Leucemia Mielóide Crônica: causas de falha do tratamento com mesilato de imatinibe

Abstract

O mesilato de imatinibe (MI) é atualmente o tratamento de escolha da Leucemoa Mielóide Crônica (LMC), mas, apesar dos excelentes resultados, não é capaz de erradicar completamente a doença, podendo ocorrer resistência ao tratamento. O mecanismo mais conhecido de resistência é o desenvolvimento de mutações do BCR-ABL, que impedem a ação ligação adequada do imatinibe à quinase, além de amplificação gênica e evolução clonal. No entanto, há uma série de outros mecanismos envolvidos e ainda pouco estudados, como alterações na absorção, efluxo e influxo de droga para o interior das células. Devem-se também considerar outros fatores, como aderência ao tratamento e uso de medicamentos concomitantes que podem interferir com imatinibe, diminuindo sua ação. O entendimento desses mecanismos poderá contribuir no desenvolvimento de novas estratégias para o tratamento dos casos resistentes. Rev.

Monitoring imatinib plasma concentrations in chronic myeloid leukemia

“…(9,15) Sensitive methods to determine imatinib in biological fluids are required to conduct TDM, pharmacokinetics and metabolic studies. (25) …”

“…(9) According to Larson et al (14) patients with lower imatinib plasma levels had higher rates of discontinuation and a higher percentage of patients stopped treatment because of unsatisfactory therapeutic effect. These data suggest that patients are more likely to achieve a satisfactory level of response to therapy or an improvement in response rates if an appropriate concentration of trough imatinib is reached and maintained.…”

“…( 5 , 10 , 12 ) Resistance to imatinib can be multifactorial, presenting problems in the drug pharmacokinetics, mediators of cellular drug uptake, like the human organic cation transporter 1 (hOCT1) protein and mutations. Mutations are more frequent in secondary rather than primary resistance, ( 9 ) with the most common being deletion of BCR-ABL by amplification of this oncogene, mutation of the binding site of BCR-ABL by altered metabolism of imatinib, and by a transport mechanism. ( 5 , 10 , 12 ) Since 2001 with the first report of a mutation in resistant patients, more than 70 others have been reported.…”

“…( 7 , 8 ) Allogeneic BMT is considered the only curative treatment for CML, with a 65% chance of cure. ( 9 , 10 ) However, only 15% to 30% of the patients can be submitted to transplantation due to the lack of histocompatible donors and the advanced age of the patients who are usually affected by the disease.…”

“…Imatinib plasma concentrations outside the recommended therapeutic levels may be related to absorption variations, biotransformation or elimination due to genetic and environmental factors, interactions with other drugs or associated to lack of patient adherence. ( 9 , 14 , 15 ) Considering the positive impact of the therapeutic monitoring of imatinib in the treatment of CML, it is necessary to know the clinical aspects of imatinib pharmacokinetics as well as to establish monitoring of plasma levels in patients with CML. This study aims to review the clinical and laboratory aspects of therapeutic monitoring of imatinib in Ph + CML patients.…”