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Introduction to CML

Posted Aug 24 2008 1:49pm
ANNOUNCER: About 4,500 people are diagnosed with chronic myeloid leukemia or CML in the United States each year and over 20,000 people are estimated to be living with the disease. This cancer of the white blood cells usually occurs in adults over the age of 40.

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: The new gene is made up of two parts and is called BCR-ABL. BCR-ABL creates an abnormal enzyme or protein, a type called a tyrosine kinase. The abnormal kinase signals a biochemical pathway which leads 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 can constantly grow. It's as if a light switch got turned on and there's no turning it off.

ANNOUNCER: There are three phases of CML.

WILLIAM G. WIERDA, MD, PhD: The chronic phase is the more indolent phase of the disease where the cells are dividing and proliferating, but they're not aggressive. As time goes on, the disease can become more aggressive patients will have a higher number of immature cells and, oftentimes, will have new chromosome abnormalities, not just the Philadelphia chromosome abnormalities. And then patients can progress to the blast crisis that is more of an acute leukemia and a very aggressive type of disease, and is typically fatal.

ANNOUNCER: 85% of patients are in the chronic phase of CML when they are diagnosed. The standard treatment is imatinib, also known as gleevec. This targeted therapy works by binding to the 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, being imatinib, specifically fits into that binding site, and in doing so keeps the kinase, or the enzyme, from being active.

ANNOUNCER: Side effects of imatinib are generally mild.

NEIL SHAH, MD, PhD: Some of the more common side effects include some nausea. Some patients can develop bothersome muscle cramps.

WILLIAM G. WIERDA, MD, PhD: Imatinib can cause rash. It can cause elevation in the liver enzymes, inflammation in the liver. It can cause weight gain and edema, swelling and fluid retention.

ANNOUNCER: A risk of heart failure has been reported as a very rare side effect. It's very uncommon but occasionally a patient's side effects from imatinib are too severe and the patient may have to stop taking the drug. Most patients are managed well on gleevec. In fact, about 90% of patients treated with gleevec for 5 years maintain a good response. However, in a small percentage of patients, imatinib stops working after a period of time and relapse occurs.

WILLIAM G. WIERDA, MD, PhD: Relapse is where a patient is receiving a treatment (for example, imatinib) and, despite receiving what should be an active dose of the drug, the leukemia returns and grows where the white count will come up or patients will have cells identified in their bone marrow with a chromosome abnormality, the Philadelphia chromosome.

ANNOUNCER: Also, a small percentage of patients can become resistant to imatinib or it may prove ineffective from the start.

STEPEHN O'BRIEN, MBChB, PHD: You can define it as primary resistance, which means that you never get a good response in that patient and that can vary from simply getting a complete hematological response, not getting a normal blood count or having the drug for say, a year and not having a reduction in the chromosomes. On the other hand, you can have someone who responds well, and after many months or even a few years, suddenly their blood count won't remain normal on the same dose of drug and they have acquired resistance as a secondary phenomenon.

ANNOUNCER: One reason for resistance may be the proliferation of the abnormal BCR-ABL enzyme. This process is 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-ABL, 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: Most resistance is caused by new genetic errors called point mutations.

NEIL SHAH, MD, PhD: Point mutations, these subtle alterations in the binding region of BCR-ABL, the kinase domain where imatinib binds, comprise the majority of cases of resistance.

WILLIAM G. WIERDA, MD, PhD: The cells can mutate and change that protein so that the inhibitor of the target doesn't fit or doesn't work in the target any longer. So the cells will develop resistance where the imatinib no longer hits its target, no longer works on the specific target that it was intended to inhibit.

NEIL SHAH, MD, PhD: If you're one of those patients who cannot tolerate imatinib or, more commonly, whose disease no longer is responding to imatinib, you are in need of another type of therapy. And there is now an FDA-approved treatment with dasatinib and there are numerous other investigational tyrosine kinase inhibitors that are being evaluated in clinical trials.

ANNOUNCER: A stem cell transplant may be another option for some patients. So while imatinib remains an important therapy for most patients with CML, a variety of treatments remain available should a patient need additional options.

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