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Monitoring Therapy in Chronic Myeloid Leukemia

Posted Aug 24 2008 1:49pm
ANNOUNCER: Treatment of chronic myeloid leukemia begins with bringing blood counts back to normal.

BRIAN DRUKER, MD: When a person is diagnosed with CML, they often will have as many as one trillion leukemia cells. Their white count is 5 to 50 times the upper limit of normal. If we can lower their blood counts to normal, we say that that's a complete hematologic response.

ANNOUNCER: Several drugs can normalize blood counts, but that doesn't mean the disease is under control. Doctors also try to reverse the underlying disease process. In order to monitor a patient's progress, doctors must be able to determine the percentage of white blood cells containing the underlying genetic abnormality.

MOSHE TALPAZ, MD: This disease has a hallmark, which is the presence of an abnormal chromosome also known as the Philadelphia chromosome. What happens in this chromosome abnormality is a phenomenon that we call translocation, a transition of a piece of a chromosome from chromosome 9 to chromosome 22 and from chromosome 22 to chromosome 9. And, as a consequence, if we look at the chromosomes under the microscope, we see particularly a deletion in the long arm of one of chromosome 22.

ANNOUNCER: Using a microscope to count white blood cells with the Philadelphia chromosome is called cytogenetic testing.

STEPHEN O'BRIEN, MBChB, PhD: A cytogenetic test is almost always done in a sample of bone marrow. So this is usually taken through a needle from the back of the pelvis, 1 or 2 milliliters, like a teaspoon full of marrow, is taken, put into a test tube, sent off to the lab and the cells are then cultured or grown. And, as they divide, you can see all the chromosomes in those cells and we're looking for this very small, this minute chromosome 22: the Philadelphia chromosome.

ANNOUNCER: It's not a very sensitive technique, because the standard sample is not very large.

NEIL SHAH, MD: One of the limitations of standard cytogenetic testing is we're only looking at twenty cells. And, so, really, to register a positive, you have to have at least 1 out of 20, or 5 percent, of the cells having the abnormal translocation. We know that patients start with an enormous burden of leukemic cells and less than 5 percent remaining could still mean a substantial number of cells in the body harboring this translocation.

ANNOUNCER: A more sensitive technique of identifying white blood cells with the Philadelphia chromosome is called fish, or fluorescence in situ hybridization.

NEIL SHAH, MD: This method allows a cytogeneticist to rapidly assess 500 cells for the presence of the translocation and if 1 is positive out of the 500, obviously that's a much greater sensitivity of this test than 1 out of 20 with standard cytogenetics.

ANNOUNCER: And if testing by fish reveals no Philadelphia chromosomes, doctors order even more sensitive testing.

NEIL SHAH, MD: So if patients become negative for evidence of this translocation by the more sensitive FISH analysis, we typically will use something called polymerase chain reaction or PCR to evaluate for disease burden that way. And this can be a very quantitative test and can detect down to a level of about one in a million cells.

STEPHEN O'BRIEN, MBChB, PhD: Now, even with that test, if you are PCR negative, it doesn't necessarily mean there's absolutely no disease there. It's, if you like, using a bigger and bigger telescope to see a smaller and smaller object. So it's a question of sensitivity rather than having an absolute test which will always show that the leukemia's gone.

ANNOUNCER: What if repeated PCR tests show no disease? Will there ever be zero cells with the Philadelphia chromosome? Will that person who has become PCR negative be cured?

STEPHEN O'BRIEN, MBChB, PhD: Traditionally, with most of the leukemias, we don't start to consider that someone's been cured unless they've been free of their disease for at least five years, and CML is no exception to that. So I am very cautious with interpreting what those PCR negative results mean. For most, of course, it's excellent news for the patient. And if you look at the survival curves, for example, in patients who've become PCR negative, they're extremely good. Then one cannot yet stamp "cure" on the case notes of those individuals until that situation remains for three, four or five years, perhaps.

ANNOUNCER: Doctors not only monitor a patient's response to medication. They also monitor the rate of that response. The rate of response may predict how long a patient will remain in remission.

JOHN GOLDMAN, DM: The more rapid the response of an individual patient, the deeper the response, the better the response and the longer it will last. So in general terms it is better to respond quickly than slowly.

ANNOUNCER: New laboratory techniques allow doctors to monitor CML with great precision. When monitoring the course of the disease so carefully, treatments can be changed and adjusted effectively, helping to minimize the impact of CML on patients' lives.

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