clinical topic updates

Next-Generation Sequencing–Detectable Mutations in Chronic Myeloid Leukemia

by Gabriela S. Hobbs, MD


Although upfront testing with next-generation sequencing (NGS) for BCR-ABL1 kinase domain mutations is not currently standard, the science of mutational analysis in chronic myeloid leukemia (CML) is still unfolding. NGS may be particularly useful for identifying ABL1 mutations that may underlie suboptimal response or a loss of major molecular response.

Expert Commentary

Gabriela S. Hobbs, MD

Assistant Professor, Medicine
Harvard Medical School
Clinical Director, Leukemia
Massachusetts General Hospital
Boston, MA

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.

Gabriela S. Hobbs, MD

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. 


Feusier JE, Arunachalam S, Tashi T, et al. Large-scale identification of clonal hematopoiesis and mutations recurrent in blood cancers. Blood Cancer Discov. 2021;2(3):226-237. doi:10.1158/2643-3230.BCD-20-0094

Soverini S, Bavaro L, De Benedittis C, et al. Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study. Blood. 2020;135(8):534-541. doi:10.1182/blood.2019002969

Soverini S, De Benedittis C, Machova Polakova K, et al. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients. Oncotarget. 2016;7(16):21982-21990. doi:10.18632/oncotarget.8010

Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118(5):1208-1215. doi:10.1182/blood-2010-12-326405

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