Leukemia: Preventing Chemotherapy-Induced Vascular Toxicity

Vincent Richeux

February 21, 2023

PARIS — Two tyrosine kinase inhibitors (TKI) used in the treatment of chronic myeloid leukemia (CML) — nilotinib (Tasigna) and ponatinib (Iclusig) — may cause atherosclerotic arterial diseases. This common side effect, which has even been seen in patients without cardiovascular risk factors, has gone unnoticed in clinical trials. So, what can be done to prevent it?

Cardiologist Gabrielle Sarlon, MD, PhD, a professor at Marseille University Hospital, Marseille, France, offered her recommendations at the European Days of the French Society of Cardiology Conference (JESFC 2023).

In the literature, we find many hypotheses that seek to explain why these drugs bring about the formation of atheromatous plaque. The findings of one French study led Sarlon to state, "I firmly believe that, in some patients, these treatments make LDL cholesterol go up." This would be the main cause of the coronary and peripheral arterial diseases that are being seen.

Therefore, "LDL-C should start being monitored when the therapy starts, and a statin may have to be prescribed," she said.

Arterial Diseases

By bringing about a marked improvement in patients' chances of survival, TKIs "have revolutionized the management of chronic myeloid leukemia," Sarlon added. But these treatments have side effects. The most common is high blood pressure, "an effect that attests to the efficacy of targeted therapies and that must be quickly treated" with antihypertensives.

It is well known that the targeted therapies cause the rise in blood pressure. What was unexpected, though, was the vascular toxicity seen with the latest generation of TKIs. "This is a real toxicity that we need to know about, detect, and manage," said Sarlon.

The prevalence of arterial diseases induced by nilotinib, a second-generation TKI, can be as high as 10%. Single-center studies have indicated much higher numbers. In a small study that Sarlon and her team conducted at Marseille University Hospital, atherosclerotic-type arterial injuries were observed in more than 30% of patients treated with nilotinib.

Sarlon noted that the signs of arterial toxicity occurring with this treatment have not appeared in clinical trials. Observations of the real-life use of nilotinib led French and German teams to sound the alarm: they noticed that some patients treated for CML had developed claudication and progression to critical limb ischemia of the lower extremities.

Risk Factors Uncovered

The first retrospective analysis to explore this risk was carried out by a German team. They included 179 patients who received nilotinib and found that 11 (6.2%) developed severe and previously unrecognized lower extremity peripheral arterial disease (PAD) that required invasive therapy. The mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16-212 weeks).

The following have emerged as major risk factors for nilotinib-induced PAD: the presence of cardiovascular risk factors, age older than 60 years, and long duration of exposure to nilotinib. Some of these factors were confirmed in the more recent study conducted at Marseille University Hospital involving patients treated with nilotinib. According to other research, there seems to be a correlation between this risk and the dose administered.

In the case of ponatinib, the side effects are even more common — so much so that, a few months after this third-generation TKI was authorized, a warning was issued about its use. A long-term follow-up study reported a 28% prevalence of cardiovascular events, while arterial diseases were observed in 20% of cases after 1-2 years on the treatment.

In terms of pathophysiology, the Marseille University Hospital study found that arterial injuries were associated with stenosis greater than 50% in almost half of cases. "The atheromatous plaques were found where they typically are," with the carotid bulb being the most involved territory, according to the researchers. But they're also found in other arteries — femoral, vertebral, even renal — "sometimes in patients without cardiovascular risk factors."

One distinctive characteristic to keep in mind is that "lipid-rich atheromatous plaques appear very dark on imaging" and thus can go unnoticed during a Doppler ultrasound. And, Sarlon added, "surprisingly, the thickening can extend to the external carotid artery."

Ankle-Brachial Index

Published last year, the first European Society of Cardiology (ESC) Guidelines on Cardio-Oncology present specific baseline risk assessment and monitoring recommendations regarding patients treated with nilotinib and ponatinib. One suggests that a cardiovascular risk assessment be done every 3 months during the first year and every 6-12 months thereafter. This assessment would include such items as ECGs, blood pressure measurements, and lipid profile tests.

In addition, it is advised that, every 6 months, an ankle-brachial index test be performed to check for PAD. At Marseille University Hospital, a Doppler ultrasound is also done at each follow-up appointment to look for arterial plaques, "even for patients at low risk for cardiovascular disease," said Sarlon. "It seems, above all, absolutely necessary that hematologists order an LDL-C test and, if needed, consider statin therapy," all the while keeping in mind that "the target LDL-C level is 1 gram per liter."

This article was translated from the Medscape French edition.

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