Oncology - A Traffic Light Model for CML

Chronic Myeloid Leukemia (CML) is a fatal blood cancer if left untreated, caused by the [t(9;22)(q34;q11)] translocation that generates the BCR::ABL1 fusion gene, leading to uncontrolled cell growth. Tyrosine kinase inhibitors (TKIs) have transformed CML therapy, increasing the 5-year survival rate to over 80%. However, reliance on lifelong TKI therapy poses challenges such as organ toxicity, financial strain, non-adherence, and reduced quality of life.

The CML laboratory at SAHMRI, led by Professor Tim Hughes, pioneered the paradigm-shifting concept of Treatment-Free Remission (TFR), enabling patients with optimal responses to TKIs to discontinue therapy. This approach improves quality of life and reduces long-term side effects. However, approximately half of the patients attempting TKI cessation relapse and require therapy resumption, whilst only 25% of all CML patients ultimately maintain durable TFR and can be considered cured. Achieving this goal remains a priority in CML management, but the absence of clinically validated predictive models leaves physicians unable to reliably assess relapse risk.

Groundbreaking work by Dr. Ilaria Pagani and colleagues has advanced this field by identifying the persistence of specific BCR::ABL1-positive cell populations as a key predictor of relapse. Using a novel lineage-specific PCR approach, they demonstrated that patients with detectable BCR::ABL1-positive granulocytes face a 100% relapse risk, whereas those without do not relapse. This insight led to the development of a clinically applicable "traffic light" model, enabling stratification of patients based on relapse risk. Such a tool could guide personalized discontinuation strategies, transforming TFR from a trial-and-error process into a precision-medicine driven approach.

Collaboration with the SAGC represented a critical step forward. Utilising SAGC's advanced genomic capabilities, the CML team identified the genomic breakpoint of the BCR::ABL1 fusion in CML patients, a cornerstone for precision monitoring of minimal residual disease. This detailed genomic mapping, specific for every patient, enhances the sensitivity of the predictive assay, enabling accurate detection of residual leukemic cells and informing relapse risk after TKI discontinuation.

Through this partnership, predictive tools for TFR will be advanced, and a framework for global implementation developed, significantly improving the management and outcomes of CML patients worldwide. Additionally, the biomarker will be validated in the context of the first Australian CML registry, ensuring that the findings are grounded in real-world data, advancing the care of CML patients globally.