For a long time we’ve known that in CML, although the core of the disease is BCR-ABL or the Philadelphia chromosome, we’ve known for decades, cytogenetic analysis, that some patients will have additional abnormalities. The clinical significance of those abnormalities, since more effective tyrosine kinase inhibitors have been developed, has been somewhat unclear. But in recent years, with improvements in sequencing technology, we’re now better able to dissect genomic complexity in CML...
For a long time we’ve known that in CML, although the core of the disease is BCR-ABL or the Philadelphia chromosome, we’ve known for decades, cytogenetic analysis, that some patients will have additional abnormalities. The clinical significance of those abnormalities, since more effective tyrosine kinase inhibitors have been developed, has been somewhat unclear. But in recent years, with improvements in sequencing technology, we’re now better able to dissect genomic complexity in CML. What’s been shown in a number of studies, including work pioneered by Sue Bradford and Naranie Shanmuganathan, who are colleagues of mine in Adelaide, we’ve seen that around 20% of patients have additional genomic abnormalities in the kind of genes that we see in MDS or AML, particularly ASXL1 is the gene most frequently mutated, and those patients seem to have inferior molecular responses to imatinib. There’s very limited evidence about whether escalating therapy in those patients and giving them a second generation tyrosine kinase inhibitor would overcome the adverse effect of those lesions. I think that’s an important question for which we’ll need more data. I know that a number of groups around the world, including the Germans in the TIGER study, which is using nilotinib, are looking at the same lesions. So I think quite soon we’ll have some idea of whether the prognostic effect differs according to the treatment that’s given. The other very interesting finding that came from Sue’s work is this class of abnormalities called Philadelphia-associated rearrangements. So we know that when BCR-ABL is formed, chromosome 9 and 22 break apart and they rejoin. But in some cases, with RNA sequencing it’s shown that there are additional deletions or inversions, sometimes involving adjacent genes on chromosome 9 or 22, or sometimes other genes on other chromosomes altogether. The formation of those abnormalities seems also to have a prognostic effect, which is quite interesting because we’ve always thought that it doesn’t really matter how you get your Philadelphia chromosome, that it always has the same effect. But these additional abnormalities do seem to be associated with a higher risk of, for instance, developing kinase domain mutations. So this work needs to be validated by other groups, but it’s giving us some insights into what goes on beyond perceiving BCR-ABL as the same in every patient.
