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From OncoLog, March 2013, Vol. 58, No. 3

New Drugs Increase Treatment Options for Patients with Imatinib-Resistant Chronic Myeloid Leukemia

By Zach Bohannan

Photo: Dr. Jorge Cortes
“To completely cure CML, we need to develop other therapeutic options and better testing for residual disease.”
– Dr. Jorge Cortes

In the past year, several new targeted drugs have been approved as second-line treatments for imatinib-resistant chronic myeloid leukemia (CML). These drugs include the second-generation tyrosine kinase inhibitor bosutinib and the third-generation tyrosine kinase inhibitor ponatinib, which may change the standard of care for CML.

CML treatment

CML is caused by the BCR-ABL fusion protein, a result of the Philadelphia chromosomal translocation. The prevalence of this protein makes CML ideal for treatment using targeted therapies. For many years now, imatinib, one of the first and most successful targeted antineoplastic agents, has been the first-line treatment for CML. “Most CML patients are diagnosed in what we call the chronic phase, which does not carry any recognizable drug-resistant mutations in BCR-ABL, so imatinib usually works very well at first,” said Jorge Cortes, M.D., a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.

The main goal of CML treatment is a complete cytogenetic response, meaning an absence of detectable Philadelphia translocations in the bone marrow. Many patients treated with imatinib have complete responses, but the subset of patients who do not are then moved to a second-line treatment. Thus, there is interest in developing second-line therapies for imatinib-resistant CML, and several drugs are currently under investigation or have recently been approved by the U.S. Food and Drug Administration for this purpose.

Bosutinib

Because ABL is a tyrosine kinase, most candidates for second-line CML treatment are tyrosine kinase inhibitors, which include dasatinib, bosutinib, and ponatinib. Bosutinib is among the most promising of these drugs. It is generally considered more potent than imatinib, and it can overcome several of the mutations that render CML resistant to imatinib.

The side effects of bosutinib are less severe—and most are less common—than those of some other tyrosine kinase inhibitors because bosutinib has less effect on the development of normal blood cells. For example, nilotinib, dasatinib, and several other tyrosine kinase inhibitors also inhibit growth factor receptors such as c-KIT and platelet-derived growth factor receptor. These receptors are important for the normal development of certain myeloid cell types. Bosutinib, however, does not affect these receptors as strongly as many other tyrosine kinase inhibitors and thus causes lower rates of neutropenia and thrombocytopenia than do nilotinib and dasatinib. Similarly, bosutinib causes lower rates of cardiotoxicity and pancreatitis than other second-generation tyrosine kinase inhibitors that are approved for treating imatinib-resistant CML. Conversely, some side effects might be more common with bosutinib.

This lack of significant side effects is one reason bosutinib is so attractive. However, Dr. Cortes said, “Although all tyrosine kinase inhibitors are very safe compared with most other chemotherapies, there can still be adverse events, and doctors should explain and discuss possible side effects with patients.” The primary side effect associated with bosutinib is diarrhea, which can occur in up to 80% of patients. However, this is usually minor and manageable.

Although bosutinib is superior to many other possible treatments for CML, it is not effective for all patients. For example, the T315I point mutation that can occur in the BCR-ABL gene renders CML resistant to imatinib, bosutinib, and most other tyrosine kinase inhibitors.

Ponatinib

Ponatinib is a very potent tyrosine kinase inhibitor that was specifically designed to treat the T315I point mutation while maintaining efficacy against all other known BCR-ABL permutations. Although ponatinib has many of the same side effects as other tyrosine kinase inhibitors, its ability to treat a previously intractable mutation makes it very promising. Because it is very effective against T315I-mutated BCR-ABL and in patients who have not responded to multiple other tyrosine kinase inhibitors, ponatinib was recently approved as a second-line treatment for CML patients.

New first-line therapy?

Current Treatments for Chronic Myeloid Leukemia

Imatinib: tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration as a first-line treatment for chronic myeloid leukemia (CML); often successful

Dasatinib: second-line tyrosine kinase inhibitor for some imatinib-resistant mutants

Bosutinib: second-line tyrosine kinase inhibitor for some imatinib-resistant mutants

Nilotinib: second-line tyrosine kinase inhibitor; slightly modified version of imatinib

Omacetaxine: alkaloid translation inhibitor for treating T315I-mutant CML

Ponatinib: second- or third-line tyrosine kinase inhibitor for treating T315I-mutant CML

Stem cell transplant: offers curative potential but with greater risks compared to therapy with tyrosine kinase inhibitors; seldom used as initial therapy but considered for patients who have not responded well to other therapies.

Because bosutinib shows so many benefits over other tyrosine kinase inhibitors, Dr. Cortes conducted some preliminary research into its use as a first-line therapy for CML. The initial research set out to determine whether bosutinib would offer a better cytogenetic and molecular response rate than imatinib. Dr. Cortes said, “We found that bosutinib and imatinib have similar cytogenetic response rates, so the primary endpoint of the study was inconclusive. However, in many of the other measures examined, such as the number of adverse events, bosutinib was superior.”

Another notable finding of that study was that bosutinib caused a complete cytogenetic response faster than imatinib did. Many studies have shown that speed of response has a major effect on long-term survival for CML patients. However, much more research, some of which is ongoing, will be needed before bosutinib can be recommended or officially adopted as the gold standard for CML treatment.

Ponatinib also is being studied as a first-line treatment. In an ongoing phase II clinical trial, Dr. Cortes and his colleagues are evaluating the drug’s effectiveness in patients with previously untreated chronic-phase CML. Laboratory data suggesting that it is difficult to induce ponatinib resistance makes ponatinib an attractive treatment option that could reduce the probability of acquiring resistance and thus improve the long-term outcome.

Future directions and challenges

CML patients require frequent monitoring to ensure their disease does not recur, and many patients remain in fear that their CML will return with a mutation that renders it resistant to currently available treatments. However, the recent approval of ponatinib and omacetaxine (a translation inhibitor also found to be active against CML) means that these mutations may prove to be less of a threat in the future.

One problem inherent in any CML treatment is that there is no way to determine whether a patient has been cured. Patients who achieve a complete cytogenetic response may undergo more sensitive molecular testing. A complete molecular response, defined as the absence of detectable BCR-ABL transcripts, is the best possible outcome a physician can assess for a CML patient, but there is still no way of knowing if the CML has been completely eliminated because even molecular tests have a limit of detection. “To completely cure CML, we need to develop other therapeutic options and better testing for residual disease,” Dr. Cortes said. “Right now, the best I can tell patients is, ‘I don’t see it (the leukemia),’ which is different from, ‘It’s gone.’” He believes that once a more powerful test is developed, tyrosine kinase inhibitors will probably need to be combined with another therapy to cure CML patients. The most likely therapy to combine with tyrosine kinase inhibition is stem cell transplantation.

However, until more powerful tests are developed, doctors will continue to treat CML as a chronic disease, which means that many patients will receive life-long targeted therapy, whether it is imatinib or sequential treatment with multiple tyrosine kinase inhibitors as the disease mutates.

For more information, contact Dr. Jorge Cortes at 713-794-5783.

Other articles in OncoLog, March 2013 issue:

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