Most patients with chronic myeloid leukemia (CML) have a normal life expectancy thanks to dramatic improvements in treatments and outcomes over the past few decades, but new treatment approaches are needed for the subset who fail to respond or who develop resistance to existing treatments, according to Jorge Cortes, MD, director of the Georgia Cancer Center, Augusta.
Several novel tyrosine kinase inhibitors (TKIs) and combination therapies show promise in early studies, he said at the Society of Hematologic Oncology virtual meeting.
Asciminib
The allosteric inhibitor asciminib (ABL-001), for example, has completed phase 1/2 trials evaluating its use as a single agent and in combination with other therapies in the first-line setting, and a pivotal phase 3 study comparing it with bosutinib in the third-line setting is underway, Dr. Cortes said.
The rate of major cytogenetic response (MCyr) to asciminib in heavily pretreated patients in a phase 1/2 study published the New England Journal of Medicine was “very good” at 77%.
“And almost half [48%] of the patients had a major molecular response by 12 months,” he said, noting that even after excluding those who had a prior response but were enrolled because they couldn’t tolerate prior treatments, the MCyr and major molecular response (MMR) rates were 60% and 36%, respectively.
Asciminib also showed activity in patients with T315I mutations: The MCyr rate was 55% and the MMR rate at 12 months was 24%.
“Now, it is important to recognize that the doses that are required for inhibition – for getting these responses in [patients with] T315I – are higher than we need for the patients that do not have T315I, so it needs higher concentrations in vitro and it needs higher doses in vivo,” he said.
Also of note, the response rates were good both in those with two or fewer prior lines of therapy and in those with three or more (12-month MMR rates were 47% and 34%, respectively). For the latter, that’s “a very good rate, even though we’re only talking about 12 months of therapy,” Dr. Cortes said.
“And even in the patients who had been resistant or intolerant to ponatinib, 40% achieved a major molecular response, so very good results regardless of the number or type of tyrosine kinase inhibitors the patient had received, ” he added. The numbers in the group with T315I mutations are small, so further exploration is needed in subsequent studies, he noted.
The emergence of resistance is a concern with asciminib, but in a xenograft model, combining it with nilotinib appeared to prevent resistance. Therefore, the combination of asciminib and various TKIs has been explored in the clinic.
In a phase 1 study of asciminib and imatinib presented by Dr. Cortes at the European Hematology Association meeting in 2019, the complete cytogenetic response and MMR rates at 48 weeks were 50% and 42%, respectively.
“Now, this is a different type of population – perhaps a little more heavily pretreated than the ones who received single-agent asciminib, but it does show the potential for synergy, and importantly it was not associated with increased toxicity,” he said.