Dr. Jaeseung Kim and colleagues have identified three subtypes of BCR-ABL1 acute lymphoblastic leukemia that respond very differently to targeted treatment.
There’s more to a rare type of leukemia than once thought, and new discoveries by OICR-supported researchers could bring about more personalized approaches to treat it.
For decades, scientists have known that two types of leukemia are driven by the ‘BCR-ABL1’ gene: chronic myelogenous leukemia (CML) and a more acute disease called BCR-ABL1 acute lymphoblastic leukemia (B-ALL). This knowledge helped generate a group of targeted drugs called tyrosine kinase inhibitors (TKIs) which have been very effective at treating CML, with most patients able to live a normal lifespan.
But patients with BCR-ABL1 B-ALL have had dramatically different outcomes with the same treatment. TKIs work very well for some and have little effect on others. About half of patients diagnosed with this type of leukemia die within five years of diagnosis, and there has been no clear reason why.
Dr. Jaeseung Kim and Dr. Faiyaz Notta have found a potential explanation and published it in a recent Nature Genetics paper.
Kim, Notta and colleagues used RNA sequencing to study samples of BCR-ABL1 B-ALL from 53 patients treated at University Health Network (UHN) in Toronto, hoping to understand how the disease’s molecular makeup impacted patients’ clinical outcomes. From that work, they identified three distinct subtypes of the disease that differed in their biology and response to treatment.
At the biological level, the subtypes are defined by how ‘mature’ blood cells were when they transformed into cancer, ranging from an early stage of maturation (“Early-Pro”) to mid stage (“Inter-Pro”) to late progenitor (“Late-Pro”). For patients, these subtypes translate to significantly different responses to TKIs. People with Early-Pro subtype had very poor outcomes, with high rates of relapse and a five-year overall survival rate of 33 per cent. Whereas people with Late-Pro subtype had markedly positive responses to treatment, with five year-overall survival at 73 per cent.
“This was traditionally thought of as a single disease,” says Kim, who started this research as a member of Dr. John McPherson’s lab at OICR and Dr. Notta’s lab at UHN and has since become a Laboratory Genetics and Genomics Fellow at Harvard Medical School. “Our study shows there are actually huge differences within this disease, and knowing which subtype a patient has could potentially influence how they are treated.”
If the findings from the study can be replicated and confirmed, Kim says they could one day be used to develop a classification tool that tells patients which subtype they have. Then, patients whose subtype has a poorer prognosis could be given more aggressive treatment earlier, giving them a better chance at fighting the disease. Findings from the study could also be used to develop drugs that specifically target the subtypes.
“This study addresses a longstanding question about this disease and how it responds to TKIs, and presents exciting new opportunities for how to treat it,” says Notta, an OICR Associate and Co-Lead of the PanCuRx Translational Research Initiative.
For Kim, one of the most encouraging aspects of the study is how effective treatment was for patients with the Late-Pro subtype.
“They had spectacular response,” he says. “If we can bring the other subtypes up to that same level of response, patients will be in a much better situation.”
