Ponatinib Stimulates 'Powerful' Response in Treatment-Resistant Leukemias

Researchers have demonstrated that ponatinib can overcome a wide range of mutations that cause treatment resistance-including the stubborn T315I mutation-in all stages of CML and Ph+ ALL.

Jorge Cortes, MD

Researchers have demonstrated that ponatinib, a new oral tyrosine-kinase inhibitor (TKI), can overcome a wide range of mutations that cause treatment resistance—including the stubborn T315I mutation—in all stages of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), while also working in cases where no mutations have been detected.

“We have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients,” said Jorge Cortes, MD, lead author and professor of Medicine, deputy chair of the Department of Leukemia, and chief of the CML and AML Sections at the University of Texas MD Anderson Cancer Center, in Houston.

Cortes presented the phase II study results during the 54th Annual Meeting and Exposition of the American Society of Hematology (ASH). Following a priority review, the FDA approved ponatinib (Iclusig) on December 14, 2012 for treatment of adult patients with chronic, accelerated, or blast phase CML that is resistant or intolerant to prior TKI therapy or for PH+ ALL that is resistant or intolerant to prior TKI therapy (Find out more).

CML and Ph+ ALL are caused by an abnormality that produces the gene BCR-ABL, which stimulates the production of the BCR-ABL tyrosine kinase and helps leukemia cells grow, according to ASH.

Revolutionary improvement in the treatability of the two diseases came with the FDA’s 2001 approval of imatinib, the first TKI for the conditions. That and more recently developed TKIs, including dasatinib and nilotinib, work by binding to the BCR-ABL tyrosine kinase and turning off its signal, Cortes said. The treatments have turned CML, which once had a prognosis of 3 to 5 years, into a condition that can be successfully managed for decades.

But 5% to 20% of patients with CML and Ph+ ALL have the T315I mutation, making their disease resistant to those treatments, according to ASH. The only alternative is a hematopoietic stem cell transplant, which has toxic side effects, according to the organization.

Ponatinib was developed using computational and structure-based design to have optimal binding to the BCR-ABL active site, and demonstrated high response rates in early clinical trials. In addition, Cortes said, there is evidence that the drug can prevent the growth of resistant cell lines.

Encouraged by that data, researchers in the United States and Europe embarked on the phase II study of ponatinib, enrolling 449 patients with CML or Ph+ ALL who had the T315I mutation and/or a history of resistance to dasatinib or nilotinib. Nearly all the patients had been treated with multiple TKIs—90% with three such drugs and 60% with two, Cortes said. The patients were separated into six cohorts based on their disease resistance or genetic profile, and then treated with ponatinib.

The primary endpoint was major cytogenetic response within 12 months of treatment for those with chronic-phase CML, and major hematologic response within 6 months after treatment for those with advanced-phase CML or Ph+ALL. Results exceeded those criteria.

Major cytogenetic response was observed in 56% of all chronic-phase CML patients (70% of those with the T315I mutation and 51% of those with other mutations). Major hematologic response was observed in 57% of patients with accelerated-phase CML (50% of those with T315I and 58% of those with other reasons for resistance or intolerance) and 34% of those with blast-phase CML or Ph+ ALL (33% of those with the T315I mutation and 35% of resistant/intolerant patients), Cortes said.

Complete cytogenetic response was achieved in 46% of patients with chronic-phase CML, with higher response rates observed in patients who were exposed to fewer prior TKIs and those with shorter disease duration.

The portion of responders estimated to maintain their primary endpoint at 1 year was 91% in chronic-phase CML, 42% in accelerated-phase CML, and 35% in blast-phase CML or Ph+ ALL, Cortes reported.

Ponatinib was well tolerated in all cohorts. The most common adverse events were skin toxicity (including rash or dry skin), elevation of pancreatic enzymes and/or pancreatitis, and myelosuppression (a side effect of cancer treatment that lowers blood cell count).

At the time of analysis, 52% of patients remained on the therapy.

“This is a fantastic drug that offers an opportunity for patients who have failed everything else and don’t have anything more to receive,” Cortes said. “It gives us the most powerful tool we have for CML. The prospects for patients to be cured and have eradication of their disease are increasing great with drugs such as ponatinib.”

Ongoing at MD Anderson are a study of ponatinib as initial therapy and a trial of the drug in comparison to imatinib, Cortes said.

Studies to start soon, he added, will involve combining ponatinib and chemotherapy in Ph+ ALL; using the novel drug in patients who have failed just one prior therapy; and administering ponatinib to patients with acute myeloid leukemia, a strategy that showed promise in phase I trials.


Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. A pivotal phase II trial of ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-month follow-up of the PACE trial. Presented at: 54th ASH Annual Meeting; December 8-11, 2012; Atlanta, GA. Abstract 163.


View coverage from the 2012 ASH Meeting

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