By Lynda Williams, Senior medwireNews Reporter
A review of BCR–ABL1 tyrosine kinase inhibitors (TKIs) highlights the need to consider cardiovascular adverse event (CV AE) risk profiles when prescribing for patients with chronic myeloid leukaemia (CML).
Authors Javid Moslehi (Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, USA) and Michael Deininger (University of Utah, Salt Lake City, USA) emphasise that the CV AEs are “critical factors” in decision-making as CML patients may have an “excellent prognosis” but their median age of over 60 years at diagnosis indicates that CV disease is common.
Long-term follow-up of patients given the first-generation TKI imatinib indicates the drug is associated with a low incidence of cardiomyopathy and may even have a protective effect against metabolic and cardiovascular events, they report in the Journal of Clinical Oncology.
The researchers note that the experience with imatinib has enlightened clinicians on the importance of differentiating between drug-dependent and drug-independent CV events in CML patients, and determining individual patients’ baseline and short-term CV risk profiles.
“[S]ystematic prospective assessment of cardiovascular risk factors is needed as newer TKIs are compared with imatinib as the benchmark for efficacy and cardiovascular risk”, they write, adding that oncology trials may offer a platform to determine potential metabolic and CV benefits associated with TKI therapy.
Indeed, inadequate consideration of these issues has “hampered” assessment of CV issues during second- and third-generation TKI development, the researchers believe.
They note that it is unclear whether the second-generation agent dasatinib is associated with an increased risk of CV events, although the US Food and Drug Administration (FDA) has issued a warning that patients should be examined for cardiopulmonary disease before and during treatment.
“Although the FDA did not specify modes of screening, we believe that an echocardiogram with Doppler flow studies would provide adequate noninvasive assessment for high-risk patients before starting dasatinib and for patients with cardiopulmonary symptoms on treatment”, say Moslehi and Deininger.
The second-generation TKI nilotinib has been linked to hyperlipidaemia, hyperglycaemia and elevated body mass index, as well as an unsubstantiated risk of ventricular arrhythmia caused by QT prolongation.
In addition, there is suggestion of an increased rate of CV and peripheral ischaemic events, with 6-year follow-up of nilotinib-treated patients showing a CV event rate of 10.0–15.9% depending on dose, compared with 2.5% in imatinib-treated counterparts.
The European Medicines Agency therefore recommends “close” CV monitoring during nilotinib treatment including blood lipid and glucose measurements and referral of high-risk patients to a cardiologist where deemed necessary.
“The finding that cardiovascular risk factors were common in patients with vascular AEs, combined with the elevations in glucose and cholesterol, suggested that nilotinib may aggravate a pre-existing arteriosclerotic condition”, the authors write, noting that the toxicity appears to affect all arterial beds.
After a median of 28 months, a study of the third-generation TKI ponatinib gave a cumulative rate of CV events of 10%, with a 7% rate of cerebrovascular and peripheral events each, 14% arterial events and 3% serious venous AEs. In particular, the presence of two or more traditional atherosclerosis risk factors predisposed patients to serious vascular AEs.
Despite ponatinib’s dose-dependent CV toxicity profile, “a subset of patients will undoubtedly benefit from the drug, particularly those with [the] BCR–ABL1 T315I” mutation, the reviewers acknowledge, although they admit modifying risk factors is “warranted” and dose reduction “seems good practice”.
By contrast, the third-generation TKI bosutinib, approved as salvage CML treatment, has a “reassuring” CV safety profile so far, the reviewers write, with 2-year results showing a comparable risk to imatinib.
Moslehi and Deininger explain that there is limited understanding of vascular AEs associated with TKIs, especially nilotinib and ponatinib, and further knowledge is required to allow screening and other strategies to prevent or treat side effects.
While statins and aspirin could be considered a low-risk intervention for patients at high risk of CV disease, the authors do not recommend prophylactic anticoagulant treatment in this population or the blanket use of antiplatelet agents in patients with a low risk of CV events.
Instead, they recommend the application of a simple algorithm currently used for prevention of CV disease in the general public and breast cancer survivors to CML patients beginning TKI therapy, considering factors such as CV disease awareness, blood pressure control, tobacco use, and cholesterol and diabetes monitoring.
The reviewers conclude: “These patient populations will require careful monitoring for late AEs over time spans that exceed the planned duration of most current clinical trials.
“A much deeper understanding of the causes of adverse effects will be needed to inform inhibitor design in a rational way, so that long-term toxicity can be minimized, while on-target activity is maintained or even improved.”
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