An investigational tyrosine kinase inhibitor, ponatinib, has shown high levels of activity in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL).
Results of the phase I trial, published in The New England Journal of Medicine, offer hope for patients with drug-resistant leukemias, with ponatinib inducing high response rates in individuals with the BCR gene region "gatekeeper" variant T315I and other resistant mutations, as well as in those with no mutations.
"Ponatinib is a very promising new treatment for patients who have run out of options," said Jorge Cortes (The University of Texas MD Anderson Cancer Center, Houston, USA), the trial's principal investigator.
Ponatinib (AP24534) is a potent oral small-molecule tyrosine-kinase inhibitor that contains a novel triple-bond linkage specifically designed to evade the T315I mutation.
The phase I trial included 81 patients with hematologic cancers, including 60 with CML and five with Ph-positive ALL. All patients had relapsed or resistant disease and were treated with oral ponatinib once daily at doses ranging from 2 to 60 mg.
With a median follow up of 56 weeks, the dose-limiting toxicities included elevated lipase or amylase levels and pancreatitis, while common adverse events were rash, myelosuppression, and constitutional symptoms.
In terms of efficacy, 98% of 43 patients with chronic-phase CML had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response.
Among the 12 patients with the T315I mutation who had chronic-phase CML, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response.
"Responses among patients with chronic-phase CML were durable," write Cortes et al.
Ponatinib had somewhat lower activity in accelerated- or blast-phase CML and Ph-positive ALL, with 36% of 22 patients having a major hematologic response and 32% having a major cytogenetic response.
Cortes et al conclude: "These findings identify ponatinib as a highly active agent for patients with CML who have shown resistance to multiple tyrosine kinase inhibitors."
Twelve patients with acute myeloid leukemia also participated in the trial; results in these individuals will be reported in a separate paper. In addition, Cortes is due to report results of a pivotal phase II trial of ponatinib at the American Society of Hematology annual meeting in December 2012.
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