Peripheral Arterial Disease Seen With Nilotinib

TON - March 2013, Vol 6, No 2 — March 26, 2013

Peripheral artery occlusive disease (PAOD) may be an adverse effect of nilotinib treatment in patients with chronic-phase chronic myeloid leukemia (CML), according to a study presented at the 54th Annual Meeting of the American Society of Hematology.1

A significantly higher frequency of PAOD was observed in patients taking nilotinib than in patients taking imatinib, as measured by prospective, sequential ankle-brachial index (ABI) and duplex ultrasonography monitoring, said Philipp le Coutre, MD, of Charité, Universitätsmedizin Berlin in Germany. The occurrence of PAOD was most notable among patients with ≥2 underlying cardiovascular risk factors, and this patient group “should be treated with caution,” le Coutre advised.

Based on a suggestion of risk from previous studies, le Coutre and colleagues assessed 159 patients with CML who received first-line imatinib (n = 53), first-line nilotinib (n = 31), or second-line nilotinib (n = 32), and those who were previously exposed to nilotinib (n = 23) or never treated with nilotinib and currently not receiving imatinib (n = 7).

Patients received nilotinib 300 mg or 400 mg twice daily for 6 months or longer. Laboratory parameters were measured as early as 4 weeks in some patients. A pathologic ABI, defined as <0.9, occurred in 31 of 129 patients with available ABI data (24%), and was found to occur more frequently among those treated with nilotinib, le Coutre reported.

At baseline, patients who received first-line imatinib tended to have a significantly longer duration of CML than those who received nilotinib (P <.0001) and a significantly longer first-line treatment duration—a median duration of 97.5 months versus 29 months with nilotinib (P <.0001). The higher risk for PAOD was observed with nilotinib, despite much shorter treatment exposure, he pointed out.

Risk of PAOD in Subgroups

PAOD was diagnosed in 6.3% of patients on first-line imatinib, compared with 26% on first-line nilotinib (P = .0297), 35.7% on second-line nilotinib
(P = .0029), 16.6% of those previously exposed to nilotinib, and 12.5% who never received nilotinib.

The rate of PAOD in patients receiving imatinib has been reported to be essentially the same as the upper limit observed historically in the non-CML population: 6.7%.2 “There is no decrease in PAOD frequency in imatinib-treated patients, when compared to historical non-CML cohorts. We believe our findings are therefore not due to a reduction in PAOD with imatinib, but that it’s a nilotinib issue,” le Coutre suggested. Five PAOD-related events occurred, all in patients who received nilotinib.

Risk Factors Associated With Nilotinib

Increases in cholesterol and low-density lipoprotein were observed with nilotinib over imatinib, but there were no significant differences in high-density lipoprotein, triglycerides, glucose, or hemoglobin A1C levels among the treatment cohorts.

Total cholesterol was 164 mg/dL among the first-line imatinib cohort, but was 209 mg/dL with first-line nilotinib (P <.0001), 222 mg/dL with second-line nilotinib (P <.0001), and 193 mg/dL after any nilotinib exposure (P <.034). Low-density lipoprotein values were 95 mg/dL, 135 mg/dL (P <.0003), 139 mg/dL (P <.0001), and 117 mg/dL (P <.03), respectively.

“Although nilotinib may cause hyperglycemia and dyslipidemia, the exact mechanism leading to PAOD is unclear. We think that atherosclerotic disease caused by dyslipidemia should take longer to develop, and we may be seeing the effect of nilotinib accelerating these metabolic problems,” le Coutre said.

These risk factors may have contributed to the development of PAOD, the investigators maintained. In a subgroup analysis of 17 patients with severe PAOD that was newly diagnosed while they were on treatment, 94% had received nilotinib and only 1 patient (6%) had received imatinib. Of these patients, 53% had 1 or 2 underlying risk factors (tobacco, hypertension, diabetes, and dyslipidemia) and 47% had 3 or 4 risk factors.

“At present, we are recommending baseline and follow-up ABI and lab chemistries before nilotinib is given, and in patients with 2 or more cardiovascular risk factors, nilotinib should be given with caution,” he concluded.

1. Schwartz M, Kim T, Mirault T, et al. Elevated risk of peripheral artery occlusive disease (PAOD) in nilotinib treated chronic phase chronic myeloid leukemia (CML) patients assessed by ankle-brachial-index (ABI) and duplex ultrasonography. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 914.
2. Lamina C, Meisinger C, Heid IM, et al. Association of ankle-brachial index and plaques in the carotid and femoral arteries with cardiovascular events and total mortality in a population-based study with 13 years of follow-up. Eur Heart J. 2006;27(21):2580-2587.

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