Over-expression of the ABCB1 drug transporter and loss of active drug from target cells explains at least some cases of imatinib resistance in chronic myeloid leukaemia, new research from Adelaide suggests.
Dr Laura Eadie, from the South Australian Health and Medical Research Institute, and colleagues found that patients who had ABCB1 mRNA expression above the median level after 3 weeks of imatinib treatment were significantly less likely to achieve an early molecular response.
They were also less likely to have a major molecular response, to achieve MR4.5 (4.5-log reduction in BCR-ABL1IS from baseline) by 12 months, or achieve a major molecular response when switched to nilotinib.
The median change in ABCB1 mRNA was a 2.2-fold rise from baseline.
“Once patients were grouped about the median into low and high fold rise [in ABCB1 expression], compelling differences in response were apparent,” the research team wrote in Leukaemia.
“Early evaluation of the fold change in ABCB1 mRNA expression may identify patients likely to be resistant to first- and second-generation TKIs and who may be candidates for alternative therapy.”
They noted that up to 35% of CML patients treated with imatinib exhibited primary or secondary resistance, and resistance to the second-line agents nilotinib and dasatinib had also been reported.
The ABCB1 mechanism is one of several possible reasons for resistance, which more commonly involves changes in the Bcr-Abl kinase domain.
ABCB1 is an efflux transporter which removes all three TKIs from leukaemic cells, so over-expression is a plausible explanation for reduced efficacy.
“Potential explanations for the observed increase in ABCB1 mRNA include imatinib exposure selecting a small population of cells with intrinsically high ABCB1 mRNA expression,” they said.
The results suggest that switching to nilotinib in this group would not be effective. A potential strategy would to use an ABCB1 inhibitor such as pantoprazole, or to switch to alternative therapies.
“Importantly, these data support the concept that better understanding of the effects of TKIs on factors with the potential to influence treatment outcome (such as drug transporters) can be used to personalise therapy,” they concluded.
The results of this study were obtained from patients enrolled in the TIDEL II trial of imatinib dose intensification followed by a switch to nilotinib if needed.