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Can Drug Rotation Therapy Delay Resistance to Treatment in CML?

By: Joseph Fanelli
Posted: Monday, August 12, 2019

For patients diagnosed with chronic myeloid leukemia (CML) who have shown resistance to targeted treatments, drug rotation therapy with available BCR-ABL1 tyrosine kinase inhibitors (TKIs) may lower the chance of treatment resistance, according to research findings presented in BMC Cancer. Ran Friedman, PhD, of Linnæus University, Kalmar, Sweden, and colleagues used a computer simulation that modeled a stochastic process. They also determined that using lower drug concentrations after a major molecular response may achieve better results.

“The greatest gains predicted by our model occur with rotations involving ponatinib,” the authors concluded. “Whereas a drug applied intermittently in a drug rotation is likely more well tolerated than if taken continuously, it seems unlikely that benefits would outweigh the risk for rotations involving ponatinib.”

To test the various drug rotation therapies, the investigators developed a computer program to simulate the growth of CML cells similar to the standard branching process. In the model, the growth of cells was expressed as a tumorigenic protein—ABL1—with any emerging mutations determined by the drugs used in therapy.

The model found that the use of bosutinib/ponatinib rotation may provide some benefits, even in situations where the mutation status is unknown. Imatinib/nilotinib rotation, alternatively, seemed unlikely to improve patient outcomes. Additionally, the authors observed that an interplay between growth inhibition and selection effects produced a nonlinear relationship in drug doses and the patient’s risk of developing resistance.

The investigators offered two potential guidelines for physicians when selecting drug rotation therapy over standard therapy. First, it may be useful in cases when the drugs have different resistance profiles, and, second, in cases when there is a suboptimal drug response from a molecular standpoint, as when the amount of inhibition achieved positions the patient in a zone where resistance occurs quicker. “For the second condition, it is clear that all drugs reduce the number of tumor cells efficiently, but some persistent cells seem to survive,” the authors observed.

Disclosure: The study authors reported no conflicts of interest.

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