A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias
J E Cortes, D-W Kim, J Pinilla-Ibarz, P le Coutre, R Paquette, C Chuah, F E Nicolini, J F Apperley, H J Khoury, M Talpaz, J DiPersio, D J DeAngelo, E Abruzzese, D Rea, M Baccarani, M C Müller, C Gambacorti-Passerini, S Wong, S Lustgarten, V M Rivera, T Clackson, C D Turner, F G Haluska, F Guilhot, M W Deininger, A Hochhaus, T Hughes, J M Goldman, N P Shah, H Kantarjian, PACE Investigators, T Hughes, A Schwarer, Peter MacCallum, J Seymour, C Arthur, A Mills, L Knoops, G Verhoef, S Assouline, J H Lipton, D Forrest, I Bence-Bruckler, P Laneuville, G Etienne, P Rousselot, V Coiteux, D Rea, F E Nicolini, F Guilhot, L Legros, F Huguet- Rigal, A-P Guerci-Bresler, P le Coutre, O G Ottmann, A Hochhaus, M C Müller, N von Bubnoff, M Baccarani, G Rosti, R Marasca, C Gambacorti, G Saglio, E Abruzzese, D-W Kim, C Chuah, F Cervantes, R de Paz Arias, F M Sanchez-Guijo, J C Hernandez-Boluda, M Ekblom, L Stenke, U Olsson-Strömberg, G Ossenkoppele, S M G J Daenen, T Holyoake, R E Clark, J Apperley, S G O'Brien, J Byrne, M Talpaz, H J Khoury, M R Baer, D J DeAngelo, M Wetzler, J K Altman, R A Larson, C A Schiffer, J O Moore, S Goldberg, J E Cortes, M Midathada, R Paquette, R V B Emmons, P L Kropf, M Mauro, E Berman, G Roboz, J DiPersio, M W N Deininger, V G Oehler, J Pinilla-Ibarz, M Baccarani, J Cortes, M Deininger, J Goldman, F Guilhot, A Hochhaus, T Hughes, N Shah, M Talpaz, J E Cortes, D-W Kim, J Pinilla-Ibarz, P le Coutre, R Paquette, C Chuah, F E Nicolini, J F Apperley, H J Khoury, M Talpaz, J DiPersio, D J DeAngelo, E Abruzzese, D Rea, M Baccarani, M C Müller, C Gambacorti-Passerini, S Wong, S Lustgarten, V M Rivera, T Clackson, C D Turner, F G Haluska, F Guilhot, M W Deininger, A Hochhaus, T Hughes, J M Goldman, N P Shah, H Kantarjian, PACE Investigators, T Hughes, A Schwarer, Peter MacCallum, J Seymour, C Arthur, A Mills, L Knoops, G Verhoef, S Assouline, J H Lipton, D Forrest, I Bence-Bruckler, P Laneuville, G Etienne, P Rousselot, V Coiteux, D Rea, F E Nicolini, F Guilhot, L Legros, F Huguet- Rigal, A-P Guerci-Bresler, P le Coutre, O G Ottmann, A Hochhaus, M C Müller, N von Bubnoff, M Baccarani, G Rosti, R Marasca, C Gambacorti, G Saglio, E Abruzzese, D-W Kim, C Chuah, F Cervantes, R de Paz Arias, F M Sanchez-Guijo, J C Hernandez-Boluda, M Ekblom, L Stenke, U Olsson-Strömberg, G Ossenkoppele, S M G J Daenen, T Holyoake, R E Clark, J Apperley, S G O'Brien, J Byrne, M Talpaz, H J Khoury, M R Baer, D J DeAngelo, M Wetzler, J K Altman, R A Larson, C A Schiffer, J O Moore, S Goldberg, J E Cortes, M Midathada, R Paquette, R V B Emmons, P L Kropf, M Mauro, E Berman, G Roboz, J DiPersio, M W N Deininger, V G Oehler, J Pinilla-Ibarz, M Baccarani, J Cortes, M Deininger, J Goldman, F Guilhot, A Hochhaus, T Hughes, N Shah, M Talpaz
Abstract
Background: 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).
Methods: 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.
Results: 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.
Conclusions: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).
Conflict of interest statement
No other potential conflict of interest relevant to this article was reported.
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Source: PubMed