Background: BCR-ABL kinase domain mutations frequently cause tyrosine kinase inhibitor(TKI)failure in chronic myeloid leukemia(CML).Ponatinib,a potent oral pan-BCR-ABL TKI,has shown preclinical activity against all single mutants tested,including T315I.The impact of baseline(BL)mutations on response to ponatinib(45 mg once daily)and end of treatment(EOT)mutations in pts discontinuing treatment were evaluated in the phase Ⅱ PACE trial.Methods: Heavily pretreated chronic phase(CP)CML pts(93%received ≥2 prior TKIs,60%≥3)resistant or intolerant to dasatinib or nilotinib(N=203)or with T315I confirmed at BL(N=64)were enrolled.The primary endpt was major cytogenetic response(MCyR).Min follow up at analysis(9 Nov 2012)was 12 mos(median 15 [0.1-25]).Sanger sequencing was done at one central laboratory.Results: At BL,no mutations were detected in 51%of pts,1 mutation in 39%,and ≥2 mutations in 10%; 26 unique mutations were observed.Responses were observed regardless of BL mutation status.MCyR rates were: 56%overall,49%in pts with no mutations,64%1 mutation,62%≥2 mutations; 57%in pts with mutation(s)other than T315I,74%T315I only,57%T315I + other mutation(s).Responses were seen against each of the 15 mutations present in >1 pt at BL,including T315I,E255V,F359V,Y253H.99 pts discontinued,56 had EOT mutations assessed.5 pts lost a mutation,46 had no change,5 gained mutations(Table).11 pts lost MCyR(none with T315I); of the 6 discontinuing,4 had EOT mutations assessed and no changes from BL were seen.Conclusions: Responses to ponatinib were observed regardless of BL mutation status.No single mutation conferring resistance to ponatinib in CP-CML has been observed to date.Data with a minimum follow up of 18 mos,including pts with advanced disease,will be presented.