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INDEX
Monitoring CML
ANNOUNCER: Treatment of chronic myeloid leukemia is effective when it limits the unregulated replication of white blood cells. So counting blood cells with a standard blood test is usually the first lab work for a person with this disease. 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. In fighting CML, now most often done with a drug called Gleevec, doctors must determine the percentage of white blood cells containing an 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 the 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.
Cytogenetic TestingANNOUNCER: Using a microscope to count 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 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.
FishANNOUNCER: A more sensitive technique 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 up even MORE sensitive testing.
Polymerase Chain Reaction (PCR)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? Might there ever be zero cells with the Philadelphia chromosome? Might that person 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: The fear, of course, is relapse. And the problem is that patients can become resistant to drug therapy. Then, even a small number of leukemia cells can multiply quickly, returning the patient to ill health. Scientists understand a great deal about what happens with relapse, or resistance. When Gleevec works, as it usually does in patients in the chronic phase of CML, the drug interferes with an abnormal enzyme coded by a gene called BCR/ABL. BCR/ABL forms with the translocation creating the Philadelphia chromosome. MOSHE TALPAZ, MD: We have learned that the mechanisms of resistance are complex, but, in many cases, they involve the development of mutation within the BCR/ABL gene. What these mutations are doing, they interfere with the ability of Gleevec to fit in into the pocket of BCR/ABL where it's supposed to fit in and, as a result, it cannot inhibit the enzyme any more, and the enzyme is functioning as it functions before exposure to Gleevec. BRIAN DRUKER, MD: Because we have a clear understanding of what causes relapse, these mutations in the target of Gleevec, a number of laboratories and drug companies have been able to develop new drugs to shut down these mutated enzymes. And those are already proceeding to clinical trials. ANNOUNCER: Often doctors benefit from knowing exactly what mutation has led to resistance in a particular patient. That requires yet another type of test, which is increasingly becoming available.
Mutational TestsNEIL SHAH, MD: Mutational tests are something new to try to determine the cause of relapse in patients whose disease has initially responded to Gleevec and has subsequently failed to respond. And this is typically done at the time when the white blood cell count is no longer controlled. ANNOUNCER: The success doctors have had in treating CML has made obsolete some of the more primitive tests used to monitor the disease. Luckily, the good news in treatment success has been coupled with progress in the lab, so more and more sophisticated and sensitive tests are available to check on the health of people with CML. | |||||||||||||||||||||
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