Tyrosine Kinase Inhibitor Rotation Therapy in CML
Posted: Tuesday, July 16, 2019
Stochastic modeling of tyrosine kinase inhibitor (TKI) rotation therapy in chronic myeloid leukemia (CML) showed that certain treatment combinations may be able to delay fixation of drug resistance mutations. Ran Friedman, PhD, and colleagues, of Linnaeus University, Sweden, sought to explore whether reduced evolutionary adaptation experienced by cell populations undergoing high rates of mutation could potentially be exploited in CML treatment paradigms. Their study results were published in BMC Cancer.
In this study, computer simulations were used to model the rate of evolution—defined as “the rate at which mutants become dominant in the population”—in the context of different CML treatment protocols. Drugs with different resistance profiles (bosutinib/ponatinib vs. imatinib/nilotinib) were paired, and a suboptimal molecular drug response was modeled.
The bosutinib/ponatinib combination seemed to confer more potential benefits, compared with imatinib/nilotinib therapy, which had treatment effects similar to those of either monotherapy protocol. A low dose (29%) of bosutinib reduced the likelihood of resistance, compared with ponatinib alone; a medium-high dose (75%) of bosutinib also seemed beneficial, albeit with increased side effects. With nearly 50% inhibition, coinciding with the highest evolution rates, the bosutinib/ponatinib rotation therapy may slow the emergence of resistance by 7.5% or 36%, over bosutinib or ponatinib alone, extending the rotation protocol’s effectiveness by about 4 months.
“The simulations give credence to the suggestion that lower drug concentrations may achieve better results following major molecular response in CML,” concluded the authors. Lastly, the distribution of observed mutations seemed to be affected by rotation therapy, which the authors proposed could be a means to “steer evolution toward more easily treatable mutations.”
Disclosure: The study authors reported no conflicts of interest.