The emergence of a BCR-ABL kinase domain mutation during dasatinib therapy, particularly T315I, is a significant concern that requires careful consideration of clinical management. The median time between dasatinib treatment initiation and T315I mutation detection in our study was 7.4 months (range, 3.5-12.3 months), which was similar to the 9.1 months reported in a previous retrospective study by Nicolini et al. .
Soverini et al. retrospectively analyzed Ph + ALL patients treated with dasatinib by cloning the BCR-ABL kinase domain in a bacterial vector and sequencing 200 independent clones per sample. Notably, T315I was detected at diagnosis in two of six patients who relapsed . Although a T315I mutation could exist prior to dasatinib treatment, evidence from both clinical trials  and mouse models  indicates that in some cases it is newly acquired as a result of selective pressures during treatment. If a resistant T315I clone was present prior to dasatinib treatment, it would likely expand under selective pressures, and its prevention likely requires a novel agent targeting T315I leukemia. However, if a resistant T315I clone was newly acquired during proliferation due to insufficiency of dasatinib therapy, it may be possible to prevent acquired genetic tyrosine kinase mutations by an increased exposure of dasatinib.
An effective transient dasatinib level of 100 nM (approximately 50 ng/mL) is sufficient to inhibit the in vitro proliferation of most cell lines expressing imatinib-resistant BCR-ABL mutations, with the exception of T315I . In vivo, the effective transient dasatinib level might represent a concentration sufficient to inhibit the proliferation of primary ALL cells prior to the emergence of T315I. Our data suggest that a plasma dasatinib concentration that inhibits proliferation of Ph + cells and induces apoptosis might inhibit the emergence of BCR-ABL mutations, including T315I, when a resistant T315I clone is not present prior to dasatinib treatment.
In conclusion, lower plasma concentrations of dasatinib were detected among Ph + ALL patients with T315I compared to those without the mutation. These data suggest that sufficient exposure of dasatinib may prohibit clonal evolution by adequately inhibiting BCR-ABL kinase. Future prospective studies with larger sample sizes of Ph + ALL patients are warranted to confirm these results.