RESUMO
e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript.
RESUMO
Background and objectives: 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. Patients and methods: 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. Results: 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). Conclusion: 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 (AU)
Fundamento y objetivos: La mayoría de los pacientes con leucemia mieloide crónica (LMC) obtienen respuesta clínica bajo tratamiento con imatinib. Sin embargo, una proporción significativa de ellos no alcanza dicha respuesta o son resistentes al tratamiento, implicándose en ello mutaciones del gen ABL. El desarrollo de inhibidores de tirosín-cinasa (ITK) de segunda generación ha permitido superar la resistencia al tratamiento con imatinib en muchos casos. El objetivo de este estudio fue analizar el tipo y frecuencia de mutaciones del gen ABL en pacientes resistentes a imatinib o que han perdido la respuesta y determinar el efecto de los ITK de segunda generación, nilotinib y dasatinib. Sujetos y métodos: Se analizó la presencia de mutaciones en el gen ABL en 45 pacientes con LMC resistentes a imatinib y se correlacionó con el estudio citogenético (realizado en 39 pacientes). También se evaluó la respuesta al tratamiento con ITK de segunda generación. Resultados: Se detectó mutación del gen ABL en 14 de los 45 casos analizados, y fue más frecuente en aquellos pacientes con evolución clonal. Nueve de los 15 pacientes portadores de una mutación en el gen ABL respondieron al cambio de tratamiento con nilotinib (n = 3), dasatinib (n = 2), interferón (n = 1) o trasplante de progenitores hematopoyéticos (n = 2) (AU)