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Clinical Trial
. 2013 Nov 7;369(19):1783-96.
doi: 10.1056/NEJMoa1306494. Epub 2013 Nov 1.

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

J E Cortes  1 , 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
Collaborators, Affiliations
Clinical Trial

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

J E Cortes et al. N Engl J Med. .

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). VSports手机版.

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 V体育安卓版. .

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% V体育ios版. 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 . ) VSports最新版本. .

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Conflict of interest statement

No other potential conflict of interest relevant to this article was reported.

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Figure 1
Figure 1. Response to Ponatinib According to Type of Leukemia, Resistance to or Unacceptable Side Effects from Previous Treatment with Dasatinib or Nilotinib, and T3151 Mutation Status
Panel A shows the percentages of patients with chronic-phase CML who had a complete hematologic response, major cytogenetic response, complete cytogenetic response, or major molecular response. It was estimated that 91% (95% confidence interval [CI], 85 to 95) of the patients with a major cytogenetic response would have a sustained response of at least 12 months. Overall survival was estimated to be 94% at 12 months. Panel B shows the percentages of the patients with accelerated-phase CML who had a major hematologic response, major cytogenetic response, complete cytogenetic response, or major molecular response. It was estimated that 48% (95% CI, 32 to 63) of the patients with a major hematologic response would have a sustained response of at least 12 months. Overall survival was estimated to be 84% at 12 months. Panel C shows the percentages of patients with blast-phase CML who had a major hematologic response, major cytogenetic response, or complete cytogenetic response. It was estimated that 42% (95% CI, 19 to 63) of the patients with a major hematologic response would have a sustained response of at least 12 months. Overall survival was estimated to be 29% at 12 months (median, 7 months). Panel D shows the percentages of patients with Ph-positive ALL who had a major hematologic response, major cytogenetic response, or complete cytogenetic response. It was estimated that 8% (95% CI, 0.5 to 29) of the patients with a major hematologic response would have a sustained response of at least 12 months. Overall survival was estimated to be 40% at 12 months (median, 8 months).
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"V体育官网" References

    1. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow-up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114(Suppl):1126. abstract.
    1. Hochhaus A, O’Brien SG, Guilhot F, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–61. Erratum, Leukemia 2010;24: 1102. - PubMed (VSports手机版)
    1. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567–76. - PMC - PubMed
    1. Shah NP, Cortes JE, Schiffer CA, et al. Four-year follow-up of patients with chronic-phase chronic myeloid leukemia (CP-CML) receiving 100 mg of dasatinib once daily. J Clin Oncol. 2010;28(Suppl):6512. abstract.
    1. Sprycel (dasatinib) tablet for oral use: prescribing information. Princeton, NJ: Bristol-Myers Squibb; Oct, 2011.

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