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Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in chronic myeloid leukemia: a single institution study

To the Editor: In recent years, two-second-generation tyrosine kinase inhibitors (TKIs), namely nilotinib and dasatinib (1, 2), have been approved for the first-line use in chronic myeloid leukemia (CML) on the basis of results of two randomized clinical trials showing a higher proportion of patients achieving early complete cytogenetic responses (CCyRs) on nilotinib (3, 4) and dasatinib (5) in comparison with imatinib. These observations have opened a passionate debate among clinicians concerning the most appropriate initial treatment for CML treated in the day-to-day practice (6, 7). The best estimate of the goodness of a drug is based on the assessment of the number of patients who are still taking the drug over the time. Such an estimate provides a joint analysis of both efficacy and toxicity. Interestingly, both the DASISION and ENESTnd trials revealed that the proportion of patients still on therapy after 2 yr from randomization were similar for both dasatinib and nilotinib in comparison with imatinib (3, 5). This indicates that the superior efficacy of nilotinib and dasatinib is compensated by other factors, most likely side effects, that lead to a permanent discontinuation of the drug. The side effect profile of nilotinib is not yet fully understood. Recently, therapy with nilotinib has been associated with some side effects rarely observed with imatinib therapy, such as elevated lipase and/or amylase levels, pancreatitis, and hyperglycemia (3, 4). In addition, nilotinib has been associated with progressive peripheral arterial occlusive disease (PAOD), although the incidence of this complication is not yet clear (7–9). Information on the issue mainly rely on observational studies of academic referral institutions or ENESTnd trial; however, information from unselected patient cohort is lacking. With this in mind, we retrospectively evaluated incidence of PAOD or other vascular occlusive events in our cohort including 82 consecutive CML patients treated at our institution with imatinib alone (n = 55) or nilotinib as first-line (n = 17) or second-line treatment after imatinib failure (n = 10) in the last 10 yr. After a median time of exposition to nilotinib of 24 months (range, 7–34 months), 4 (14.8%) 27 patients developed an episode of severe and previously unrecognized PAOD or other vascular occlusive events (2 PAOD, 1 myocardial infarction, 1 ictus). All 4 patients were more than 60 yr old and 3 of 4 were male while obesity was never observed. A history of nicotine abuse could be found in 2 of 4 patients, while the presence of arterial hypertension or dyslipidemia was observed in 2 of 4. When the incidence PAOD or other vascular occlusive event incidence was analyzed in 55 patients treated with imatinib alone, we found only one patient who experienced myocardial infarction after 135 months of therapy. We then evaluated the likelihood of developing PAOD in the subset of patients treated only with imatinib and in those who received nilotinib, respectively. The projected 10-yr actuarial probability of remaining PAOD-free was 100% in the imatinib group and 67% in the nilotinib group (HR, 14.6; P = 0.0008) (Fig. 1). Interestingly, the two patient cohorts were alike with respect to age (P = 0.76), gender (P = 0.80), number cardiovascular risk factors (i.e., hypertension, dyslipidemia, diabetes) (P = 0.62), and body mass index (P = 0.59). The only difference we observed was a significantly longer exposition to drug among patients treated only with imatinib (median, 79.5 months; range, 3–135) in comparison with those who received nilotinib (median, 21.5 months; range, 3–56; P < 0.001). This is a survey carried out in a cohort of patients observed at a single institution series and dealing with cardiovascular side effect of TKIs. Generally, patients were treated according to current practice. Interestingly, 2 of 4