CV risk assessment essential for CML TKI trial design

Oct 22 2015

By Lynda Williams, Senior medwireNews Reporter

The risk and impact of cardiovascular (CV) adverse events (AEs) in long-term users of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukaemia (CML) is highlighted in a review published in the Journal of Clinical Oncology.

While TKI therapy for CML targets BCR–ABL1, the drugs are known to also affect other kinases including vascular endothelial growth factor receptors (VEGFRs), and platelet-derived and fibroblast growth factor receptors, as well as non-kinase processes.

These unintended actions are associated with nonhaematological AEs that were considered “acceptable” when reversible and occurring in trial patients under close surveillance, whereas CV side effects reported in real-world populations require “reassessment”, write Javid Moslehi, from Vanderbilt University in Nashville, Tennessee, USA, and Michael Deininger, from Huntsman Cancer Institute in Salt Lake City, Utah, USA.

However, they emphasise that “given the excellent prognosis of CML and the high incidence of cardiovascular disease in the general population, it is important to dissect drug-dependent from drug-independent cardiovascular events.”

The reviewers therefore highlight the need for oncologists and cardiologists to collaborate so that future TKI clinical trials can define baseline CV disease and include CV and cardiometabolic endpoints and risk factors in their design, allowing accurate assessment of AEs in CML patients using TKIs.

They note that “[t]he fact that many of these issues were insufficiently considered when 2G and 3G TKIs were developed has hampered the development of rational strategies to prevent and treat [CV] AEs”.

Moslehi and Deininger observe that imatinib is associated with a low incidence of cardiomyopathy and a lower rate of CV events than the second-generation TKI nilotinib, and note that imatinib may have “favorable metabolic and vascular effects.”

The second-generation TKI dasatinib has been associated with a possible increased risk of arterial ischaemia and the US Food and Drug Administration recommends that patients should be assessed for cardiopulmonary disease before treatment following reports of pleural effusion and pulmonary arterial hypertension.

While a risk of ventricular arrhythmia associated with QT prolongation has not been confirmed in patients given the second-generation TKI nilotinib, reports have suggested an increased risk of hyperglycaemia and peripheral arterial disease, including severe events requiring invasive therapy or amputation.

“The finding that [CV] 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 researchers say, noting that an increased risk of cerebrovascular and CV events too suggests that any toxicity may affect “all arterial beds”.

While longer follow-up is required, the results for the second-generation TKI bosutinib – approved as a salvage therapy – are so far “reassuring”, the team writes, noting that the 2-year risk of CV events appears to be “relatively low” compared with imatinib.

The third-generation TKI ponatinib has “potent inhibition” of a raft of TKs, including the VEGFR pathway and has been shown to have increasing rates of cumulative CV, cerebrovascular and peripheral arterial AEs over time, and the “most significant [CV] risk” so far, the authors note. And AE rates are particularly elevated in patients with several of the traditional atherosclerosis risk factors, such as hypertension and diabetes.

“Dose optimization studies are planned to identify the optimal ponatinib dose that minimizes toxicity while maintaining efficacy”, the reviewers say, questioning whether a “truly safe drug dose” is possible for ponatinib.

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