December 21, 2012
Three new therapies increase options for CML and some ALL patients
BY Scott Merville
Patients with chronic myeloid leukemia (CML) or acute lymphoblastic leukemia that carries the Philadelphia chromosome (Ph+ALL) who can't tolerate the targeted drugs that revolutionized care for these leukemias now have three new options.
The U.S. Food and Drug Administration (FDA) has approved three new drugs in the past few months. Ponatinib (Iclusig) was approved last week, an effective drug for many patients with treatment-resistant disease. This comes on the heels of approvals of bosutinib (Bosulif) in September and omacetaxine (Synribo) in October.
Patients with both leukemias have enjoyed strong responses to imatinib (Gleevec) and second-generation drugs nilotinib (Tasigna) and dasatinib (Sprycel). All work by inhibiting proteins called tyrosine kinases on leukemia cells, in particular the aberrant BCR-ABL protein that causes these diseases.
However, 30-40 percent of patients' CML resists imatinib. Nilotinib and dasatinib work for about 40-50 percent of those patients.
"It's important to have as many therapies against cancer as we can, because rarely does one drug or combination succeed for all patients," said Jorge Cortes, M.D., professor in MD Anderson's Department of Leukemia. "These new drugs cover different gaps in treatment, so they can serve our patients in different ways."
"Ponatinib's availability will drastically improve the outcome of most patients with CML and PH+ALL who are resistant or intolerant to prior tyrosine kinase inhibitor therapy," Cortes says.
Developed by ARIAD Pharmaceuticals, ponatinib was designed to thwart treatment-resistant mutations. The most prominent is T315I, present in up to 20 percent of patients, which blocks the docking station where other tyrosine kinase inhibitors normally connect to the mutant protein.
In a pivotal phase II clinical trial, which Cortes presented in early December at the 54th American Society of Hematology Annual Meeting and Exposition in Atlanta, ponatinib showed responses against CML at early stage (chronic phase) CML, accelerated phase and blast phase, the most heavily mutated and hard to treat late stage of the disease.
Ponatinib is the only one of the five tyrosine kinase inhibitors that can successfully shut down CML with the T315I mutation.
Bosutinib (Bosulif) Approved by the FDA in September, bosutinib is a second-generation tyrosine kinase inhibitor developed by Pfizer that works against many BCR-ABL mutations that cause resistance. An important exception is the T315I mutation, which only ponatinib attacks directly.
"Bosutinib works equally as well as dasatinib and nilotinib," Cortes said. "The significant difference is bosutinib is more specific in its activity, inhibiting BCR-ABL and SRC, but not other tyrosine kinases. This leads to fewer harsh side effects."
There are no issues with cardiotoxicity or pancreatitis, for example, which can arise with other tyrosine kinase inhibitors.
Omacetaxine (Synribo) Omacetaxine works in a completely different manner from the five tyrosine kinase inhibitors. It stifles creation of the aberrant BCR-ABL protein, rather than blocking the protein's activity. So it also can thwart T315I mutant disease, but by preventing its expression rather than by disabling it.
"This is an important option for patients who've had several tyrosine kinase inhibitors fail and for those who cannot tolerate those drugs," Cortes said. "A small percentage of patients just need a new approach to get a good response."
Omacetaxine is a synthetic version of a long-time CML drug called homoharringtonine, which is derived from an evergreen tree found in China.
Known commercially as Synribo, this drug marketed by Teva Pharmaceuticals Industries was approved by the FDA in October. Clinical trials combining omacetaxine and tyrosine kinase inhibitors are planned.
Challenges: Matching patients to drugs; disease eradication
"We need to identify which patients to treat with each drug. Who are the ones I can treat well with imatinib, and who are the patients who need to start with some of the newer drugs?" Cortes said. "Right now, we start everyone with imatinib, dasatinib or nilotinib."
While current drugs reduce CML to extremely low, even undetectable, levels, most patients must remain on treatment to prevent recurrence. "The idea is to get patients to a certain point where you can stop treatment and know the disease won't come back," Cortes said.
That will take development of a reliable method of knowing when the disease is eradicated and of drugs or combinations that wipe out all malignant cells.