nilotinib over imatinib in the frontline treatment of chronic myeloid leukemia (CML) and ongoing studies with dasatinib and bosutinib are rapidly changing the treatment landscape for CML. In this review, the authors discuss currently available therapies for CML, focusing on mechanisms of resistance to imatinib and treatment strategies to overcome resistance. Relevant articles were identified through searches of PubMed and abstracts from international hematology/oncology congresses. Additional information sources were identified from the bibliographies of these references and from the authors' own libraries and expertise. In vitro 50% inhibitory concentration (IC(50) ) data alone are not sufficient to guide the choice of a tyrosine kinase inhibitor (TKI) in the presence of a mutant breakpoint cluster region-v-abl Abelson murine leukemia viral oncogene homolog (BCR-ABL) clone, because there is a lack of data regarding how well such IC(50) values correlate with clinical response. A small subset of BCR-ABL mutant clones have been associated with impaired responses to second-generation TKIs (tyrosine to histidine mutation at codon 253 [Y253H], glutamic acid to lysine or valine mutation at codon 255 [E255K/V], and phenylalanine to cysteine or valine mutation at codon 359 [F359C/V] for nilotinib; valine to leucine mutation at codon 299 [V299L] and F317L for dasatinib); neither nilotinib nor dasatinib is active against the threonine to isoleucine mutation at codon 315 (T315I). For each second-generation TKI, the detection of 1 of a small subset of mutations at the time of resistance may be helpful in the selection of second-line therapy [corrected]. For the majority of patients, comorbidities and drug safety profiles should be the basis for choosing a second-line agent. Clinical trial data from an evaluation of the response of specific mutant BCR-ABL clones to TKIs is needed to establish the role of mutation testing in the management of CML.

Figure 1

This chart compares the predicted C_max/GI₅₀ values (ie, ratio of the in vivo maximum drug concentration to 50% growth inhibition of in vitro chronic myeloid leukemia cell colonies) from in vitro data and complete cytogenetic responses (CCyRs) in clinical trials. Previously published CCyR rates for patients with specific mutations were plotted against adjusted values to assess the correlation between in vitro GI₅₀ data (adjusted for in vivo plasma levels) and observed clinical responses in patients. The shaded areas indicate that, despite similar C_max/GI₅₀ values, clinical responses differed between mutations, suggesting that the 50% concentration values have limited use in predicting clinical resistance. WT indicates wild type; G250E, glycine to glutamic acid mutation at codon 250; F317L, phenylalanine to leucine mutation at codon 317; F359V, phenylalanine to valine mutation at codon 359. (Reprinted with permission: VC American Society of Clinical Oncology 2010. Laneuville P, Di Lea C, Yin O, Woodman R, Mestan J, Manley P. Comparative in vitro cellular data alone are insufficient to predict clinical responses and guide the choice of BCR-ABL inhibitor for treating imatinib-resistant chronic myeloid leukemia. J Clin Oncol. 2010; 28:e169–e171.)

Figure 2

This chart illustrates the suggested treatment algorithm for patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase. An asterisk indicates that imatinib and nilotinib are the only approved tyrosine kinase inhibitors (TKIs) for the frontline treatment of CML. Nilotinib recently was approved by the US Food and Drug Administration after it demonstrated superior response rates and a significant improvement in the time to progression compared with imatinib; those improvements persisted at a median follow-up >18 months in an international, phase 3, randomized trial.^, Dasatinib also demonstrated superior response rates compared with imatinib in a phase 3 randomized trial and is under review for regulatory approval in several countries. Bosutinib is being evaluated in a randomized trial of patients with newly diagnosed CML, and those results are expected in 2010. The dagger indicates that randomized clinical trials currently are underway to examine the value of an early switch to second-generation TKIs in patients who have a suboptimal response to imatinib. CyR indicates cytogenetic response; PCyR, partial cytogenetic response; MMR, major molecular response; F317L, phenylalanine to leucine mutation at codon 317; V299L, valine to leucine mutation at codon 299; E255K/V, glutamic acid to lysine or valine mutation at codon 255; Y253H, tyrosine to histidine mutation at codon 253; F359C/V, phenylalanine to cysteine or valine mutation at codon 359; HSCT, hematopoietic stem cell transplantation.