EHA Education Session: CML in Blast Crisis – still a poorly understood, difficult to treat condition
Brian Huntly from the Cambridge Institute for medical Research, UK, was presenting about research in CML blast crisis in the CML Education Session at the EHA congress. CML in blast crisis still has a grim outlook. Life expectancy is still poor with 7-11 months, and transplant is required for long-term survival. About 10% of CML patients are still diagnosed in advanced or blast phase, and around 5-10% progress within first 10 years of Imatinib therapy due to persistence and resistance of CML stem cells, so in total around 20% of CML patients are somehow affected by blast crisis.
The biology of CML progression is still poorly understood. BCR-ABL itself seems to be genotoxic and is providing the environment for mutations. Mutational studies are still rare, many conducted with old-fashioned sequencing technologies on a small number of patients, rarely studies with genome sequencing. Collaborating mutations as highly heterogeneous. Potential drugs that ar currently in use are Sorafenib (RAF inhibitor in use in renal and hepatic cancer), PD0325901 (MEK inhibitor in use in lung cancer), GSK343-EZH2, I-BET (Myc inhibitor in use in AML, Myeloma) and Ruxolitinib (JAK1/2 inhibitor). Therefore, potential molecular targets for blast crisis are MYC, EZH2/PRC2, RAS-RAF-MEK-ERK, JAK-STAT which are being investigated.
In summary, CML progression is a rare but still catastrophic disorder which is poorly understood and very difficult to treat. Mouse models are in use to better understand the human disease and the mutational spectrum, and can inform both on biological mechanisms and development of therapies. Some drugs on the aforementioned targets are in early phase clinical testing. However, outlook is still poor so it is of key importance to prevent progression of CML into advanced phases.
-- Jan Geissler, 10 June 2016