Regimens for relapsed or refractory Ph-positive ALL…Treatment options based on BCR-ABL1 mutation profile…Dasatinib…Contraindicated mutations...T315I/A, F317L/V/I/C, or V299L

DNA from 64 pts with newly diagnosed Ph+ ALL treated with hyper-CVAD plus a TKI....Of the 18 pts who relapsed...Clonal resistance mutations were detected at relapse in 9 pts (64% of sequenced samples): T315I in 6 pts, and F317I, V229L and V338G in 1 pt each (all in pts treated with dasatinib, except V338G in pt on imatinib).

Eight patients had primary resistance to dasatinib...All the five patients...who already had evidence of a T315I before the onset of dasatinib – at least by direct sequencing – failed to achieve any response….The T315I is usually observed in approximately 15% of Ph+ leukemia patients who are resistant to imatinib,13–15 but is likely to become the prevalent mutation in those who fail to benefit from second-line treatment with dasatinib or other novel inhibitors for which threonine 315 is a critical binding residue....In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317.