How to find the optimal dose with mathematical modelling

Specific targeted therapies are commonly used for blood cancer patients suffering from chronic myeloid leukemia (CML). Although these medications are very effective, most patients need to take these drugs their whole life. Reducing the dosage and adapting it to each patient individually is the goal of a mathematical model developed by systems medicine scientists from Dresden.

Tyrosine kinase inhibitors (TKIs) are state-of-the-art therapies for patients with chronic myeloid leukemia, a malignant bone marrow disease. The drugs show very high response rates and usually a strong reduction of tumor cells can be achieved within short time. However, in order to prevent a return of the disease, the TKIs are administered permanently.
If the patient responds well to the initial treatment, the therapy may be completely stopped after a few years. Clinical trials are currently underway, however, with approximately 50% of patients experiencing a recurrence of the tumor, in which case the therapy is being restarted. Instead of a complete therapy stop, dose reduction could be an alternative. Advantages would be lower side effects, such as cardiovascular complications or pleural effusions and a reduction in therapy costs.

A safe dose reduction without lowering the effect, however, has hardly been studied so far. The e:Med scientist Professor Dr. Ingo Röder and Dr. Ingmar Glauche from the TU Dresden and their team developed a mathematical model based on data from patients undergoing TKI treatment from two Phase 3 trials. This model simulates the behavior of blood cells at different drug concentrations and can predict the tumor burden and the individually required dose.

The researchers found that in most of these patients, a 50% reduction in the TKI dose also leads to remission maintenance. To calculate a patient-specific, optimal dose, first the amount of medication is reduced by 50%. After adjusting the resulting parameters, the individual dose is then determined, which can be up to 2/3 lower than the standard dose. The results of this simulation are comparable to the preliminary results of an ongoing study in which patients received the halved TKI dose after receiving a good response. The model developed here, however, goes beyond this and additionally allows patient-specific dose optimization.

Further clinical studies are needed to confirm the model predictions. If the model results are confirmed, side effects and overtreatment could be significantly reduced for the benefit of the patients. The model illustrates the potential of systemic medicine, which aims to use analytical or computerized methods to understand complex biological systems, thus enabling personalized medicine.

Original article:

Fassoni, A.C., Baldow, C., Roeder, I., Glauche, I., 2018. Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: A simulation study based on phase 3 trial data. Haematologica. doi.org/10.3324/haematol.2018.194522

Editorial: www.haematologica.org/content/103/11/1756

Press release NCT Dresden (German)

ContaCt:

Prof. Dr. Ingo Röder, Technische University Dresden, Project leader HaematoOPT