National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
December 11, 2012 • Volume 9 / Number 24

Special Report

Experimental Drug Shows Promise against Drug-Resistant Leukemias

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An experimental drug called ponatinib may be a new treatment option for patients with chronic myeloid leukemia (CML) that is resistant to other therapies, researchers said Sunday at the American Society of Hematology (ASH) annual meeting in Atlanta. Patients with a type of acute lymphoblastic leukemia (ALL) that resists current treatments may also benefit from ponatinib.

The drug was designed to inhibit a range of mutant forms of the BCR-ABL fusion protein that are associated with drug resistance, as well as the unaltered form of the protein. This protein, which is derived from a genetic abnormality known as the Philadelphia chromosome, spurs the overproduction of white blood cells, a hallmark of CML.

"Ponatinib seems to be a very good treatment for patients who have run out of options because the other available drugs have failed," said Dr. Jorge Cortes of the University of Texas MD Anderson Cancer Center, one of the lead investigators. "The drug had a very high response rate in our studies, which included heavily pretreated patients."

The findings are from an ongoing phase II trial that included nearly 500 patients with relapsed or resistant CML or Philadelphia chromosome-positive ALL, which also expresses BCR-ABL. Ninety percent of the participants had previously received at least two BCR-ABL inhibitors, such as imatinib (Gleevec), dasatinib (Sprycel), or nilotinib (Tasigna).

Resistance to these drugs often occurs because of mutations in the BCR-ABL protein. Because of its chemical structure, ponatinib appears to be effective against all known mutations in BCR-ABL, including a mutation known as T315I, which is present in about 20 percent of patients with CML.

Consistent Results

Overall, the new results were consistent with those of a recent phase I clinical trial led by the same researchers. That study, which appeared in the November 29 issue of New England Journal of Medicine (NEJM), enrolled 81 patients with resistant blood cancers, including 65 with CML and 5 with Philadelphia chromosome-positive ALL.

In both trials, most patients experienced a complete hematologic response (all blood counts normal) while being treated with ponatinib, a pill taken once daily. More important, many patients achieved a complete cytogenetic response (no residual cells with the Philadelphia chromosome identified), the researchers noted.

"During the [phase I] trial, it was exciting to see responses in patients whose disease had progressed on all currently available treatments," said co-author Dr. Michael Deininger of the University of Utah Huntsman Cancer Institute. "The activity of this drug in these difficult-to-treat patients is really remarkable."

The side effects of ponatinib include a dose-related inflammation of the pancreas, which was manageable in nearly all cases, the researchers said. Another side effect was skin rashes, which were also generally manageable.

The results are "very encouraging," commented Dr. John M. Goldman of Imperial College London in an accompanying editorial in NEJM. He noted that ponatinib was a third-generation tyrosine kinase inhibitor that "could prove to be the best of the bunch for managing CML."

New Treatments Needed

The Food and Drug Administration (FDA) is reviewing ponatinib as a treatment for CML or Philadelphia chromosome-positive ALL that is resistant or does not respond to current therapies. (Update: The FDA approved ponatinib for these uses on December 14, 2012.) 

Considerable progress has been made in the treatment of CML since imatinib was introduced in the late 1990s, but new treatments are needed. "As good as current treatments for CML are, some patients don't do well over the long term," Dr. Cortes noted.

In about 25 percent of patients with CML, the disease does not respond to or becomes resistant to imatinib. Resistance is often caused by mutations in the BCR-ABL protein that prevent imatinib from binding to the BCR-ABL protein. About half of these patients benefit from the second-generation BCR-ABL inhibitors, dasatinib and nilotinib. But in many patients who initially respond to these inhibitors, the disease eventually becomes resistant to them as well.

An illustration showing how ponatinib fits into the targeted protein and an image of ponatinib's triple bond (Courtesy of the New England Journal of Medicine ©2012)Panel A: Ponatinib (blue and yellow spheres) fits in the binding cavity of the targeted protein (indicated by a mesh pattern). Panel B: The triple bond (yellow) is a unique structural feature of ponatinib (blue) that allows the drug to overcome the limitations of other BCR-ABL inhibitors. (Courtesy of the New England Journal of Medicine ©2012)

Ponatinib was an attractive drug to evaluate in the clinic, Dr. Cortes explained, because it was molecularly designed to overcome these limitations. "The drug has performed as we had hoped; it was very effective," he said.

More research is needed to determine how long responses to ponatinib will last and whether the drug causes toxic effects with long-term use. There are no data available on the use of ponatinib in the first-line setting, although a clinical trial has been launched to compare the efficacy of ponatinib and imatinib in patients with newly diagnosed CML in the chronic phase.

"If ponatinib gains regulatory approval, we may soon have a very good treatment for patients after the failure of dasatinib and nilotinib," said Dr. Deininger.

Ponatinib may have other uses as well. The drug targets a number of tyrosine kinases in addition to BCR-ABL, including KIT, PDGFRA, FGFR1, and FLT3, and may help treat tumors with mutations in the genes that make these proteins, Dr. Goldman noted.

"Ponatinib may turn out to be another step forward in the march toward real success with molecularly targeted therapy for cancer," he concluded.

Edward R. Winstead

This research was supported in part by the National Institutes of Health (CA016672).