clinical topic updates
Cardiovascular Side Effects of Available Tyrosine Kinase Inhibitors
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) to such an extent that this once-lethal disease has become a manageable chronic condition for most patients. Cardiovascular comorbidity is one of several patient-level factors that are considered, along with TKI toxicity profiles, when selecting and adjusting therapy.
Director, Adult Leukemia Service
“We give quite a bit of consideration to cardiovascular side effects, particularly as we change medications and try to balance the impacts of TKIs on the CML and on comorbid cardiovascular disease.”
We have decades of data suggesting that imatinib is a reasonably safe option. In a younger patient (eg, aged 30 years) with low-risk CML, one would generally begin with imatinib. If imatinib is poorly tolerated, there are a number of options for your next choice of TKI. In contrast, some older patients who have significant cardiovascular comorbidity (eg, congestive heart failure and atrial fibrillation) may present with high-risk CML, and decisions may be more complicated in these cases. As such, we give quite a bit of consideration to cardiovascular side effects, particularly as we change medications and try to balance the impacts of TKIs on the CML and on comorbid cardiovascular disease. This includes the consideration of potential interactions with cardiovascular medications that the patients may already be taking. TKIs are extensively metabolized by cytochrome P450 enzymes, which can show substantial interindividual variability. Beta blockers can have drug interactions with TKIs that may increase the exposure to the TKI, the beta blocker, or both. Interactions have also been reported with calcium channel blockers and statins.
The mechanisms behind cardiovascular adverse events associated with specific TKIs are not completely understood. TKIs for CML are designed to have activity against BCR-ABL1, but there may be off-target toxicities, and the extent to which they have activity against other relevant kinases, such as VEGFR, for instance, could be important. VEGFR inhibition and resulting hypertension might be implicated in some of these toxicity profiles. However, when these events have occurred, it has often been challenging to understand the independent contribution of the TKI, in part because of uncertainty about the baseline cardiovascular risk profile of patients with CML (ie, irrespective of therapy or as they commence therapy). A current ongoing prospective study (NCT03045120) is assessing the baseline cardiovascular risk factors and the follow-up cardiovascular risks of a real-world population of patients with CML on chronic TKI therapy.
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