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06-11-2014 | Oncology | Article

Location, number of BCR–ABL kinase domain mutations predict CML outcomes


Free abstract

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 ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2014

By Shreeya Nanda, Senior medwireNews Reporter

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