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

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.

Jabbour E ，Branford S ，Saglio G ，Jones D ，Cortes JE ，Kantarjian HM ... -  《-》

BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome.

Discovery of imatinib mesylate (IM) as the targeted BCR-ABL protein tyrosine kinase inhibitor (TKI) has resulted in its use as the frontline therapy for chronic myeloid leukemia (CML) across the world. Although high response rates are observed in CML patients who receive IM treatment, a significant number of patients develop resistance to IM. Resistance to IM in patients has been associated with a heterogeneous array of mechanisms of which point mutations within the ABL tyrosine kinase domain (TKD) are the frequently documented. The types and frequencies of mutations reported in different population studies have shown wide variability. We screened 125 Malaysian CML patients on IM therapy who showed either TKI refractory or resistance to IM to investigate the frequency and pattern of BCR-ABL kinase domain mutations among Malaysian CML patients undergoing IM therapy and to determine the clinical significance. Mutational screening using denaturing high performance liquid chromatography (dHPLC) followed by DNA sequencing was performed on 125 IM resistant Malaysian CML patients. Mutations were detected in 28 patients (22.4%). Fifteen different types of mutations (T315I, E255K, G250E, M351T, F359C, G251E, Y253H, V289F, E355G, N368S, L387M, H369R, A397P, E355A, D276G), including 2 novel mutations were identified, with T315I as the predominant type of mutation. The data generated from clinical and molecular parameters studied were correlated with the survival of CML patients. Patients with Y253H, M351T and E355G TKD mutations showed poorer prognosis compared to those without mutation. Interestingly, when the prognostic impact of the observed mutations was compared inter-individually, E355G and Y253H mutations were associated with more adverse prognosis and shorter survival (P=0.025 and 0.005 respectively) than T315I mutation. Results suggest that apart from those mutations occurring in the three crucial regions (catalytic domain, P-loop and activation-loop), other rare mutations also may have high impact in the development of resistance and adverse prognosis. Presence of mutations in different regions of BCR-ABL TKD leads to different levels of resistance and early detection of emerging mutant clones may help in decision making for alternative treatment. Serial monitoring of BCR-ABL1 transcripts in CML patients allows appropriate selection of CML patients for BCR-ABL1 KD mutation analysis associated with acquired TKI resistance. Identification of these KD mutations is essential in order to direct alternative treatments in such CML patients.

Elias MH ，Baba AA ，Azlan H ，Rosline H ，Sim GA ，Padmini M ，Fadilah SA ，Ankathil R ... -  《-》

Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management.

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one-two cases per 100,000 adults and accounts for ∼15% of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein. Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for the first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. For patients who fail standard-dose imatinib therapy, imatinib dose escalation is a second-line option. Alternative second-line options include 2nd generation TKIs. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs and are candidate for clinical trials. Allogeneic transplantation remains an important therapeutic option for CML-CP harboring the T315I mutation, patients who fail 2nd generation TKIs, and for all patients in advanced phase disease.

Jabbour E ，Kantarjian H 《-》

Choosing the best second-line tyrosine kinase inhibitor in imatinib-resistant chronic myeloid leukemia patients harboring Bcr-Abl kinase domain mutations: how reliable is the IC₅₀?

Soverini S ，Rosti G ，Iacobucci I ，Baccarani M ，Martinelli G ... -  《-》

Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?

Branford S ，Melo JV ，Hughes TP 《-》