CML arterial adverse events rate dependent on TKI choice

By Lynda Williams, Senior medwireNews Reporter

The risk of major arterial adverse events (AEs) in chronic myeloid leukaemia (CML) patients may significantly differ between tyrosine kinase inhibitors (TKIs), suggests a meta-analysis published in Leukemia & Lymphoma.

The pooled composite rate of major arterial AEs – defined as peripheral arterial occlusive disease (PAOD), ischaemic heart disease and stroke or transient ischaemic attack – was 1.0 events per 100 patient–years in CML patients who received any treatment, prompting the authors to describe these outcomes as “not uncommon” with TKI therapy.

This per 100 patient–years rate ranged from 0.1 and 0.4 events for patients given imatinib or bosutinib, respectively, to 1.1 events for dasatinib-treated patients, 2.8 events for nilotinib-treated patients and 10.6 events for patients treated with ponatinib. The rate for patients given treatment other than TKIs was 0.8 events per 100 patient–years.

“In the front-line setting, patients who are at a high risk of cardiovascular disease or have had a previous episode of stroke or myocardial infarction should avoid TKIs that may increase their risk of arterial events”, recommend Christopher Hillis, from Juravinski Cancer Centre in Hamilton, Ontario, Canada, and co-authors.

“Moreover, during TKI treatment, patients should have ongoing cardiovascular risk assessments.”

The systematic review and meta-analysis included data for 15,706 patients with chronic phase or accelerated phase CML who participated in four randomised trials and 25 observational studies testing TKI efficacy, including 20 reports of nilotinib, 12 of imatinib, four ponatinib, and one trial each of dasatinib and bosutinib.

Analysis of the individual adverse outcomes gave a pooled rate for PAOD of 0.3 events per 100 person–years, ranging from 0.1 events for patients treated with imatinib or bosutinib to 3.9 events for ponatinib-treated patients.

The pooled rate for ischaemic heart disease was 0.8 events per 100 patient–years, with the lowest rates reported for imatinib and the highest for ponatinib (0.1 vs 6.0 events per 100 patient–years). And the pooled rate for cerebrovascular disease was 0.3 events per 100 patient–years, ranging from less than 0.1 events for imatinib and 0.1 events for bosutinib to 2.9 events for ponatinib.

Nilotinib and imatinib were directly compared in eight studies and the relative risk of arterial thrombotic disease was a significant 5.3 for patients given nilotinib, with a 5.5 fold increased risk of PAOD.

Nevertheless, Hillis et al caution that there were “discrepancies” in trial design and the incidence of arterial events was higher in the observational studies than the trials, suggesting that there may have been underreporting in the years before TKI treatment was linked to arterial events.

But observational study participants had different demographical and clinical profiles to those of trial patients and underwent more rigorous investigation for cardiovascular disease, the reviewers note.

In addition, sensitivity analysis showed a lower pooled rate for major arterial events in patients enrolled in studies of first-line therapy than in participants of studies that included first-, second- and third-line therapies (2 vs 5%).

“In the present analysis we cannot consider that major arterial events are a class-effect for TKIs, as arterial events appeared to occur at higher rates with some TKIs but not all TKIs”, the analysts therefore conclude.

However, they caution: “It is impossible to truly define which TKI has the highest risk of arterial events owing to limitations in the present analysis, significant heterogeneity across studies, lack of direct comparisons with each TKI and that patients with arterial events potentially had received multiple lines of previous TKI therapy.”

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