Michael E. Williams, MD

High response rates were observed in previously treated and resistant patients, but with increased risk for arterial thrombotic complications.

Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL) who are resistant to or intolerant of second-generation tyrosine kinase inhibitors (TKIs) have had limited treatment options. Now, investigators have conducted an industry-sponsored, phase II, multinational, open-label trial (PACE) of the novel TKI ponatinib (45 mg orally once daily) for 449 CML and Ph+ALL patients previously treated with nilotinib, dasatinib, or both.

Major cytogenetic response (MCR, the primary endpoint) was achieved in 56% of chronic-phase CML patients, including 34% with major molecular response. Impressively, 70% of patients with the BCR-ABL T315I mutation, which is commonly observed in patients resistant to all previously available TKIs, achieved an MCR. MCRs were also achieved in 39% of accelerated-phase CML patients and 23% of patients with blast-phase CML or Ph+ALL. The durability of responses was >12 months in more than half of the responding patients. Grade 3 or 4 thrombocytopenia (26%–33% of patients) or neutropenia (14%–26%) was observed, with rash, abdominal pain, and pancreatitis in ≤10%. However, cardiovascular, cerebrovascular, and peripheral vascular arterial thrombotic events were observed in 3.6% to 7.1% of the patient populations.

Citation(s):

Cortes JE et al. A phase 2 trial of ponatinib in Philadelphia chromosome–positive leukemias. N Engl J Med 2013 Nov 7; 369:1783.

Doroshow JH.Overcoming resistance to targeted anticancer drugs. N Engl J Med 2013 Nov 7; 369:1852.