Vol 1, No 3 (2010)
Case report
Published online: 2010-07-27

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Clinical significance of ABL1 kinase mutation sensitivity to tyrosine kinase inhibitors by in vitro assessment - case report

Tomasz Sacha, Kajetana Foryciarz
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

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Hematology in Clinical Practice