Ponatinib Is Highly Active in Resistant Chronic Myeloid Leukemia

Tyrosine kinase inhibitors that target the BCR–ABL fusion protein are highly effective in chronic myeloid leukemia (CML), but resistance can arise through mutation of the BCR–ABL kinase domain or other mechanisms. A particularly troubling mutation substitutes the threonine-315 gatekeeper residue with a bulky isoleucine that prevents drug binding and confers resistance to imatinib, dasatinib, and nilotinib. Ponatinib was identified as a small-molecule pan-BCR–ABL kinase inhibitor with preclinical activity in CML cells and xenografts harboring drug-resistant kinase domain mutations, including the T315I mutant. Cortes and colleagues report findings from a multicenter phase I dose-escalation trial of ponatinib in which heavily pretreated patients with refractory CML were enrolled. The primary objective was to determine a maximum tolerated dose, and secondary endpoints included safety, antitumor activity, pharmacokinetics, and pharmacodynamics. Myelosuppression and low-grade skin disorders were the most common adverse events, and dose-limiting toxicities included elevated lipase or amylase and pancreatitis. Ponatinib reached serum levels sufficient for BCR–ABL inhibition in vitro and strongly reduced BCR–ABL target protein phosphorylation in a dose-dependent manner, indicating that the drug had on-target activity. Strikingly, of 43 enrolled patients with chronic-phase CML, 98% had a complete hematologic response, 63% had a complete cytogenetic response, 44% had a major molecular response, and the median duration of response had not yet been reached after more than 2 years of treatment. Among 12 patients with a T315I mutation, 100% had a complete hematologic response, and similarly high response rates were observed among patients with other BCR–ABL mutations or with no detectable mutations. Notably, major hematologic and cytogenetic responses were also observed in approximately one third of patients with advanced CML, which responds poorly to other tyrosine kinase inhibitors. Although further clinical testing is required, ponatinib shows promise for patients with resistant CML who lack other treatment options.

Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome–positive leukemias. N Engl J Med 2012;367:2075–88.

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