Dr Mauro on How Genetic Alterations Impact TKI Decisions in CML

"Mutation testing still remains important [for] choosing drugs, identifying resistance and understanding the complexity of resistance. Now, [it is] increasingly [utilized] to profile the background."

Michael J. Mauro, MD, a hematologist and director of the Myeloproliferative Neoplasms Program, Leukemia Service at Memorial Sloan Kettering Cancer Center, discussed the prevalence of BCR::ABL mutations in chronic myeloid leukemia (CML) and how they inform the use of TKIs for patients with this tumor type.

CML is recognized as the first and most classic example of a human cancer driven by a single genetic abnormality, known as the Philadelphia chromosome, Mauro began. This genetic change results in the creation of an abnormal protein called BCR::ABL, which functions as the driver of the cancer. Critically, BCR::ABL can exist in different forms and may undergo alteration or mutation that directly impacts the choice and efficacy of certain drugs, he noted.

Mauro explained that mutations may occur early on simply due to the nature of the disease, reflecting an unstable genetic landscape for untreated CML. However, the emergence of mutations is certainly observed with treatment, driven perhaps by selection or other factors. These resistance-driving mutations significantly, although not in the majority of cases, influence the choice of subsequent lines of therapy and push patients into scenarios of selective resistance.

A particularly challenging example discussed is the BCR::ABL1 T3151 mutation. This specific mutation affects drugs that bind the active site, namely ATP-competitive drugs. The presence of T3151 severely limits treatment choices because many conventional TKIs are rendered unable to bind effectively.

In recent years, experts have expanded the focus beyond just BCR::ABL mutations to recognize alterations outside of the primary target that are part of the genome and regulation of the myeloid compartment. For example, mutations seen in other blood diseases, such as acute myeloid leukemia and myeloproliferative disorders—specifically ASXL1—are relevant. Mauro noted that these external mutations may foster higher rates of mutations in the target of the drugs, BCR::ABL. This implies that if mutations exist outside of BCR::ABL, it may lead to more mutations within BCR::ABL itself, which presents challenges for the summation of treatment and other drugs.

Despite this complexity, Mauro suggested that this situation may also present an opportunity, potentially allowing for combinations of therapy to be used in genetically unstable or complex scenarios, particularly those considered higher risk. Ultimately, mutation testing remains crucial not only to choose drugs and identify resistance, but also to understand the complexity of resistance, and increasingly, to profile the overall background of the myeloid compartment.