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Sensitive Assays for Leukemia Cells: Detection of Minimal Residual Disease

Leukemia is a disease characterized by the proliferation of white blood cells. Usually white blood cells divide only infrequently in a process controlled by a careful scheme of checks and balances. Very rarely, as the cell develops, something goes awry, and instead of maturing, a cell divides, and divides again. These prodigy cells divide, and on and on unchecked until at diagnosis the patient has on the order of 1012 leukemia cells.(1) That's

1,000,000,000,000 cells

Induction therapy reduces the burden of leukemia cells several orders of magnitude, but the patient may still have 1010 leukemia cells after induction.(2) That's

10,000,000,000 cells

Since the proliferation began with a single cell, the thought comes naturally to mind that each and every cell must be killed to eliminate the disease. Thus, therapy should continue as long as it takes to kill all these cells, and only as long as it takes to kill them. The doctors’ job would be easy if they could just peer at the patient and easily see each leukemia cell, or even if they had a simple test detect a single leukemia cell in the body.

This is not the case: not only can they not see one leukemia cell in the body, they cannot see 109 leukemia cells. Traditional methods can only detect leukemia cells if they make up 1% of the studied cell population, or 1 in 102 cells. There are over 1012 cells in the blood stream, so there must be 1010 cells for these traditional methods to detect any leukemia cells. This means that they cannot distinguish a patient with no cells from a patient with 109 cells. Therefore, after induction, treatment continues for all patients for two to three years irrespective of the real number of leukemia cells that they have. These treatment methods do work: most children are cured of leukemia. Current therapies for acute lymphoblastic leukemia are able to either eliminate all of these leukemia cells or at least to prevent them from growing back in about 75% of the leukemia patients.(3)

On the other hand, perhaps the reason the other 25% of the patients have a relapse of the disease is because not every cancer cell was destroyed? Perhaps better detection methods would find leukemia cells, cells that could not be detected by looking at a microscope slide? Perhaps they could discontinue treatment as soon as all the leukemia cells are gone?

Questions like these led many researchers to apply developing technologies to increase the sensitivity of leukemia cell assays. They have now found ways to measure one leukemia cell in a population of 103 cells (or better). They call the presence of leukemic cells that they find in these assays minimal residual disease, or MRD.

With MRD assays in hand, they have begun to monitor low levels of leukemia cells in patients during treatment and correlate these values with relapse rates. At this moment in time, there are many papers of small studies and a few large studies of the association of MRD and relapse. The hope is that they can use these new values as a prognostic factor to tailor treatment to levels of minimal residual disease.

The results so far are not as clear-cut as the researchers hoped for. Some of the reasons for this lie in the highly technical nature of the assays; some in the low numbers of children enrolled so far in the studies; some in the scientific problem of finding one method which will accurately measure MRD in each and every patient. The intent of following sections is to explain currently available MRD assays to parents of leukemia patients - to give them a better understanding both of the complexities and the drawbacks of the tests, and to review some of the results of the correlations of test results with relapse.

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