Clinical cardiac safety profile of nilotinib

Abstract

BackgroundNilotinib is a second-generation tyrosine kinase inhibitor with significant efficacy as first-or second-line treatment in patients with chronic myeloid leukemia. Despite preclinical evidence indicating a risk of prolongation of the QT interval, which was confirmed in clinical trials, detailed information on nilotinib's cardiac safety profile is lacking. Design and MethodsHere, we retrospectively assessed cardiovascular risk factors in 81 patients who were being or had previously been treated with nilotinib therapy and evaluated cardiovascular parameters by longitudinal monitoring of the QT interval and left ventricular ejection fraction. Detailed information on the occurrence and management of defined cardiac adverse events was extracted. ResultsThe median duration of nilotinib therapy was 26 months (range, 1-72). The median QT interval at baseline was 413 msec (range, 368-499 msec). During follow-up, the median QT was not significantly different from the baseline value at any time-point. Sixteen of 81 patients (20%) had new electrocardiographic changes. Cardiac function, as assessed by measurement of left ventricular ejection fraction, did not change significantly from baseline at any time-point. During a median follow-up of 44 months (range, 2-73), seven patients (9%), all of whom had received prior imatinib therapy, developed 11 clinical cardiac adverse events requiring treatment. The median time from the start of nilotinib therapy to an event was 14.5 months (range, 2-68). Five of seven patients were able to continue nilotinib therapy with only one brief interruption. ConclusionsWhereas new electrocardiographic abnormalities were recorded in 20% of all patients and some of them developed severe or even life-threatening coronary artery disease, QT prolongation, changes in left ventricular ejection fraction, and clinical cardiac adverse events were uncommon in patients treated with nilotinib.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review

“…The weighted proportion of QTc prolongation of any grade with nilotinib was 2.7% with QTc of >500 ms, seen in 0.3% of cases. Caution and periodic ECG monitoring are advised when using nilotinib 71, 73, 74, 76, 77, 79, 80. QTc prolongation was common (37%) in patients with hepatic impairment treated with bosutinib,10 but this was not seen in other smaller studies 11, 12.…”

Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management

“…During preclinical development, nilotinib was shown to potentially prolong the QT interval, and parameters were put in place to monitor for this complication after the drug was approved. In a retrospective review of 81 patients using the drug in clinical practice, the QT interval for the entire cohort was not statistically significantly prolonged at any time point during the duration of the study [30]. No patient experienced a QT interval >500 msec.…”

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“…Anti-EGFR inhibitors can target the skin cells, which often express abundant EGFR thus inhibiting the normal growth of skin cells and making it harder for the skin to retain moisture, resulting in scaly and itchy skin [107]. Nilotinib, used in the treatment of chronic myelogenous leukemia carries a warning for possible heart complications [108]. Development of resistance to these drugs is another major drawback and cancer cells acquiring resistance to drugs such as crizotinib and vemurafenib have been reported [109,110].…”