Severe Peripheral Arterial Disease During Nilotinib Therapy

In BCR-ABL-positive chronic myeloid leukemia (CML), the tyrosine kinase inhibitor (TKI) imatinib acts as an antileukemic agent and reconstitutes normal hematopoiesis ( 1 ). Because imatinib-treated patients may develop drug resistance or intolerance, the second generation TKI nilotinib (Tasigna; Novartis Pharmaceuticals, East Hanover, NJ) was designed and has been approved for treatment of CML ( 2 ). In newly diagnosed CML, nilotinib (300 or 400 mg twice daily) was superior to standard therapy with imatinib, with major molecular response rates of 44% (300 mg) and 43% (400 mg) vs 22% for imatinib at 1 year. Adverse events with nilotinib at either dose included reversible constitutional symptoms and elevations in lipase (24%–29% of patients), bilirubin (53%–62%), fasting glucose (36%–41%), and cholesterol (22%) ( 3 , 4 ). Recently, we noted severe peripheral arterial disease (PAD) and other arteriopathies, including myocardial infarction, in three of 24 CML patients who were receiving nilotinib therapy in one of our centers ( 5 ). Given the irreversible nature of severe PAD, we retrospectively analyzed 179 patients who received nilotinib in four centers. Of these patients, 151 were enrolled in clinical trials, including several frontline trials. Four of these 179 patients had hypereosinophilic syndrome, acute lymphoblastic leukemia, or systemic mastocytosis and 175 had CML. Among the 179 patients, 11 (6.15%) patients developed severe and previously unrecognized PAD that required invasive therapy. Of these 11 patients, one had no detectable cardiovascular risk factors, whereas four (36.4%) had a history of nicotine abuse, seven (63.6%) had arterial hypertension, three (27.3%) had diabetes mellitus, five (45.5%) had dyslipidemia, three (27.3%) were obese, six (54.5%) were male, and seven (63.6%) were older than 60 years (all cardiovascular risk factors). All 11 PAD patients had at least a cytogenetic remission while on nilotinib. One patient with hypereosinophilic syndrome and one patient with CML received nilotinib as first-line treatment. Previous treatments for the remaining patients were hydroxyurea (nine patients), interferon alpha (seven patients), imatinib (nine patients), dasatinib (one patient), or another agent (four patients). In these 11 patients, the mean time from CML diagnosis to initiation of nilotinib was 347 weeks (range = 8–651 weeks) and the mean time from initiation of nilotinib to the first PAD event was 105.1 weeks (range = 16–212 weeks) ( Table 1 ). In all cases, the lower limbs were affected; in nine patients, the femoral superficial artery was involved. These patients were treated with angioplasty (eight patients), stent implantation (eight patients), and/or amputation (four patients). Patient characteristics before and at cardiovascular event * CML CP = chronic myeloid leukemia in chronic phase; PAD = peripheral arterial disease. Patient characteristics before and at cardiovascular event * CML CP = chronic myeloid leukemia in chronic phase; PAD = peripheral arterial disease. The frequency of PAD in this retrospective analysis appears to exceed that found in the general population and in a retrospective analysis of CML patients treated with imatinib ( 6 , 7 ). It is noteworthy that elevations in cholesterol and fasting glucose were observed in clinical trials with nilotinib and that 10 of the 11 PAD patients had cardiovascular risk factors present before treatment, suggesting that nilotinib may aggravate a preexisting arteriosclerotic condition. We recommend that the issue of arteriosclerotic events in nilotinib-treated patients be prospectively addressed in a larger cohort and that clinicians carefully monitor patients receiving nilotinib who are at risk for PAD.