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ATLANTA -- Ponatinib, a third-generation kinase inhibitor, produced major responses in many patients with heavily pretreated drug-resistant leukemias in a pivotal phase II study reported here.

Depending on the disease subtype, rates of major cytogenetic and hematologic responses to daily oral treatment with the drug ranged from 33% to 70% in the 449-patient PACE trial after 12 months, said Jorge Cortes, MD, of the MD Anderson Cancer Center in Houston.

Except for a few cases of grade 3/4 pancreatitis, no important toxicities were seen, Cortes said at the American Society of Hematology annual meeting.

"Ponatinib had outstanding clinical activity," Cortes said at an ASH press briefing. Major responses were common and were seen "regardless of the stage of the disease, regardless of the presence or absence of mutations, and the responses were very deep and very rapid and sustained."

His presentation here follows an equally positive report from a phase I study published last month in the New England Journal of Medicine.

Ponatinib was designed to get around one of the most common mutations that confer resistance to tyrosine kinase inhibitors (TKIs), the "gatekeeper" T315I substitution that blocks binding for all three currently approved drugs: imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna).

Ponatinib is considered a pan-BCR-ABL inhibitor because it is effective against native and all tested mutant forms of the BCR-ABL protein produced by the Philadelphia chromosome, which gives rise to chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (ALL).

The current open-label study enrolled 449 patients who had previously failed treatment with other TKIs. Most showed resistance to dasatinib or nilotinib as well as imatinib.

Diagnoses included chronic-phase CML in 270 patients, acute-phase CML in 85, and either blast-phase CML or Ph-positive ALL in 94.

Major cytogenetic or hematologic responses had been achieved with previous therapies in 15% to 26% of patients in these groups. Fewer than 10% had achieved major molecular responses on prior therapy.

Primary outcomes in the trial were major cytogenetic and major hematologic responses, with results stratified by leukemia type, presence of the T315I mutation, and resistance to dasatinib or nilotinib.

Response rates were as follows:

• Chronic-phase CML: overall 56%, with T315I mutation 70%, with kinase inhibitor resistance 51%
• Acute-phase CML: overall 57%, with T315I mutation 50%, with kinase inhibitor resistance 58%
• Blast-phase CML and Ph+ ALL: overall 34%, with T315I mutation 33%, with kinase inhibitor resistance 35%

Cortes also reported that 46% of the chronic-phase CML patients had obtained complete cytogenetic responses and 34% had major molecular responses. Median time to response was 2.8 months for major cytogenetic responses and 5.5 months for the molecular responses.

The responses were also durable, with 91% of chronic-phase CML patients with major cytogenetic responses maintaining them for 12 months (95% CI 85% to 95%). None of the patients with T315I mutations relapsed during follow-up.

The authors noted that response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration.

Common side effects included rashes, dry skin, abdominal pain, headache, and constipation, all seen in about 40% of patients. But the vast majority of these effects were mild, Cortes said.

The only really serious toxicity associated with ponatinib was pancreatitis, seen at grade 3 or 4 in 6% of patients, Cortes said. But only one patient in the phase II study had to stop treatment because of this problem, he added.

ASH press briefing moderator Aaron Schimmer, MD, of Princess Margaret Cancer Centre in Toronto, said ponatinib would be welcomed by patients and clinicians alike.

The T315I mutation typically develops with kinase inhibitor treatment, he noted. "When this happens, there is no available TKI [and] the outlook for these patients is very poor," Schimmer told 名媛直播. "With this drug, there is a dramatic response rate. It's going to be huge for this group of patients."

Cortes said that studies were now under way with ponatinib as a first-line therapy, which Schimmer called "an intriguing possibility."

The drug "is clearly effective in this group of patients with the mutation," Schimmer said. "What if you give it to newly diagnosed patients up front? Will you prevent the development of these kinds of complications, and could response rates be even better? That's unknown."

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