Choosing the most effective cure for chronic myeloid leukemia

Recent research, published in the journal Cancer Cell, reports that scientists have identified and characterized mutated versions of the genes that encoding BCR-ABL, the unregulated enzyme driving the blood cancer chronic myeloid leukemia (CML).


Tyrosine kinase inhibitors (TKIs), targeted on BCR-ABL, are already in use, and are effective at controlling the disease. They do not cure CML but control it in a way that allows patients to get back to normal life and a normal expected lifespan. Before the arrival of TKIs, the 5-year survival rate for CML was 30% at best; now that figure is above 95%.

As indicated in trials, most cases of CML resistance are derived from a single mutation in BCR-ABL, and drugs to control resistance to TKI treatment caused by various single mutations have already been discovered. But BCR-ABL compound mutants that contain 2 mutations in the same molecule make some or all of the available TKIs ineffective.

The research team focused on BCR-ABL compound mutants observed in patients and tested them against all approved TKIs, creating a dataset that can potentially help clinicians decide which drug will be most effective for each mutation combination. They found that none of the TKIs are effective for some compound mutations, indicating the need for further research to accommodate the increasing population of CML patients.

Scientists sequenced about 100 clinical samples, which rendered a large body of data to shed light on the number of compound mutations and how they develop. One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.


 BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia. Cancer Cell, 2014

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