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GE-based biomarkers in CML
rant self-renewal properties, broad resistance to cytotoxic therapies, and eventual patient demise from bone mar- row failure.2 The arrival of TKI at the turn of the century resulted in remarkable responses, such that most individ- uals treated in chronic phase (CP) CML can expect to achieve near-normal life expectancies.3 Nevertheless, CML-related deaths are still reported, mainly due to resistance and progression to BC, especially in the first few years of treatment.4
Current treatment aims and features of an ideal biomarker
Current therapeutic aims are directed at achieving suf- ficiently deep molecular responses that the risks of BC transformation are effectively negligible and, in the longer-term, increasing the rates of treatment-free remis- sion.5-7 Clinical guidelines toward achieving deep molecu- lar responses have been reviewed elsewhere,8 and at their core, prescribe the measurement of BCR-ABL1 transcript levels using the International Scale (IS) every 3 months as a readout of the depth of the response to TKI. In turn, the depth of TKI response serves as a critical biomarker guid- ing patient management and prognostication (Figure 1).
Given current treatment goals, an ideal biomarker would accurately predict patients who will achieve a deep molecular response with first-line TKI, or require a switch to alternative therapy, and, among those who
achieve a deep molecular response, those who will be able to stop TKI successfully (Figure 1). The biomarker would be informative from the time of diagnosis and prior to TKI initiation, since this would enable early strat- ification of patients for therapy with a first-generation versus a second/third-generation TKI, allosteric BCR- ABL1 inhibitor, a clinical trial, or preparation for allogene- ic transplantation. Additionally, among patients who meet the criteria for stopping TKI therapy, the ideal bio- marker would identify additional therapies that would enhance treatment-free remissions. Finally, gene expres- sion (GE)-based biomarkers should be clinically robust, and widely available among centers and regions in both low and high Human Development Index countries.9
Why gene expression-based biomarkers?
Contributions from genetic and epigenetic mediators to TKI resistance and BC transformation are well document- ed,10-14 and it is axiomatic that genetic or epigenetic factors mediating these outcomes will contribute to a cell’s GE signature. Accordingly, GE signatures offer a molecular profile that integrates risk factors encoded by both muta- tions and epigenetic states. However, faithfully extracting and interpreting GE-based information in clinical settings is challenging. Barriers to adoption include technical lim- itations, logistical factors, as well as differences in study design and data analysis, and are described below.
Figure 1. Features of an ideal chronic myeloid leukemia biomarker. Curves indicate changes in BCR-ABL1 transcript levels, meausred using the International Scale (BCR-ABL1IS), following initation of tyrosine kinase inhibitor (TKI) therapy in patients with chronic phase (CP) chronic myeloid leukemia (CML). The corresponding molecular response (MR) value is provided next to the BCR-ABLIS value. Green, orange, and red curves are representative of patients in European LeukemiaNet 2020 ‘optimal’, ‘warning’, and ‘failure’ cateogories respectively. Major (MMR) and deep (DMR) molecular remissions are defined as 0.1% (MR 3) and 0.01% (MR4) BCR- ABLIS, respectively. Green, orange, and yellow bullet points indicate guidelines for each category of response. Gray boxes describe predictive capabilities of an ideal biomarker. HCT: hematopoietic stem cell transplant.
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