Long-Term Clinical Benefit With Ponatinib in Heavily Pretreated Chronic Phase Chronic Myeloid Leukemia

Ponatinib is a potent third-generation tyrosine kinase inhibitor (TKI) with activity against both native and mutant BCR-ABL kinases, including T315l, which is resistant to other TKIs. Based on results from the pivotal phase II PACE trial (N = 449) ponatinib was approved in 2012 for treatment of patients with chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) who are resistant or intolerant to other TKIs.

The current analysis focuses on efficacy and safety from the PACE trial in 267 evaluable patients with chronic phase CML with 56.8-month median follow-up. The initial analysis in this heavily pretreated patient population (more than 90% received at least 2 prior TKIs) showed that responses to ponatinib were rapid, with 56% of patients achieving major cytogenetic response (MCyR) by 12 months. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 80 and 94%, respectively.

In the final 5-year analysis, ponatinib continued to demonstrate deep and durable responses. A total of 60% of patients achieved MCyR, and 54% achieved complete cytogenetic response (CCyR). An estimated 82% of patients achieving MCyR by 12 months maintained their response for 5 years. Major molecular response (MMR) was achieved in 40% of patients, and 59% of these patients remained in response at 5 years. Deep molecular response (MR4.5) was achieved by 24% of patients. The estimated 5-year PFS and OS were 53% and 73%, respectively. Only 9 patients (3%) transformed to acute phase or blast phase CML.

The pivotal trial evaluated the efficacy of ponatinib at a starting dose of 45 mg daily with dose reductions to 30 mg or 15 mg to manage adverse events (AEs). However, beginning in October 2013, proactive dose reductions were recommended in response to concerns regarding accumulation of arterial occlusive events (AOEs). A post hoc analysis aimed to assess the effect of prospective dose reductions on maintenance of response showed that dose reduction did not impact response in patients who had achieved MCyR or MMR, with greater than 90% of patients retaining their response. The cumulative incidence of AOEs increased over time to 31%, but the exposure-adjusted incidence of newly occurring AOEs did not increase with longer duration of ponatinib treatment. The authors explained that this may be due to a number of factors, including the natural history or etiology of AOEs, dose reductions, or lower risk for these events in some patients. The most common treatment-related AEs were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%).

The investigators concluded that the final analysis of PACE supports the initial assessment of ponatinib as effective treatment with durable and clinically meaningful responses, irrespective of dose reduction in heavily pretreated patients with chronic phase CML.  Risk of AOEs may be an important factor to consider when selecting patients for ponatinib treatment.  The ongoing prospective phase II dose-ranging OPTIC trial is evaluating the impact of 3 starting doses (45 mg, 30 mg, and 15 mg daily) and dose reductions for patients with response at predetermined time points on the efficacy and safety of ponatinib in patients with refractory chronic phase CML.

Blood. 2018 Mar 22 [Epub ahead of print].