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TKI Resistance and Compound BCR-ABL1 Kinase Domain Mutations in Leukemia

By: Anna Nowogrodzki
Posted: Monday, January 7, 2019

Compound BCR-ABL1 kinase domain mutants appear to be more common in chronic myeloid leukemia (CML) in accelerated or blastic phase and in acute lymphoblastic leukemia (ALL)—and not as common in CML in chronic phase, according to a new study based on next-generation sequencing screening. The researchers, led by Simona Soverini, PhD, a molecular biologist at the University of Bologna, Italy, also found one particular compound mutant that was consistently associated with ponatinib failure: T315I plus E255V. They presented their research findings at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 789). Findings were also published in the journal Blood.

“The prevalence of compound mutants has never been assessed in prospective studies,” the authors noted, “although in vitro data suggest that many of them may be challenging for all tyrosine kinase inhibitors (TKIs) including ponatinib.”

The study included 751 patients with Philadelphia chromosome–positive leukemia receiving TKI therapy. Of these patients, 664 had CML “with failure or warning response,” and 87 had ALL “with relapsed or refractory disease.” The researchers prospectively explored the results of routine next-generation sequencing–based BCR-ABL1 kinase domain mutation screening over a 3-year period.

Dr. Soverini and colleagues found that 10% of patients in the study (73) had compound mutations. A total of 4% of patients with CML in chronic phase had compound mutations. By contrast, 32% of patients with CML in accelerated or blastic phase, as well as 37% of patients with ALL, exhibited compound mutations. One particular compound mutant, T315I plus E255V, was consistently associated with ponatinib therapy failure in the study population.

Disclosure: The study authors’ disclosure information may be found at bloodjournal.org.



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