Patient characteristics may guide TKI use in CML

By Lynda Williams, Senior medwireNews Reporter

The likelihood of complications associated with tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukaemia (CML) may be reduced by considering patient factors and differences in the toxicity profiles of the different drug options, a review suggests.

Delphine Rea, from Hôpital Saint-Louis in Paris, France, explains in the Annals of Hematology that TKI dose reduction or interruption, or switching TKIs is usually effective at controlling adverse events, the majority of which are mild or moderate and resolve spontaneously.

However, “some worrisome and unanticipated complications of therapy have recently emerged especially with the new-generation TKIs, such as metabolic abnormalities that may predispose to CVD [cardiovascular disease] and cardiovascular and pulmonary toxicities”, she writes.

Pulmonary adverse events are “almost exclusively” associated with dasatinib, most commonly unilateral or bilateral pleural effusions, and these do not reduce over time, Rea notes. Age, history of CVD, autoimmune disease and pulmonary disease are all associated with pleural effusions; dasatinib dosing may be tailored using plasma levels to reduce the risk of this side effect, or switched for an alternative TKI.

Dasatinib has also been linked with the “very rare”, but potentially irreversible complication, pulmonary arterial hypertension, requiring permanent discontinuation of this TKI, Rea adds.

The review also highlights the potential for CV complications, some of which may not be reversible.

Patients should have electrolyte imbalances corrected to reduce the risk of QTc prolongation during TKI therapy, and electrocardiogram monitoring is advisable for those with congenital long QT interval, underlying heart disease or other medications associated with this risk.

Hypertension may arise from or be aggravated by use of ponatinib, thought to be through the inhibition of vascular endothelial growth factor receptor. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be useful in this scenario, the author suggests.

Patients with cardiac disease should also be monitored during new-generation TKI treatment for the risk of congestive heart failure, thought to occur in up to 5% of patients depending on the TKI.

Arterial occlusion has been linked to use of ponatinib and nilotinib, and patients with underlying CVD or risk factors for CVD are thought to be at greatest risk. Patients should be assessed for CVD before beginning ponatinib and an alternative TKI chosen for those with a history of myocardial infarction or stroke, Rea writes, while those using nilotinib should switch to a different TKI if arterial occlusion occurs.

The reviewer observes that nilotinib is also associated with a decrease in fasting glucose, especially in patients with Type 2 diabetes, so that glucose metabolism should be assessed in diabetic patients before and during treatment.

Lipid disorders are also an issue for nilotinib, with the risk of early-onset hypercholesterolemia introducing a potential need for lifestyle intervention or lipid-lowering treatment, Rhea writes.

Finally, imatinib, dasatinib and nilotinib have also been linked to abnormal thyroid function, although a causal association has not been proven. While changes are usually “subclinical and transient”, patients who have undergone thyroid surgery may need levothyroxine dose alternations, the reviewer observes.

Noting that many of the complications reported are thought to be influenced by patient characteristics and dependent on the TKI used, Rea therefore concludes: “[I]ndividualized risk assessment integrating both CML and patient characteristics should strongly influence treatment choices and clinical management.”

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