New Drug Shows Promise against Drug-Resistant Leukemias
A new drug called ponatinib (Iclusig™) may be a new treatment option for patients with chronic myeloid leukemia (CML) that is resistant to other therapies, researchers said December 9, 2012, 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 native, 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.
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.
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 John M. Goldman, D.M., F.R.C.P., of Imperial College London in an accompanying editorial in NEJM. He noted that ponatinib is a third-generation tyrosine kinase inhibitor that "could prove to be the best of the bunch for managing CML."
New Treatments Needed
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.
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 imatinibin patients with newly diagnosed CML in the chronic phase.
With ponatinib’s regulatory approval, doctors now have what Dr. Deininger said may be “a very good treatment for patients after failure of dasatinib and nilotinib.”
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.