The ne plus ultra for deep BCR-ABL sequencing?

摘要

Soon after the introduction of the first tyrosine kinase inhibitor (TKI) imatinib 12. years ago, the first reports appeared of escape mechanisms of malignant clones bearing mutations in the BCR-ABL kinase domain of resistant patients. These mutations confer clinical resistance by introducing steric changes of the BCR-ABL protein and thereby hinder binding of BCR-ABL inhibitors. More than 100 different mutations have been described so far, all of them verified by conventional Sanger sequencing. Of these, only 7 mutated amino acid sites remained problematic for selecting a presumably effective "next-line" TKI. One of the open clinical questions is why some resistant patients with 1 or more of the 7 mutations do not respond even though rationally selecting treatment according to in vitro and in vivo experiences. European LeukemiaNet recommendations have been published for how best to identify BCR-ABL mutations in case of unsatisfying response or frank failure on TKI treatment.