December 6, 2010 (Orlando, Florida) — The results are preliminary, but a new tyrosine kinase online pharmacy has shown promise in patients with refractory hematologic malignancies. The investigational agent, ponatinib (developed by ARIAD Pharmaceuticals), is a potent pan-BCR-ABL inhibitor that has demonstrated activity against all tested mutants that are resistant to imatinib (Gleevec), including T315I, for which there is currently no available therapy.

There have been tremendous advances in the treatment of chronic myeloid leukemia (CML) with the advent of first- and second-generation tyrosine kinase inhibitors, explained lead author Jorge Cortes, MD, who presented the findings here at the American Society of Hematology 52nd Annual Meeting.

"Imatinib is a great drug and we have excellent second-line therapies," said Dr. Cortes, who is deputy chair and professor of medicine in the Department of Leukemia at the University of Texas M.D. Anderson Cancer Center in Houston. "Moving these drugs forward into the front line has further improved outcomes."

However, a number of CML patients will fail these therapies or develop resistance. One reason is the development of the T315I mutation; CML cells that harbor this mutation are resistant to all of the currently available drugs that target BCR-ABL.

Currently, there are no effective treatment options for patients with a T315I mutation. Preclinical research has demonstrated that ponatinib can inhibit the entire spectrum of mutations that cause resistance to other BCR-ABL inhibitors, Dr. Cortes explained.

"Ponatinib can also prevent the emergence of cells that have resistance and mutations," he said, citing findings from experimental trials. "So this can be a very valuable drug for these patients."

In addition to the T3151 mutation, ponatinib has demonstrated potent activity against an array of BCR-ABL variants, and also targets other therapeutically relevant kinases. These include inhibition of FLT3, FGF, VEGF and PDGF, and c-KIT.

Major Responses Seen

Dr. Cortes and colleagues conducted a dose-escalation phase 1 multicenter trial to evaluate the safety of ponatinib and to establish a recommended dose. They also assessed evidence of antileukemic activity in a cohort of patients with refractory hematologic malignancies.

The cohort was comprised of 74 patients, the majority of whom had CML (n = 60; 44 chronic, 7 accelerated, 9 blast phase). In addition, there were 4 patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), 8 with acute myeloid leukemia, and 4 with other hematologic malignancies.

Previous therapies received by all CML/Ph+ patients included imatinib (97%), dasatinib (Sprycel) (90%), and nilotinib (Tasigna) (57%). Nearly all of the patients (95%) had failed at least 2 previous therapies, and 65% had failed at least 3 tyrosine kinase inhibitors.

Approximately three quarters of the patients (72%) had BCR-ABL mutations at study entry. Of this group, 18 (38%) had T315I mutations, 7 (11%) had F317L mutations, and 4 (6%) had G250E mutations. Forty patients (63%) had 1 or more mutations, and 5 patients (8%) had 2 or more.

The drug was well tolerated, and the 45 mg dose was chosen as the recommended dose for further study, Dr. Cortes said. "Very importantly, we saw an excellent rate of response. About two thirds of patients achieved a major cytogenetic response, with about half of the patients achieving a complete cytogenetic response."

Of 9 evaluable patients in chronic-phase CML with T3151 mutations, 100% achieved a complete hematologic response, 100% achieved a major cytogenetic response, and 89% (n = 8) achieved a complete cytogenetic response. Overall, for the 38 evaluable patients in chronic-phase CML, 95% achieved a complete hematologic response, 66% a major cytogenetic response, and 53% a complete cytogenetic response.

The results for patients in accelerated and blast-phase CML, and in those with Ph+ ALL, were less striking. There were no complete hematologic responses, and only 35% achieved a major hematologic response. A major cytogenetic response was achieved by 24%, and a complete cytogenetic response was achieved by 12%. In the subgroup with T3151 mutations, 20% achieved a major hematologic response and 20% achieved a major cytogenetic response. There were no complete responses.

"These are very exciting responses in these patients," Dr. Cortes noted.

The toxicity profile of ponatinib was acceptable, he added. The most common adverse events observed were thrombocytopenia (24%), headache (14%), nausea (14%), arthralgia (13%), fatigue (13%), anemia (11%), increased lipase (11%), muscle spasms (11%), rash (11%), myalgia (10%), and pancreatitis (10%). At a dose of 60 mg, dose-limiting toxicities (elevated pancreatic enzymes and pancreatitis) were reported in 4 of 14 patients.

Is Imatinib Obsolete?

This is an important study, said Karen Ballen, MD, clinical director of the leukemia program at Massachusetts General Hospital Cancer Center in Boston.

"Even though the results are preliminary, the data are promising for patients who have no other options," said Dr. Ballen, who was not involved in the study.

The researchers are now moving ahead with a phase 2 trial, which was initiated in September 2010.

"As we get first-, second-, third-generation drugs — hopefully, the next generations are better than the old ones," said Peter Emanuel, MD, director of the Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock. "The question is: Will imatinib eventually become a historical drug?"

Dr. Emanuel was not involved in the study; he moderated a press briefing in which the highlights of the study were presented.

Dr. Cortes reports receiving research funding from ARIAD, ChemGenex, and Deciphera. Dr. Emanuel reports relationships with Bristol Myers Squibb, Novartis, and Genzyme

American Society of Hematology (ASH) 52nd Annual Meeting. Abstract 210. Presented December 6, 2010.

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"Regulators are cracking down on a Marcellus Shale natural gas driller after finding out that truckloads of the company's wastewater had been improperly sent to the Delaware watershed.

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