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

Jorge 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. RiveraT. Clackson, C. D. Turner, F. G. Haluska, F. Guilhot, M. W. Deininger, A. Hochhaus, T. Hughes, J. M. Goldman, N. P. Shah, H. Kantarjian

Research output: Contribution to journalArticle

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.)

Original languageEnglish (US)
Pages (from-to)1783-1796
Number of pages14
JournalNew England Journal of Medicine
Volume369
Issue number19
DOIs
StatePublished - Jan 1 2013
Externally publishedYes

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Philadelphia Chromosome
Leukemia
Cytogenetics
Mutation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Protein-Tyrosine Kinases
Leukemia, Myeloid, Accelerated Phase
ponatinib
Leukemia, Myeloid, Chronic Phase
Blast Crisis
Isoleucine
Threonine
Exanthema
Thrombocytopenia
Abdominal Pain
Phosphotransferases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cortes, J. E., Kim, D. W., Pinilla-Ibarz, J., Le Coutre, P., Paquette, R., Chuah, C., ... Kantarjian, H. (2013). A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. New England Journal of Medicine, 369(19), 1783-1796. https://doi.org/10.1056/NEJMoa1306494

A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. / Cortes, Jorge 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.

In: New England Journal of Medicine, Vol. 369, No. 19, 01.01.2013, p. 1783-1796.

Research output: Contribution to journalArticle

Cortes, JE, Kim, DW, Pinilla-Ibarz, J, Le Coutre, P, Paquette, R, Chuah, C, Nicolini, FE, Apperley, JF, Khoury, HJ, Talpaz, M, DiPersio, J, DeAngelo, DJ, Abruzzese, E, Rea, D, Baccarani, M, Müller, MC, Gambacorti-Passerini, C, Wong, S, Lustgarten, S, Rivera, VM, Clackson, T, Turner, CD, Haluska, FG, Guilhot, F, Deininger, MW, Hochhaus, A, Hughes, T, Goldman, JM, Shah, NP & Kantarjian, H 2013, 'A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias', New England Journal of Medicine, vol. 369, no. 19, pp. 1783-1796. https://doi.org/10.1056/NEJMoa1306494
Cortes JE, Kim DW, Pinilla-Ibarz J, Le Coutre P, Paquette R, Chuah C et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2013 Jan 1;369(19):1783-1796. https://doi.org/10.1056/NEJMoa1306494
Cortes, Jorge 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. / A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 19. pp. 1783-1796.
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T1 - A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias

AU - Cortes, Jorge E.

AU - Kim, D. W.

AU - Pinilla-Ibarz, J.

AU - Le Coutre, P.

AU - Paquette, R.

AU - Chuah, C.

AU - Nicolini, F. E.

AU - Apperley, J. F.

AU - Khoury, H. J.

AU - Talpaz, M.

AU - DiPersio, J.

AU - DeAngelo, D. J.

AU - Abruzzese, E.

AU - Rea, D.

AU - Baccarani, M.

AU - Müller, M. C.

AU - Gambacorti-Passerini, C.

AU - Wong, S.

AU - Lustgarten, S.

AU - Rivera, V. M.

AU - Clackson, T.

AU - Turner, C. D.

AU - Haluska, F. G.

AU - Guilhot, F.

AU - Deininger, M. W.

AU - Hochhaus, A.

AU - Hughes, T.

AU - Goldman, J. M.

AU - Shah, N. P.

AU - Kantarjian, H.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.)

AB - 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.)

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