Personalized Medicine Support System for Chronic Myeloid Leukemia Patients

Personalized medicine offers the most effective treatment protocols to the individual Chronic Myeloid Leukemia (CML) patients. Understanding the molecular biology that causes CML assists in providing efficient treatment. After the identification of an activated tyrosine kinase BCR-ABL1 as the causative lesion in CML, the first-generation Tyrosine Kinase inhibitors (TKI) imatinib (Glivec®), were developed to inhibit BCR-ABL1 activity and approved as a treatment for CML. Despite the remarkable increase in the survival rate of CML patients treated with imatinib, some patients discontinued imatinib therapy due to intolerance, resistance or progression. These patients may benefit from the use of secondgeneration TKIs, such as nilotinib (Tasigna®) and dasatinib (Sprycel®). All three of these TKIs are currently approved for use as frontline treatments. Prognostic scores and molecularbased predictive assays are used to personalize the care of CML patients by allocating risk groups and predicting responses to therapy. Although prognostic scores remain in use today, they are often inadequate for three main reasons. Firstly, since each prognostic score may generate conflicting prognoses for the risk index and it can be difficult to know how to treat patients with conflicting prognoses. Secondly, since prognostic score systems are developed over time, patients can benefit from newly developed systems and information. Finally, the earlier scores use mostly clinically oriented factors instead of those directly related to genetic or molecular indicators. As the current CML treatment guidelines recommend the use of TKI therapy, a new tool that combines the well-known, molecular-based predictive assays to predict molecular response to TKI has not been considered in previous research. Therefore, the main goal of this research is to improve the ability to manage CML disease in individual CML patients and support CML physicians in TKI therapy treatment selection by correctly allocating patients to risk groups and predicting their molecular response to the selected treatment. To achieve this objective, the research detailed here focuses on developing a prognostic model and a predictive model for use as a personalized medicine support system. The system will be considered a knowledge-based clinical decision support system that includes two models embedded in a decision tree. The main idea is to classify patients into risk groups using the prognostic model, while the patients identified as part of the high-risk group should be considered for more aggressive imatinib therapy or switched to secondgeneration TKI with close monitoring. For patients assigned to the low-risk group to imatinib should be predicted using the predictive model. The outcomes should be evaluated by comparing the results of these models with the actual responses to imatinib in patients from a previous medical trial and from patients admitted to hospitals. Validating such a predictive system could greatly assist clinicians in clinical decision-making geared toward individualized medicine. Our findings suggest that the system provides treatment recommendations that could help improve overall healthcare for CML patients. Study limitations included the impact of diversity on human expertise, changing predictive factors, population and prediction endpoints, the impact of time and patient personal issues. Further intensive research activities based on the development of a new predictive model and the method for selecting predictive factors and validation can be expanded to other health organizations and the development of models to predict responses to other TKIs.Thesis (Ph.D.) -- University of Adelaide, School of Computer Science, 201