Vol 1, No 3 (2010)
Case report
Published online: 2010-07-27
Clinical significance of ABL1 kinase mutation sensitivity to tyrosine kinase inhibitors by in vitro assessment - case report
Hematologia 2010;1(3):267-270.
Abstract
The presence of ABL1 kinase mutations has been identified as one of the major mechanisms of
acquired resistance to tyrosine kinase inhibitors (TKI). In patient with chronic myeloid
leukemia (CML) resistant to imatinib (IM) at dose of 400 and 600 mg/d. subsequently treated
with dasatinib, and who did not achieve major molecular response (MMolR), L348M mutation was detected. After the sensitivity analysis, based on IC50, treatment with nilotinib was
introduced. However, the level of BCR-ABL1 transcript rose to 2%. The next analysis of
mutation sensitivity consisting with IC50 and plasma maximum TKI concentration pointed to
dasatinib as a potent drug to overcome the resistance. The level of BCR-ABL1 dropped down to
0,32% upon this treatment. The clinical usefulness of ABL1 kinase mutation sensitivity
assessment, based on in vitro studies and IC50 value, is still a matter of controversies. The
method incorporating the evaluation of plasma TKI concentration and correction of TKI
activity normalized to activity of IM against wild type BCR-ABL1, as proposed recently, does
not improve the interpretation of IC50 values for clinical usage. Plasma concentrations of TKI
could have however a negative predictive value by excluding the less potent drug. Tables
presenting in vitro sensitivity of ABL1 mutants to TKI are providing only the information of
how much less efficacious the drug will be against a certain ABL1 mutant as compared to
unmutated BCR-ABL1. Beyond its limitations, the mutations sensitivity index could provide
data and help to choose potentially most effective drug.
Hematologia 2010; 1, 3: 267-270
Hematologia 2010; 1, 3: 267-270
Keywords: chronic myeloid leukemiaABL1 mutationssensitivity to TKI