Location, number of BCR–ABL kinase domain mutations predict CML outcomes
medwireNews: The location and number of mutations in the kinase domain of the BCR–ABL oncogene can predict outcomes in patients with chronic myeloid leukaemia (CML), with P-loop, T315I and compound mutations conferring a worse prognosis, research suggests.
BCR–ABL kinase domain mutations (KDMs), irrespective of the location within the kinase domain, were significantly associated with CML disease progression, with 12 (46%) of 26 patients with KDMs progressing to the accelerated or blast phase compared with 57 (20%) of 279 of those without mutations.
Writing in the International Journal of Hematology, the researchers note that the specific region of the kinase domain that carries a mutation largely predicts progression-free survival (PFS) and overall survival (OS) in CML.
Median OS from time of diagnosis in patients with BCR–ABL kinase domain mutations (KDMs) was 22 months in those with P-loop (n=3) mutations, 109 months in those with T315I mutations (n=13) and not reached in those with non-P-loop mutations (n=10). When measured from the time that mutations were detected, the median OS was 5.4 months in individuals with P-loop mutations versus not reached in those with T315I and non-P-loop mutations.
Similarly, the median PFS from the time of diagnosis varied according to mutation location, at 10 months, 34 months and not reached in the P-loop, T315I and non-P-loop cohorts, respectively.
Kendra Sweet (H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA) and colleagues found that participants with double/compound mutations (regardless of location; n=7) had a median OS of 109 months, whereas this endpoint was not reached in those with single mutations (n=26).
PFS was significantly shorter in patients with double/compound mutations than in the single mutation group (10 months vs not reached).
Of the six individuals with double/compound mutations for whom cytogenetic data from time of diagnosis were available, five had additional chromosomal aberrations, leading the authors to speculate that genetic instability may be a possible aetiology for the development of KDMs.
Sweet and co-workers explain that the most common cause of resistance to tyrosine kinase inhibitors (TKI) is KDM development, and add that “[i]t remains of upmost importance to further delineate the mechanisms of mutation development to circumvent their resistance to currently available therapies.”
They conclude: “Whether the mutations themselves are the sole cause of resistance or whether it is their role as a surrogate for genetic instability is debatable; what remains certain is the need for improved treatment options to evade the complex mechanisms of TKI resistance.”
medwireNews (www.medwirenews.com) is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2014
By Shreeya Nanda, Senior medwireNews Reporter