CML – a model disease

Chronic myeloid leukemia represents a model for cancer treatment and monitoring since its unique pathogenesis has been discovered.

 

The introduction of tyrosine kinase inhibitors as standard treatment of chronic myeloid leukemia was paralleled by the establishment of molecular diagnostics to routinely assess the activity of disease. The quantitative measurement of the BCR-ABL oncogene levels allows the exact determination of the individual treatment response, which correlates with prognosis and makes chronic myeloid leukemia a disease that is manageable like few others. PCR diagnostics can be performed from blood samples and surpass the sensitivity of conventional cytogenetics, which is of particular importance since the majority of patients today achieve very deep responses. In case of resistance, the detection of BCR-ABL mutations has become the major tool to guide second-line tyrosine kinase inhibitor treatment.

History of BCR-ABL monitoring

Since the year 2000 global harmonization approaches have been performed in order to generate comparable molecular results.

 

Comparability of molecular results is highly heterogeneous since multiple platforms, protocols and procedures are currently used by different laboratories. The IRIS trial was the first global multicenter study aiming to follow-up patients not only by conventional cytogenetics, but also by molecular diagnostics from peripheral blood. Therefore, the main three monitoring laboratories (Adelaide, Australia; London, UK and Seattle, USA) shared samples from 30 patients at initial diagnosis and performed qRT-PCR. In order to be able to compare results from different laboratories around the world, the median BCR-ABL expression level of these samples was determined at each site and a conversion factor was derived to transform this median to a 100% level, which from there on has been considered as the standardized IRIS baseline.

In 2006, an expert panel agreed on continuing to use this baseline as an anchor from which the definition of a MMR as a 3-log reduction was derived. From then on, a worldwide harmonization approach was conducted starting from the Australian laboratory in Adelaide by performing control rounds using spiked cell line dilutions and patient leukocytes. Furthermore, the hereby standardized laboratories took the role of reference laboratories for certain regions, for example the Mannheim laboratory in a European approach with extension to more than 60 laboratories in 28 European countries. The aim of these sample exchanges is the calculation and validation of conversion factors, which can be used to multiply local BCR-ABL expression results and end up with BCR-ABL expression results according to the International Scale (BCR-ABLIS). This approach has shown to be a valuable tool to enable different laboratories to speak the same language.

2014 Institute for Hematology and Oncology. All rights reserved.