This work investigated patient-specific genomic BCR-ABL1 fusions as markers of measurable residual disease (MRD) in chronic myeloid leukaemia, with a focus on relevance to treatment-free remission (TFR) after achievement of deep molecular response (DMR) on tyrosine kinase inhibitor (TKI) therapy. DNA and mRNA BCR-ABL1 measurements by qPCR were compared in 2189 samples (129 patients) and by digital PCR in 1279 sample (62 patients). A high correlation was found at levels of disease above MR4, but there was a poor correlation for samples during DMR. A combination of DNA and RNA MRD measurements resulted in a better prediction of molecular relapse-free survival (MRFS) after TKI stop (n = 17) or scheduled interruption (n = 25). At 18 months after treatment cessation, patients with stopped or interrupted TKI therapy who were DNA negative/RNA negative during DMR maintenance (green group) had an MRFS of 80% and 100%, respectively, compared with those who were DNA positive/RNA negative (MRFS = 57% and 67%, respectively; yellow group) or DNA positive/RNA positive (MRFS = 20% for both cohorts; red group). Thus, we propose a “traffic light” stratification as a TFR predictor based on DNA and mRNA BCR-ABL1 measurements during DMR maintenance before TKI cessation.
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This work was funded by the Project Grants #15–31540A and #16–30186A from the Czech Health Research Council and by the European Treatment and Outcome study (EUTOS) for CML. The authors thank for the institutional support #00023736 (Institute of Hematology and Blood Transfusion) and #00064203 (University Hospital Motol) from Ministry of Health of the Czech Republic and the Czech Leukaemia Study Group for Life. This work was further supported by ERA-Net ERACoSysMed JTC-2 project “prediCt” (project number 031L0136A) to IR. We would like to thank to Dr. Milada Småstuen (Oslo Metropolitan University) for the consolations on statistical analysis. The authors are grateful to the patients for providing their samples for this study.
Conflict of interest
KMP, TE, NCPC and AH received support by Novartis through the European Treatment and Outcome Study (EUTOS) for CML. The authors declare that they have no conflict of interest.
This work was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committees of the Institute of Hematology and Blood Transfusion, Prague and Faculty Hospital Brno.
All patients provided written informed consent for the use of their samples for this research.
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Machova Polakova, K., Zizkova, H., Zuna, J. et al. Analysis of chronic myeloid leukaemia during deep molecular response by genomic PCR: a traffic light stratification model with impact on treatment-free remission. Leukemia 34, 2113–2124 (2020). https://doi.org/10.1038/s41375-020-0882-1