My favorite part of the abstract:---------------------------------------------------------------------------------------------------Of 32 evaluable CML CP pts, 30 (94%) had complete hematologic response (CHR), and 20 (63%) had major cytogenetic response (MCyR): 12 complete CyR (CCyR), 8 partial CyR (PCyR). Of 20 CML CP cytogenetic responders, 18 remain on treatment (mean duration 326 [range 142-599] days) without progression, 13 of whom had response confirmed with at least a second assessment (9 with MCyR =6 months), and 2 pts treated at 4 and 15 mg progressed after PCyR. Of 11 CML CP pts with T315I mutation, 11 (100%) had CHR, 9 (82%) had MCyR (8 CCyR). For 16 evaluable CML AP/BP or Ph+ ALL pts, 5 (31%) had major hematologic response (MHR), 3 (19%) had MCyR, 1 (6%) had minor CyR. Of 9 CML AP/BP or Ph+ ALL pts with T315I mutation, 3 (33%) had MHR, 2 (20%) had MCyR. Responses were also observed in heavily refractory pts with no mutations, and pts with other mutations, who are resistant to approved TKIs: 1 CCyR and 1 PCyR in 2 F317L pts who each failed imatinib, dasatinib, and nilotinib; a F359C pt who failed imatinib and nilotinib had CHR and CCyR. Overall, 13/60 (22%) Ph+ pts achieved major molecular response (MMR), including 12/42 (28%) CP pts, 6/15 (40%) with T315I mutation confirmed at baseline, 10/40 (25%) with starting doses =30 mg. 12 MMRs occurred in pts who were on treatment =4 months (4 MMRs =2 months). MMRs were also achieved in pts with M351T, F359C, F317L, M244V, G250E mutations, and 1 pt with no mutation. PD data demonstrate sustained inhibition of CrkL phosphorylation above 15 mg. Initial safety, PK/PD, and molecular response data suggest both dosage forms behave similarly. Importantly, at doses =30 mg, both result in trough concentrations >40 nM—the target concentration for inhibiting all BCR-ABL mutants, including T315I. Conclusion: The 45 mg dose (tablet form) was chosen as the recommended dose for further study. There is strong and continually increasing evidence of anti-leukemic activity in pts with T315I mutations, and pts resistant to second generation TKIs. Emerging MMR data demonstrate early responses in pts refractory to second line agents-
AI
