NGS is a topic that is currently very relevant and important. Contemporary guidelines in CML are helpful in determining when we should check for mutations and what to do about those mutations. Right now, we are looking for BCR-ABL1 (ABL1) kinase mutations only in very specific circumstances, but this is a rapidly evolving area of medicine and, thus, we can expect changes in how NGS will be used in CML in the future. ABL1 kinase domain mutations are rare, and, therefore, guidelines do not recommend checking for them up front in the standard patient with CML. Further, the initial selection of a specific tyrosine kinase inhibitor (TKI) is not generally based on the presence of these mutations. However, this area is evolving and there are unanswered questions (eg, how should very low–frequency mutations influence treatment selection?). 

It is appropriate to check for an ABL1 kinase mutation by NGS if a patient does not have an optimal response or has an initial response and then loses that response (eg, loss of major molecular response). If mutations are identified, a TKI should be selected that is sensitive to that mutation. For instance, the most feared mutation in the ABL1 kinase domain is the T315I mutation, as this indicates resistance to all TKIs except for ponatinib. There are other mutations that also guide treatment and are helpful in selecting treatment in the second line. Testing for ABL1 kinase mutations may take several weeks to get results and, thus, follow-up is important.

NGS is widely used, particularly in leukemia care, and most patients with leukemia will undergo NGS testing for recurrently mutated genes in hematologic malignancies at the time of diagnosis.  Some patients have other mutations, such as an ASXL1 mutations, and we do not truly know yet how certain mutations may be clinically significant or actionable. When it comes to defining accelerated-phase disease or blast-phase disease, the presence of additional cytogenetic abnormalities defines advanced disease; however, there is less research focused on how to integrate additional non–BCR-ABL mutations. In the future, additional mutations are likely to help us with upfront risk stratification and will likely help guide how we treat our patients.