Problems with PCR analysis for detection of minimal residual disease

The major concern with PCR-based disease detection will always be the fear of false-positive results because of the ability of the technique to amplify even minute amounts of contaminating DNA. Unlike cell culture assays, it is not possible to determine whether cells detected by PCR are clonogenic (i.e. capable of division and causing relapse). Cells bearing a translocation may be committed progenitors incapable of further proliferation, or might have been sufficiently damaged by previous exposure to chemotherapy or radiotherapy

Months after ABMT

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Fig 6.11 Detection of relapse of CLL in a patient undergoing autologous bone marrow transplantation using PCR

In the samples before (pre) and after (post) purging of the patient's marrow, PCR positivity is clearly seen. Six months after ABMT no PCR-detectable signal is seen. However, 15, 27 and 32 months after the transplant PCR positivity is easily detected. These findings were confirmed clinically and using standard morphological examination of the patient's bone marrow.

Months after ABMT

-118 bp

Fig 6.11 Detection of relapse of CLL in a patient undergoing autologous bone marrow transplantation using PCR

In the samples before (pre) and after (post) purging of the patient's marrow, PCR positivity is clearly seen. Six months after ABMT no PCR-detectable signal is seen. However, 15, 27 and 32 months after the transplant PCR positivity is easily detected. These findings were confirmed clinically and using standard morphological examination of the patient's bone marrow.

to be already dead but will still be detectable by PCR analysis. A potential problem with the use of PCR of the BCL-2/IgH translocation is that this translocation may not be specific for lymphoma cells. Cells bearing the translocation have been detected in hyperplastic lymphoid tissue in healthy individuals with no evidence of lymphoma, and more recently have been shown to occur rarely in normal B cells.

Methodologies have been developed for the sensitive detection of MRD in lymphoma and leukemia that are applicable to many patients. The question that now remains to be answered is whether these techniques will have any clinical utility and will predict which patients will relapse. In NHL these studies are most advanced in patients with t(14;18). In these patients, conventional-dose chemotherapy does not appear to be capable of depleting PCR-detectable lymphoma cells, although lymphoma cells were detectable in PB in only half of the patients studied. Following ASCT, the persistence or reappearance of PCR-detectable lymphoma cells in the BM was associated with an increased likelihood of relapse. In lymphomas that do not express the t(14;18), it is not yet clear whether failure to detect MRD in PB and BM will predict which patients will relapse since other subtypes of lymphoma may relapse in nodal sites without detectable lymphoma cells in the circulation.

From the available data, there are clearly diseases in which the persistence of PCR-detectable disease following treatment predicts relapse and others in which it does not. The full relevance of these findings will become clearer as we understand more about the biology of the diseases and additional data are generated as part of ongoing major clinical trials.

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