Patient Disposition and Baseline Characteristics
Between September 2010 and October 2011, 449 patients were enrolled in the PACE trial, including 270 with chronic phase CML (CP-CML), 85 with accelerated phase CML (AP-CML), 62 with blast phase CML (BP-CML), and 32 with Ph+ ALL. The median age at baseline was 59 years, with 47% being female. Most patients (93%) had previously received at least two approved tyrosine kinase inhibitors (TKIs), and 56% had received at least three. Nearly one-third (29%) of patients had the BCR-ABL1T315I mutation at study entry.
Efficacy in Patients with CP-CML
Among the 267 evaluable CP-CML patients, 60% achieved major cytogenetic response (MCyR) at any time, with 54% achieving complete cytogenetic response (CCyR). Additionally, 40% achieved major molecular response (MMR), and 24% achieved a 4.5-log molecular response (MR4.5). Responses were durable, with 82% and 59% of patients maintaining MCyR and MMR, respectively, at 5 years.
Efficacy in Patients with Advanced Disease
Patients with AP-CML, BP-CML, and Ph+ ALL also showed significant response rates, with rapid achievement of responses. However, the durability of responses and overall survival rates were lower compared to CP-CML patients.
Safety
The most common treatment-emergent adverse events (TEAEs) in CP-CML patients included rash, abdominal pain, thrombocytopenia, headache, dry skin, and constipation. Serious adverse events (SAEs) such as pancreatitis, atrial fibrillation, pneumonia, and angina pectoris were reported. The study also noted the occurrence of arterial occlusive events (AOEs) and venous thromboembolic events (VTEs), with a cumulative incidence of AOEs increasing over time but the exposure-adjusted incidence remaining constant.
Discussion
Ponatinib provided clinical benefit for heavily pretreated CML or Ph+ ALL patients, with significant response rates and durability. The study underscores the importance of dose adjustments and active monitoring to manage adverse events effectively. The ongoing OPTIC trial aims to evaluate the impact of different starting doses and dose reductions on the safety and efficacy of ponatinib in patients with refractory CP-CML.
