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Overcoming Treatment Resistant CML

Posted Aug 24 2008 1:49pm
ANNOUNCER: Most people with chronic myeloid leukemia, or CML, are benefiting from treatment with a targeted anti-cancer drug called imatinib. But resistance to imatinib sometimes occurs. It can fall into one of two broad categories.

STEPHEN NIMER, MD: Primary resistance is if you give a patient imatinib, or Gleevec, and from the very beginning, they don't have a very good response. And the second type, secondary or acquired resistance, is when a patient initially responds to Gleevec, but then over time they lose the responsiveness.

ANNOUNCER: To understand both types of resistance, we need to understand something of what goes wrong when a person develops CML.

GWEN NICHOLS, MD: What we think is the initial or the most important cause of CML is what we call a translocation, or a criss-crossing, of two pieces of genetic material, one on chromosome 9 and one on chromosome 22, that during the division of the cells, these two chromosomes criss-cross, break, and fuse to each other. And in doing so, they create a gene that wasn't there before.

ANNOUNCER: Made up of the two parts, the new gene is called BCR-ABL. BCR-ABL creates an abnormal protein, or enzyme, a type called a tyrosine kinase. Kinases signal in biochemical pathways, in this case, leading to the uncontrolled production of white blood cells.

ERIC FELDMAN, MD: It's what we call a signal transducer, a signal transduction protein, meaning that it signals to the cell to grow, and if it's constantly in the "on" phase, the cell constantly grows. It's as if a light switch got turned on and there's no turning it off.

ANNOUNCER: Imatinib, also known as Gleevec, works by binding to the aberrant BCR-ABL enzyme, at a particular site on the molecule.

GWEN NICHOLS, MD: Within the kinase, there is an energy center which is called the ATP binding site, and this is critical for the kinase's activity. The molecule, the imatinib, specifically fits into that binding site, and in doing so keeps the kinase, or the enzyme, from being active.

ANNOUNCER: One reason imatinib may be ineffective is a possible proliferation of the faulty BCR-ABL enzyme. This can happen in a process called gene amplification.

STEPHEN NIMER, MD: So, normally, in any given CML cell, there's only one gene of BCR-ABL. Sometimes the cell can, what we call amplify, the number of copies of this BCR-ABLE, and it can make twenty copies. And so, if there's twenty times as much BCR-ABL in the cell, then the imatinib may not be able to inhibit it completely, and so the cell can escape.

ANNOUNCER: This type of resistance may, in some cases, be overcome with an increase in the dose of medication.

STEPHEN NIMER, MD: In many of these circumstances, if you simply go up to a higher dose of imatinib, you can recapture the response.

ANNOUNCER: Researchers believe the most common reason for resistance to imatinib is something called a point mutation. It's a small genetic change in the BCR-ABL gene, leading to a small change in the ATP energy center of the BCR-ABL enzyme.

GWEN NICHOLS, MD: The most common mechanism leading to resistance with imatinib is that the cells are able to make mutations in the ABL kinase itself that change the ability of imatinib to be able to specifically bind into this energy center. And in doing so, they don't bind as securely or as well, and so they're less able to inhibit the enzyme.

ANNOUNCER: When doctors suspect point mutations may be responsible for resistance, they may ask patients to consider, or reconsider, a stem cell transplant.

STEPHEN NIMER, MD: And so the good news is that Gleevec is well-tolerated and that the patients have great responses, but at some point, if patients become resistant, you then have to figure out an alternative strategy. For some patients, the alternative strategy is to think about a bone marrow transplant or a stem cell transplant.

ANNOUNCER: But stem cell transplants are risky, and require a good tissue match. The age of the patient, other medical problems, or lack of a donor, may preclude this option. Another approach is to investigate participation in clinical trials testing new, targeted drug therapies.

STEPHEN NIMER, MD: First of all, patients who are in this situation need to make sure that they're seeing a doctor who is an expert in managing CML. There are a number of clinical trials that are available to patients who have acquired mutations and their doctors, hopefully, can direct them to a center that's doing that kind of research.

ANNOUNCER: One drug under study is called BMS354825, also known as dasatinib.

STEPHEN NIMER, MD: And this drug works in CML cells in two ways. One is it can inhibit BCR-ABL itself, but it also has properties of inhibiting other families of kinases other than BCR-ABL. And so, this drug has the ability to target two different pathways in the cell and, therefore, to kill cells that may be resistant to imatinib.

ANNOUNCER: The other drug is called AMN107.

ERIC FELDMAN, MD: The AMN107 drug is a much more powerful form of imatinib, if you will. It binds much more tightly to the binding site and has a much more powerful inhibitory effect against BCR-ABL.

ANNOUNCER: Another factor that may affect how well imatinib inhibits CML is the possible development of genetic mutations in the CML cell, mutations in addition to BCR-ABL. Some of these may contribute to the disease via cell-signaling pathways NOT involving the BCR-ABL enzyme.

GWEN NICHOLS, MD: Cells in the chronic phase of CML are completely dependent upon the BCR-ABL kinase for their growth. In these cells, imatinib is very effective at inhibiting the proliferation or the growth of the cells. If the cells are able to develop new mutations that have nothing to do with the BCR-ABL kinase, the kinase inhibitor imatinib is no longer able to control these cells. This kind of resistance is felt to be an acceleration of the CML and a different phase of the disease that will require different types of treatment.

ANNOUNCER: Doctors have found the effectiveness of medical therapies can also depend on how aggressive the disease is when it is first diagnosed.

GWEN NICHOLS, MD: Clearly, different people respond differently to imatinib, and when you come to the doctor's office, if you have very high white blood cell counts, a very large spleen, or what we consider a large, what we call bulk of disease, a large amount of CML cells in your body, it may take longer for the imatinib to work, or the imatinib may be less effective than in patients where the only abnormality that is found is a slightly elevated white blood cell count.

ANNOUNCER: It's too soon to tell how widespread the problem of resistance may become, for it was only in late 2002 that imatinib was approved for use as the first course of therapy in newly-diagnosed patients. So doctors are cautious when they talk with their patients about the future.

STEPHEN NIMER, MD: And so the message that at least I try to get out to patients is, yes, they're reading a lot about it; yes, they're hearing a lot about it; no doubt, it's going to become increasingly a problem over time. But, fortunately, in terms of the percentage of patients who actually become resistant in any given year, the number's very small.

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