Responses maintained to 5 years with ponatinib in chronic-phase CML

Patients with heavily pretreated chronic-phase chronic myeloid leukemia (CP-CML) achieve durable and clinically meaningful responses when treated with the third-generation tyrosine kinase inhibitor (TKI) ponatinib, according to 5-year results from a major clinical trial.

In the pivotal phase 2 trial known as Ponatinib Ph+ ALL and CML Evaluation (PACE), 82% of patients with CP-CML who achieved major cytogenetic response (MCyR) at 12 months maintained their responses for 5 years, found researchers led by Jorge Cortes, MD, deputy chair and professor of medicine, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX. They reported their data in Blood.

Ponatinib has potent activity against native and mutant BCR-ABL, including BCR-ABL T315I. The T315I mutation is present in up to 20% of patients with TKI-resistant disease and confers resistance to the other approved BCR-ABL TKIs.

The PACE trial included 449 patients with CP-CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who were resistant/intolerant to dasatinib or nilotinib or who had the BCR T315I mutation. The current analysis focused on the 267 evaluable patients with CP-CML, who were followed for a median of 56.8 months.

In the main analysis in the CP-CML population, responses to ponatinib were rapid: 56% of the patients had a MCyR, 46% had a complete cytogenetic response, and 34% had a major molecular response to ponatinib at a starting dose of 45 mg/day at a median follow-up of 15 months. The estimated rate of a sustained MCyR of at least 12 months was 91%. The estimated 12-month progression-free survival (PFS) was 80%, and overall survival (OS) was 94%.

In addition to the 82% of responders who maintained their response at the most recent follow-up, 59% (of the 40% who achieved a major molecular response at 12 months) maintained that response at 5 years. A deep molecular response (MR4.5) was achieved by 24% of patients.

The patients were enrolled in PACE from September 2010 to October 2011. Ponatinib dose reductions (to 30 or 15 mg/day) were implemented in October 2013 to lessen the risk of arterial occlusive events based on a previous post hoc analysis of the PACE data, which suggested that these events may be dose-related.

At least 90% of patients who elected to reduce their dose maintained their responses 40 months after doing so. The cumulative incidence of arterial occlusive events increased over time to 31% while the adjusted incidence of new events did not increase over time.

The estimated 5-year PFS was 53%, and OS was 73%. Only 3% of patients transformed to acute phase or blast phase CML.

The most common treatment-related adverse events included rash in 47%, abdominal pain in 46%, thrombocytopenia in 46%, headache in 43%, dry skin in 42%, and constipation in 41%.

Long-term 5-year results from PACE demonstrate that irrespective of dose reductions, ponatinib continues to show deep, lasting, clinically meaningful responses over time in heavily-pretreated patients with CP-CML.

The risk of arterial occlusive events may be an important factor in the selection of patients for ponatinib, the authors believe. In an ongoing, prospective, phase 2, dose-ranging trial called OPTIC, researchers will evaluate three ponatinib starting doses (45 mg, 30 mg, and 15 mg daily) and dose reductions for responders at predetermined time points in patients with refractory CP-CML.