Description:
While the vast majority of chronic phase CML patients achieve optimal responses with BCR::ABL1-directed tyrosine kinase inhibitors (TKIs), there remains a select group of patients who either experience resistance and/or disease progression despite TKI therapy. Strategies for improving outcomes in this challenging cohort need to be formulated and advances in technology, understanding of disease biology and therapeutics can further ongoing innovation in this area. This educational session will explore the recent developments in blast phase CML, including a focus on updates in therapeutics directed against this phase of disease. Addressing the mechanisms underpinning resistance, including kinase domain mutations, will also be reviewed. Lastly, we will discuss atypical CML, an orphan disease, which although shares a similar name has a completely different disease biology, treatment and management approach.

Dr Naranie Shanmuganathan will outline the key updates in disease definitions within recent guidelines affecting how clinicians classify the phases of CML, attempting to identify which patients have the highest transformation potential. Identification of a CML-like acute lymphoblastic leukaemia (ALL) phenotype may assist in differentiating Ph+ ALL from de novo lymphoid blast crisis CML which remains a challenge. Furthermore, technological advances with next generation sequencing have also aided in unmasking the complexity of the genomic landscape associated with disease progression which may offer future therapeutic targets. Lastly, novel strategies to treat blast phase CML will be explored and can offer an alternative approach to conventional treatment.

Associate Professor Simona Soverini will follow on with a discussion regarding the impact of kinase domain mutations in CML which still continues to be the best understood mechanism of resistance in CML. An unsatisfactory response to TKI therapy may indicate the presence of mutations in the BCR::ABL1 kinase domain. Associate Professor Soverini will explore the optimal timing for BCR::ABL1 kinase domain mutation testing with a detailed review of the available and developing technologies. She will also illustrate how the presence of a TKI-resistant mutation should trigger a change of therapy, and detection of specific mutations can help direct sequential TKI therapy to maximise response and minimize expansion of a resistant clone.

Finally, Associate Professor Massimo Breccia will explore updates to the diagnostic criteria based on the recent iteration of the WHO and the ICC. Next generation sequencing has also started to expose the genomic landscape associated with atypical CML, with a particular focus on SETBP1 and ETNK1 variants. While a consensus on prognostic stratification is yet to be agreed upon, the various factors that have been associated with prognostication will be discussed, including the Mayo clinic model. A summary of possible treatments will also be reviewed including the appropriateness of an allogeneic stem cell transplant even after the identification of actionable targets.