Frequency of ABL gene mutations in chronic myeloid leukemia patients resistant to imatinib and results of treatment switch to second-generation tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients do not achieve the optimal response or are resistant to TKI. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKI has produced high rates of hematologic and cytogenetic responses in mutated ABL patients. The aim of this study was to determine the type and frequency of ABL mutations in patients who were resistant to imatinib or had lost the response, and to analyze the effect of second-generation TKI on their outcome. The presence of ABL mutations in 45 CML patients resistant to imatinib was evaluated by direct sequencing and was correlated with the results of the cytogenetic study (performed in 39 cases). The outcome of these patients after therapy with nilotinib or dasatinib was analyzed. ABL mutations were detected in 14 out of 45 resistant patients. Patients with clonal cytogenetic evolution tended to develop mutations more frequently than those without clonal evolution. Nine out of the 15 patients with ABL mutation responded to a treatment switch to nilotinib (n=4), dasatinib (n=2), interferon (n=1) or hematopoietic stem cell transplantation (n=2). The frequency of ABL mutations in CML patients resistant to imatinib is high and is more frequent among those with clonal cytogenetic evolution. The change to second-generation TKI can overcome imatinib resistance in most of the mutated patients.

Marcé S ，Zamora L ，Cabezón M ，Xicoy B ，Boqué C ，Fernández C ，Grau J ，Navarro JT ，Fernández de Sevilla A ，Ribera JM ，Feliu E ，Millá F ，Grupo ICO de estudio de mutaciones de ABL en pacientes afectos de LMC ... -  《-》

[Research advance on molecular genetics of CML blast crisis].

Zhu HQ ，Zhang S ，Liu XL 《-》

Analysis of ABL kinase domain mutations conferring resistance to tyrosine kinase inhibitors in chronic myeloid leukemia cases from India.

Bagadi S ，Saikia T ，Pany A ，Das B ... -  《Clinical Laboratory》

Dynamic change of T315I BCR-ABL kinase domain mutation in Korean chronic myeloid leukaemia patients during treatment with Abl tyrosine kinase inhibitors.

We analysed the dynamic change of imatinib-resistant mutations in BCR-ABL kinase domain focusing on T315I mutation during dasatinib or nilotinib therapy. Fifty-five imatinib-resistant chronic myeloid leukaemia patients (32 patients with imatinib-resistant mutations and 23 patients without mutation) in different disease phases were treated with dasatinib (median 17.3 months) or nilotinib (median 6.8 months). Among the 32 patients with baseline mutation, mutations including M244V, G250E, E255K, M351T, H396R, S417Y, E450K and E459K disappeared in 8 patients and new mutations were detected in 9 patients, all of which were T315I. Among the 23 patients without baseline mutation, 4 patients showed newly developed mutations including T315I, T315I + E459K, M244V and F359V. The T315I was the most frequently detected mutation in imatinib therapy (16%, 9 of 55) as well as in dasatinib or nilotinib therapy (24%, 11 of 44). Patients with imatinib resistant baseline mutations had a higher rate of mutation development during dasatinib or nilotinib treatment compared to patients without baseline mutations (28% vs. 17%).

Kim WS ，Kim D ，Kim DW ，Kweon IY ，Kim SH ，Goh HG ，Park SH ，Lee J ... -  《-》

Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations.

Jabbour E ，Jones D ，Kantarjian HM ，O'Brien S ，Tam C ，Koller C ，Burger JA ，Borthakur G ，Wierda WG ，Cortes J ... -  《-》