Cardiac Safety Profile of Imatinib and Nilotinib In Patients (pts) with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Results From ENESTnd

Nilotinib is a potent and the most selective inhibitor of BCR-ABL. In the phase 3 ENESTnd trial, nilotinib demonstrated superior efficacy vs imatinib with higher and faster molecular responses and a significantly lower rate of progression on treatment to accelerated or blast phases of CML. Nilotinib has been previously shown to prolong the QT interval. The cardiac safety profile of nilotinib was previously described in pts with imatinib-resistant and -intolerant CML-CP enrolled in phase 2 clinical trials. Here, we report cardiac safety data on nilotinib 300 and 400 mg twice daily (bid), and imatinib, in pts with newly diagnosed CML-CP from the ENESTnd trial.

A total of 836 pts were included in the safety analysis of ENESTnd (279, 277, and 280 pts in the nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively) with a median follow-up of 18 months. Pts were excluded from study participation if they had known uncontrolled or medically significant cardiac disease, left ventricular ejection fraction (LVEF) < 45%, or QTcF interval > 450 msec. Prospective cardiac monitoring was conducted throughout the study for QT prolongation (via electrocardiogram) and LVEF (via echocardiogram) at regular intervals.

QTcF increases of > 30 msec from baseline occurred in 26% of pts in each nilotinib arm and in 18% of pts in the imatinib arm. QTcF increases of > 60 msec from baseline were uncommon, occurring in < 1% of pts in all three arms (Table). The highest mean changes from baseline in QTcF interval were 10.4, 12.4, and 7.9 msec in nilotinib 300 mg bid, nilotinib 400 mg bid, and imatinib arms, respectively, which occurred between months 3–6 of therapy in all arms. Furthermore, there was a modest linear correlation between nilotinib serum concentration and QTcF change from baseline that was similar to previously reported results. No pt in any treatment arm demonstrated an absolute QTcF interval > 500 msec. Analysis was conducted to identify any potential case of clinically symptomatic QT prolongation. Only events of syncope were identified (1 pt in each arm with drug-related events) by this analysis and none of these could be attributed to QT prolongation; there were no episodes of torsades de pointes in any treatment arm. Additionally, there was no decrease from baseline in mean LVEF observed anytime on treatment in any arm (Table). No patient in any treatment arm had a LVEF of < 45% on treatment or an absolute reduction from baseline in LVEF of > 15%. Importantly, no pt discontinued therapy due to QT prolongation or LVEF change. An analysis of grouped adverse event terms was performed to identify cases consistent with ischemic heart disease (IHD) or left ventricular dysfunction. A total of 11 pts in all treatment arms experienced IHD events after median treatment duration of 18 months: 3 (1%) on nilotinib 300 mg bid, 6 (2%) on nilotinib 400 mg bid, and 2 (< 1%) on imatinib. Of these 11 pts, 10 had preexisting cardiac disease or risk factors and only 1 pt discontinued treatment due to an IHD event. Nine pts reported angina pectoris. Two pts experienced myocardial infarction (MI) and 1 of these pts died during coronary artery bypass surgery (perisurgical MI). A total of 7 pts in all treatment arms with events consistent with left ventricular dysfunction were identified: 1 (< 1%) on nilotinib 300 mg bid, 4 (1%) on nilotinib 400 mg bid, and 2 (< 1%) on imatinib. Of these 7 pts, 4 pts experienced reduction in LVEF (3 were asymptomatic grade 1/2) and 3 pts experienced cardiac failure/congestive failure; 5 of these 7 pts had prior history of cardiovascular disease and/or preexisting cardiovascular risk factors. None of these 7 pts discontinued treatment due to events with left ventricular dysfunction. There were no sudden deaths reported on study.

Overall, QT prolongation, changes in LVEF, and clinical cardiac events were uncommon in all arms and seldom led to discontinuation. There was no cumulative effect of nilotinib exposure on cardiac safety with a median of 18 months follow-up. Nilotinib at both doses had a favorable cardiac safety profile that was similar to imatinib in pts with newly diagnosed CML-CP.

Larson: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus: Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Lopez: Novartis: Consultancy; Bristol Myers Squibb: Consultancy. Goldberg: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Gallagher: Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp: Novartis: Employment. Ortmann: Novartis: Employment. Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Kantarjian: Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.