Three new therapies increase options for CML patients

Path-breaking targeted therapies have extended the lives of people with chronic myeloid leukemia (CML) or acute lymphoblastic leukemia that shares the central CML mutation.

But what happens when Gleevec and the second-generation drugs that followed it stop working? Or patients simply cannot tolerate this class of drugs, tyrosine kinase inhibitors that stifle the aberrant BCR-ABL protein that drives these leukemias?

The U.S. Food and Drug Administration (FDA) has approved three new drugs in the past few months that provide new choices for patients and their oncologists.

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). 

However, 30-40 percent of CML patients resist imatinib.  Nilotinib and dasatinib work for about 40-50 percent of those patients.

"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," said Jorge Cortes, M.D., professor and deputy chair, in The University of Texas MD Anderson Cancer Center Department of Leukemia.

Cortes led the clinical trials for all three drugs.He and other Leukemia Department faculty also led many of the clinical trials for the three previously approved CML therapies.

"It's important to have as many therapies against cancer as we can, because rarely does one drug or combination succeed for all patients," Cortes said. 

"These new drugs cover different gaps in treatment, so they can serve our patients in different ways," Cortes said. "We hope to have effective treatment options for all of them."



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Ponatinib (Iclusig)

Ponatinib, developed by ARIAD Pharmaceuticals, 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), accelerated phase and blast phase, the most heavily mutated and hard-to-treat late stage of the disease.

Ponatinib is the only tyrosine kinase inhibitor that's effective against T315I mutant disease.

Bosutinib (Bosulif)

Approved by the FDA in September, bosutinib is a second-generation tyrosine kinase inhibitor that works against many BCR-ABL mutations that cause resistance. An important exception is the T315I mutation, which only ponatinib attacks directly
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"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.
 
"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.
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Known commercially as Synribo, this drug is marketed by Teva Pharmaceuticals.  Clinical trials combining omacetaxine and tyrosine kinase inhibitors are planned.

Challenges: Individualizing therapy; eradicating disease

"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.

Doing that will require development of way to conclusively show that the disease is completely gone and drugs or combinations that achieve eradication.