Some Tyrosine Kinase Inhibitors Risk Greater Cardiovascular Events

MedicalResearch.com Interview with:

Jonathan Douxfils Pharm.D. - Ph.D. Research assistant Faculty of Medicine - Department of Pharmacy NAmur Research Institute for LIfe Sciences (NARILIS) Namur Thrombosis and Hemostasis Center (NTHC)

Dr. Jonathan Douxfils

Jonathan Douxfils Pharm.D. – Ph.D.
Research assistant
Faculty of Medicine – Department of Pharmacy
NAmur Research Institute for LIfe Sciences (NARILIS)
Namur Thrombosis and Hemostasis Center (NTHC)

Medical Research: What is the background for this study? What are the main findings?

Dr. Douxfils: We decided to perform this study based on the release of the FDA regarding the risk of arterial occlusive events associated with ponatinib. We then hypothesize that the risk was not only restricted to ponatinib but also to other TKIs. This study shows that dasatinib, nilotinib and ponatinib increase the risk of vascular occlusive events compared to imatinib.

Medical Research: What should clinicians and patients take away from your report?

Dr. Douxfils: We suggest that patients treated with these molecules should be more frequently monitored, i.e. by an intensive support of associated comorbidities. In addition, even if they appear to have a better efficacy in terms of molecular response, new generation TKIs does not improve the overall survival at one year.

As we have not access to individual data, it was impossible to clearly identify categories of patients for whom the risk of cardiovascular occlusive events is predominant. Therefore, the intensive monitoring proposed should be applied to all patients treated with these molecules. Regarding the choice of the therapy, the physician should certainly consider the goals of the treatment. For elderly patients, improving survival is the main objective and in this context, imatinib remains an excellent choice. For patients with a life expectancy greater than 10 years in whom we aim to achieve a deep molecular response to potentially reach a point of treatment cessation, dasatinib and nilotinib could be preferred. However, the choice of dasatinib or nilotinib as first-line treatments should involve a screening for potential risk factors such as diabetes, prior vascular occlusive events or any risk that could increase these adverse events.

For second- and third-line treatments, the choice of the treatment has to be based on mutational analysis, previous adverse events, and the medical condition of the patient. Thus, in case of intolerance or resistance, the switch to one of the other TKIs approved for first-line therapy is an option. If treatment failure still occurs, a more potent TKI, i.e. bosutinib, is preferred. Importantly, ponatinib is reserved to patients with the T315I mutation and must be avoided in patients with good prognosis.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Douxfils: Importantly, our study does not discriminate between arterial or venous occlusive events and this need to be addressed. The mechanism behind the pro-thrombotic potential of these drugs should also be investigated. For instance, we know that nilotinib-treated patients might develop increased fasting glucose levels as well as an elevation of cholesterol level consistent with this pro-thrombotic potential, this could not be the same mechanism for dasatinib and ponatinib. In addition, as the risk was suggested to be dose related (this has not been assessed in this study), dose-ranging studies are crucial to determine the optimal starting and maintenance doses for these treatments. This will help for the implementation of risk minimization measures to ensure a safe use of these compounds.   

Medical Research: Is there anything else you would like to add?

Dr. Douxfils: The main concern is probably not with ponatinib, which is reserved to patients with serious condition carrying the T315I mutation, but with drugs proposed as first-line treatment such as dasatinib or nilotinib. Therefore, we suggest that regulatory agencies trigger a complete assessment of the risk of vascular occlusive events with these drugs. There is also a need to harmonize the reporting of cardiovascular events in cancer trials and to implement specific registries to prospectively collect these data in a real-life setting.

Citation:

Jonathan Douxfils Pharm.D. – Ph.D. (2016). Some Tyrosine Kinase Inhibitors Risk Greater Cardiovascular Events