Chronic myeloid leukemia - A minimalistic view of post-therapeutic monitoring

As new technology emerges, so paradigms dictating standards of care in MRD testing in CML evolve (Figure 2). Based on the currently published data, the following key points emerge. 1) There are two scenarios in which MRD testing is appropriate in CML: following SCT, to allow for early detection of relapse, and following IFN-α, to gauge response. 2) There is a high concordance between peripheral blood and bone marrow testing, indicating that the less-invasive former procedure may suffice in monitoring MRD. 3) A single qualitative (and probably also quantitative) positive RT-PCR result is not predictive of relapse in an individual patient. 4) Most patients are qualitatively RT-PCR positive in the first 6 months following SCT, and this is not of consequence. 5) Patients who are RT-PCR positive after 6 months post-SCT are at high risk of relapse. 6) In a relapsing patient, RT-PCR positivity precedes cytogenetic and hematological relapse by several months. 7) Qualitative RT-PCR is of no value in patients being treated with IFN-α. 8) For both SCT and IFN-α, using quantitative RT-PCR, low or falling levels correlate with continued remission. 9) For both SCT and IFN-α, using quantitative RT-PCR, high or rising levels predict relapse. 10) RT-PCR relapse may be reasonably defined as a 10-fold or greater increase in the expression of BCR-ABL, determined by a minimum of three consecutive quantitative PCR analyses. 11) Notwithstanding the different technologies and therapeutic contexts, it appears that the critical level above or below which outcome differs is ∼0.02%, which is of the order of 10-4, and which, interestingly, seems similar to that for other targets in other leukemias and lymphomas. 12) Since there are, as yet, no large, prospective (but keenly anticipated) RQ-PCR studies evaluating outcome, it is too soon to propose guidelines based on this technology. 13) Although based on older technology, the EICML frequency of testing recommendations that have been presented are currently appropriate to follow. However, the key question still remains: can a measured threshold be defined, above which the majority of patients are destined to relapse, and below which the majority of patients can be expected to remain in remission? Although the figure of ∼10-4 appears to prevail, the answer is likely no, given that there is probably a continuum of measurements, with the chances of relapse dictated by other, not currently measured, biological factors, such as PR1-specific T cells. Moreover, we cannot definitively determine this until we have standardized the following: technology, timing of assay, and units of measurement. As with any laboratory test used in clinical medicine, we, as molecular pathology practitioners, need to be certain that we offer an assay that is standardized, reproducible, and reliable. Rigorous and regular quality assurance programs are mandatory. Of concern, in the context of both initial diagnosis and monitoring, unacceptable interlaboratory variability was evident. In the survey of diagnostic laboratories, using uniform analytes (plasmids and dilutions of a cell line) a rather alarmingly high false positive rate (10% and 6% for the two different substrates, respectively) emerged. In addition to having to grapple with profound issues pertinent to current real time technology, there are always alternative emerging technologies. These include the use of manifold supports to capture mRNA directly from cell lysates, measuring the fusion transcript in plasma, and in situ amplification and laser scanning cytometry in individual cells. In summary, the kinetics of change of the size of the BCR-ABL clone is probably the major determinant in predicting outcome in CML post-therapy, in the context of both SCT and therapy with IFN-α, indicating that serial testing is mandatory to allow for rational therapeutic intervention. However, dogmatic guidelines are likely to become redundant, as technology, therapy, and our understanding of the biology of CML, evolves. Copyright © American Society for Investigative Pathology and the Association for Molecular Pathology.