“An important question is, why does the optimal schedule take that specific form? In our parameter estimates, we see that dasatinib is better at killing progenitors than nilotinib, while nilotinib is better at killing differentiated cells,” the authors state. The sequential combination therefore reduces the progenitor cell population at the beginning of treatment with dasatinib, and then targets the population of differentiated cells toward the end of treatment with nilotinib.

The difference in efficacy of the sequential combination is much more modest if the patient harbors a pre-existing F317L mutation, and is diminished if the patient harbors multiple BCR-ABL mutations particularly due to E255K, which is resistant to all 3 agents.

Toxicity modeling demonstrates that ANC decreases at a constant rate each month for each regimen, and increases at a constant rate to near the level at the start of treatment after a month-long drug holiday. “This indicates that a 1-month drug holiday may be too long for the patient,” write the authors.

“An exciting application of this work would be the development of personalized optimal therapeutic schedules. We believe that the testing procedure needs to be standardized before it becomes helpful for the treatment of CML,” indicate the authors. Once standardized, this approach may help clinicians monitor response and impact on leukemic growth kinetics, enabling a dynamic feedback of response to therapy and suggestions for an optimized treatment regimen.

Disclosures: The author has no relevant relationships to report.

Reference

  1. He Q, Zhu J, Dingli D, Foo J, Leder KZ. Optimized treatment schedules for chronic myeloid leukemia. PLoS Comput Biol. 2016 Oct 20. doi: 10.1371/journal.pcbi.1005129 [Epub ahead of print]