ABCB1 mRNA overexpression may predict CML TKI outcomes

Leukemia 2016;advance online publication

medwireNews: Monitoring early changes in ABCB1 messenger (m)RNA expression could identify chronic phase chronic myeloid leukaemia (CML) patients likely to respond poorly to tyrosine kinase inhibitor (TKI) treatment, shows a post hoc analysis of a phase II trial.

The Australian investigators explain that “[t]he amount of TKI that enters and is retained in the target leukaemic cells influences the degree of [BCR–ABL] kinase inhibition.” Thus, higher levels of the ABCB1 drug efflux transporter could lead to lower intracellular TKI levels and a suboptimal response to therapy, they hypothesise in Leukemia.

And indeed, among 155 newly diagnosed patients enrolled in the TIDEL II trial, increases in ABCB1 mRNA levels from baseline to completion of 3 weeks of imatinib therapy were associated with worse molecular outcomes.

For instance, early molecular response (BCR–ABL1 <10% at 3 months) was achieved by 80% of the 79 patients with a high fold rise in ABCB1 mRNA levels, defined as a minimum 2.2-fold increase. This was significantly lower than the 91% rate for the 76 participants with a low fold change, that is, below the 2.2 cutoff.

Similarly, participants with a high versus low fold rise in ABCB1 levels were less likely to achieve major molecular response (MMR; BCR–ABL1 <0.1%) at 12 and 24 months, with rates of 48% versus 78% and 62% versus 89%, respectively. This was also the case for MR4.5 (4.5-log reduction in BCR–ABL1 from baseline) at both timepoints, with corresponding rates of 11% versus 25% and 19% versus 53%.

Furthermore, the fold change in ABCB1 expression at day 22 relative to baseline was high for the 19 patients who subsequently discontinued imatinib – 17 as a result of emergent mutations, progression to blast phase or suboptimal response, and two due to intolerance. Of note, ABCB1 mRNA expression was high prior to progression for all three patients who developed blast crisis.

According to the protocol of the TIDEL II study, suboptimal imatinib responders could switch to the second-generation TKI nilotinib. And the researchers found that participants with a high fold rise in ABCB1 expression also had a lower likelihood of attaining MMR with nilotinib, at a rate of 49% of 35 compared with 82% of 17 who had a low fold rise.

Deborah White (South Australian Health and Medical Research Institute, Adelaide) and co-workers say this “intriguing” finding makes sense as ABCB1 mediates the export of both imatinib and nilotinib, but urge caution as a result of the smaller sample size.

Nonetheless, they conclude: “An increase in levels of ABCB1 mRNA may serve as an easily translatable early warning assay for loss of response/development of resistance to imatinib and, following validation in further studies, could serve to identify poor responders who may benefit from the addition of an ABCB1 inhibitor (for example, pantoprazole) to their treatment regimen or from switching to alternate therapies.”

By Shreeya Nanda, Senior medwireNews Reporter

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