Arterial Thrombotic Events in CML Patients Treated with First-Line Nilotinib: Incidence, Management and Impact on the Long Term Outcome — a Gimema CML WP Analysis

Background: Nilotinib has better efficacy compared to imatinib, with higher chances of achieving treatment-free remission. However, nilotinib is associated to a higher incidence of arterial thrombotic events (ATEs), limiting its use in selected patients.

Aims: To investigate the characteristics of ATEs and their impact on the long-term outcome of CML patients treated with nilotinib first-line.

Methods: We retrospectively analyzed 345 patients ≥ 18 years of age (18-49 years, 147 patients; 50-64 years, 109 patients; > 64 years, 89 patients) with CP CML enrolled in multicenter prospective clinical trials of the GIMEMA CML WP investigating nilotinib as first-line treatment (Clinical.Trials.gov: NCT00481052; NCT00769327; NCT01535391). The median age at CML diagnosis was 53 (18 - 86) years. The median follow-up was 58 (22-82) months; total nilotinib exposure: 1043 patient-years. We analyzed the rate, type, management, and outcome of ATEs; moreover, we compared the molecular response rates and the long-term outcome of patients with or without ATEs.

Definitions: ATEs: peripheral arterial obstructive disease (PAOD), ischemic heart disease (IHD), significant carotid stenosis and ischemic stroke, or other significant ischemic events; major molecular response (MMR): BCR-ABL≤ 0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies.

Results: Incidence and characteristics of ATEs: 30/345 (8.7%) patients had ATEs during treatment with nilotinib. Most common ATEs were IHD (4.1%), PAOD (2.3%), and (asymptomatic) carotid stenosis (1.1%). The median age at CML diagnosis of these patients was 64 (43-85) years, and the median age at ATEs was 67 (47 - 89) years. In patients of 18-49, 50-64, and > 64 years of age the rate of ATEs was 2%, 11%, and 15.7%, respectively; ATEs / 100 patient-years: 0.53, 2.7, and 3.6, respectively (relative risk in patients > 64 years vs. patients of 18-49 years: 6.7). The median duration of nilotinib treatment at ATE was 25 (1- 78) months: 87% and 60% of patients had achieved a MMR and MR4, respectively. These rates were comparable to those observed in patients without ATEs (MMR: 83%; MR4: 64%).

Management of ATEs: 50% of patients received medical treatment only, while the remaining required invasive interventions, including coronary angioplasty with stent positioning (30%), lower limbs amputations (10%), and peripheral vascular by-passes (7%). Overall, 70% of patients were hospitalized; 80% of patients (7% of the whole cohort) permanently discontinued nilotinib because of ATEs. Nilotinib dose reduction was performed in most of the remaining patients.

Outcome of ATEs: the median follow-up after ATE was 15 (1 - 58) months (total patient-years after ATEs: 52). No patient died for ATEs. The 5-year progression-free survival and overall survival were similar in patients with or without ATEs (PFS: 96% vs. 92%, p=0.55; OS: 96% vs. 93%, p=0.79)

Summary: After a median follow-up of almost 5 years, 8.7% of patients treated in first-line with nilotinib had ATEs. In patients > 64 years the relative risk of ATEs was 6.7 times higher compared to patients < 50 years of age. For the management of ATEs, half of the patients received medical treatment only; the remaining patients required invasive procedures, including major surgeries in 20% of cases. Importantly, no patient died for ATEs, and ATEs did not significantly affect response rates and long-term outcome of CML patients treated with nilotinib first-line.