A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.

Cortes, J E; Kim, D-W; Pinilla-Ibarz, J; le Coutre, P; Paquette, R; Chuah, C; Nicolini, F E; Apperley, J F; Khoury, H J; Talpaz, M; DiPersio, J; DeAngelo, D J; Abruzzese, E; Rea, D; Baccarani, M; Müller, M C; Gambacorti-Passerini, C; Wong, S; Lustgarten, S; Rivera, V M; Clackson, T; Turner, C D; Haluska, F G; Guilhot, F; Deininger, M W; Hochhaus, A; Hughes, T; Goldman, J M; Shah, N P; Kantarjian, H; PACE Investigators; Hughes, T; Schwarer, A; MacCallum, Peter; Seymour, J; Arthur, C; Mills, A; Knoops, L; Verhoef, G; Assouline, S; Lipton, J H; Forrest, D; Bence-Bruckler, I; Laneuville, P; Etienne, G; Rousselot, P; Coiteux, V; Rea, D; Nicolini, F E; Guilhot, F; Legros, L; Huguet- Rigal, F; Guerci-Bresler, A-P; le Coutre, P; Ottmann, O G; Hochhaus, A; Müller, M C; von Bubnoff, N; Baccarani, M; Rosti, G; Marasca, R; Gambacorti, C; Saglio, G; Abruzzese, E; Kim, D-W; Chuah, C; Cervantes, F; de Paz Arias, R; Sanchez-Guijo, F M; Hernandez-Boluda, J C; Ekblom, M; Stenke, L; Olsson-Strömberg, U; Ossenkoppele, G; Daenen, S M G J; Holyoake, T; Clark, R E; Apperley, J; O'Brien, S G; Byrne, J; Talpaz, M; Khoury, H J; Baer, M R; DeAngelo, D J; Wetzler, M; Altman, J K; Larson, R A; Schiffer, C A; Moore, J O; Goldberg, S; Cortes, J E; Midathada, M; Paquette, R; Emmons, R V B; Kropf, P L; Mauro, M; Berman, E; Roboz, G; DiPersio, J; Deininger, M W N; Oehler, V G; Pinilla-Ibarz, J; Baccarani, M; Cortes, J; Deininger, M; Goldman, J; Guilhot, F; Hochhaus, A; Hughes, T; Shah, N; Talpaz, M     «

Cortes, J E; Kim, D-W; Pinilla-Ibarz, J; le Coutre, P; Paquette, R; Chuah, C; Nicolini, F E; Apperley, J F; Khoury, H J; Talpaz, M; DiPersio, J; DeAngelo, D J; Abruzzese, E; Rea, D; Baccarani, M; Müller, M C; Gambacorti-Passerini, C; Wong, S; Lustgarten, S; Rivera, V M; Clackson, T; Turner, C D; Haluska, F G; Guilhot, F; Deininger, M W; Hochhaus, A; Hughes, T; Goldman, J M; Shah, N P; Kantarjian, H; PACE Investigators; Hughes, T; Schwarer, A; MacCallum, Peter; Seymour, J; Arthur, C; Mills, A; Kn...     »

Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL).We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).     «

Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL).We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side eff...     »