Chronic Myeloid Leukemia
Unmet Needs in Chronic Myeloid Leukemia and Insights From Next-Generation Studies
As reflected in data presented at the 63rd ASH Annual Meeting and Exposition, efforts are underway to refine current approaches to the management of chronic myeloid leukemia (CML) and to address unmet needs.
Following these proceedings, featured expert Elias Jabbour, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Jabbour’s clinical perspectives are presented here.
Professor of Medicine, Department of Leukemia
“I think that we must take advantage of the available technology to identify outliers and to develop biomarkers that can be used to tailor our therapy. We also need to learn how to improve our approach to BP-CML.”
We have several unmet needs in CML, and blast-phase CML (BP-CML) is one that I would like to highlight here. Despite the progress that we have made with chronic-phase CML (CP-CML), study after study has shown that the outcomes are generally poor once a patient has progressed to BP-CML. Therefore, we need to have a better understanding of this phase of CML, including more effective strategies for treatment.
CP-CML is characterized by the overproduction of mature differentiated cells. These cells are functional to a certain extent, but not fully. In BP-CML,, the cells are very immature, and there is a blockage of differentiation. At ASH 2021, Zhao and colleagues performed a meta-analysis of published CML transcriptomes and identified a small set of genes with consistently low expression (abstract 59). They reported that MS4A3 expression was low in resistant CML cells. Although this study is just a starting point, it illustrates where we need to go with our research. If we could restore MS4A3 expression, we might have a therapeutic effect whereby we restore the differentiation function and eventually help reduce the impact of BP-CML.
There is also an unmet need relating to the early stem cells that give rise to CML. These stem/progenitor cells are insensitive to tyrosine kinase inhibitors (TKIs), and residual CML persists in most patients with CP-CML who are on TKI therapy. Novel approaches to be investigated might include combination therapies that may target these early stem cells (eg, a TKI plus venetoclax or a TKI plus a hypomethylating agent). By doing so, we might prevent resistance. The dormant cells can then go into apoptosis, and, eventually, treatment-free remission rates can improve.
Early response remains of major prognostic value for long-term outcomes in CP-CML. Predicting which patient will have an early response with which therapy is another area of active research, and next-generation sequencing may have a role in the future. Using a technique called duplex sequencing, where you sequence both DNA brands, we have shown that you can identify certain mutations up front. I am not proposing that upfront sequencing should be performed for patients with CML right now. However, if you have a patient with a polymerase chain reaction of 0.1 going to 0.2 or 0.3, do you have a mutation? We do not know, and Sanger sequencing may not reveal it. Identifying the development of TKI resistance due to a kinase mutation is an appropriate use of deep sequencing. For now, I think that the message regarding sequencing is as follows: One should not intervene in a patient who is responding to therapy, but, in an individual who responded initially but is now having a suboptimal response, identifying the mutation may help you to determine the appropriate next steps.
In addition to kinase mutations, mutations in cancer-related genes other than ABL1 may explain variable responses to treatment. At ASH 2021, Zhang and colleagues presented data from China where they did deep targeted sequencing for cancer-related mutations on DNA samples from patients with CML who had failed prior imatinib therapy and/or second-generation TKI therapy (abstract 308). They found that ASXL1 mutations with a variant allele frequency of 17% or higher and PHF6 mutations were linked to poor responses to third-generation TKI therapy. Additionally, STAT5A and RUNX1 mutations, as well as high-risk additional chromosomal abnormalities, were also associated with worse outcomes in patients on third-generation TKI therapy.
So, trying to identify certain genomic cancer mutations that may be predictive is important work. Not all patients respond the same way, and having biomarkers is very useful for determining which therapies are appropriate. I think that we must take advantage of the available technology to identify outliers and to develop biomarkers that can be used to tailor our therapy. We also need to learn how to improve our approach to BP-CML.
Banjar H, Ranasinghe D, Brown F, et al. Modelling predictors of molecular response to frontline imatinib for patients with chronic myeloid leukaemia. PLoS One. 2017;12(1):e0168947. doi:10.1371/journal.pone.0168947
Karasu N, Akalin H, Gokce N, et al. Detection of mutations in CML patients resistant to tyrosine kinase inhibitor: imatinib mesylate therapy. Med Oncol. 2021;38(10):120. doi:10.1007/s12032-021-01571-1
Soverini S, Abruzzese E, Bocchia M, et al. Next-generation sequencing for BCR-ABL1 kinase domain mutation testing in patients with chronic myeloid leukemia: a position paper. J Hematol Oncol. 2019;12(1):131. doi:10.1186/s13045-019-0815-5
Zhang X, Li Z, Qin Y, Gale RP, Huang X, Jiang Q. Correlations between mutations in cancer-related genes, therapy responses and outcomes of the 3rd generation tyrosine kinase-inhibitor (TKI) in persons with chronic myeloid leukemia failing prior TKI-therapy [abstract 308]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.
Zhao H, Pomicter AD, Eiring AM, et al. MS4A3 promotes differentiation in chronic myeloid leukemia by enhancing common β chain cytokine receptor endocytosis [abstract 59]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.
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