Ponatinib in refractory Philadelphia chromosome-positive leukemias

Jorge E. Cortes, Hagop Kantarjian, Neil P. Shah, Dale Bixby, Michael J. Mauro, Ian Flinn, Thomas O'Hare, Simin Hu, Narayana I. Narasimhan, Victor M. Rivera, Tim Clackson, Christopher D. Turner, Frank G. Haluska, Brian Druker, Michael W N Deininger, Moshe Talpaz

Research output: Contribution to journalArticle

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Abstract

BACKGROUND:Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. METHODS:In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). RESULTS:Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. CONCLUSIONS:Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)

Original languageEnglish (US)
Pages (from-to)2075-2088
Number of pages14
JournalNew England Journal of Medicine
Volume367
Issue number22
DOIs
StatePublished - Nov 29 2012

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Philadelphia Chromosome
Leukemia
Protein-Tyrosine Kinases
Leukemia, Myeloid, Chronic Phase
Cytogenetics
Mutation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Precursor Cell Lymphoblastic Leukemia-Lymphoma
ponatinib
Blast Crisis
Poisons
Amylases
Exanthema
Lipase
Pancreatitis
Phosphotransferases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cortes, J. E., Kantarjian, H., Shah, N. P., Bixby, D., Mauro, M. J., Flinn, I., ... Talpaz, M. (2012). Ponatinib in refractory Philadelphia chromosome-positive leukemias. New England Journal of Medicine, 367(22), 2075-2088. https://doi.org/10.1056/NEJMoa1205127

Ponatinib in refractory Philadelphia chromosome-positive leukemias. / Cortes, Jorge E.; Kantarjian, Hagop; Shah, Neil P.; Bixby, Dale; Mauro, Michael J.; Flinn, Ian; O'Hare, Thomas; Hu, Simin; Narasimhan, Narayana I.; Rivera, Victor M.; Clackson, Tim; Turner, Christopher D.; Haluska, Frank G.; Druker, Brian; Deininger, Michael W N; Talpaz, Moshe.

In: New England Journal of Medicine, Vol. 367, No. 22, 29.11.2012, p. 2075-2088.

Research output: Contribution to journalArticle

Cortes, JE, Kantarjian, H, Shah, NP, Bixby, D, Mauro, MJ, Flinn, I, O'Hare, T, Hu, S, Narasimhan, NI, Rivera, VM, Clackson, T, Turner, CD, Haluska, FG, Druker, B, Deininger, MWN & Talpaz, M 2012, 'Ponatinib in refractory Philadelphia chromosome-positive leukemias', New England Journal of Medicine, vol. 367, no. 22, pp. 2075-2088. https://doi.org/10.1056/NEJMoa1205127
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2012 Nov 29;367(22):2075-2088. https://doi.org/10.1056/NEJMoa1205127
Cortes, Jorge E. ; Kantarjian, Hagop ; Shah, Neil P. ; Bixby, Dale ; Mauro, Michael J. ; Flinn, Ian ; O'Hare, Thomas ; Hu, Simin ; Narasimhan, Narayana I. ; Rivera, Victor M. ; Clackson, Tim ; Turner, Christopher D. ; Haluska, Frank G. ; Druker, Brian ; Deininger, Michael W N ; Talpaz, Moshe. / Ponatinib in refractory Philadelphia chromosome-positive leukemias. In: New England Journal of Medicine. 2012 ; Vol. 367, No. 22. pp. 2075-2088.
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abstract = "BACKGROUND:Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. METHODS:In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). RESULTS:Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91{\%} had received two or more approved tyrosine kinase inhibitors, and 51{\%} had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98{\%} had a complete hematologic response, 72{\%} had a major cytogenetic response, and 44{\%} had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100{\%} had a complete hematologic response and 92{\%} had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100{\%} had a complete hematologic response and 62{\%} had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36{\%} had a major hematologic response and 32{\%} had a major cytogenetic response. CONCLUSIONS:Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)",
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T1 - Ponatinib in refractory Philadelphia chromosome-positive leukemias

AU - Cortes, Jorge E.

AU - Kantarjian, Hagop

AU - Shah, Neil P.

AU - Bixby, Dale

AU - Mauro, Michael J.

AU - Flinn, Ian

AU - O'Hare, Thomas

AU - Hu, Simin

AU - Narasimhan, Narayana I.

AU - Rivera, Victor M.

AU - Clackson, Tim

AU - Turner, Christopher D.

AU - Haluska, Frank G.

AU - Druker, Brian

AU - Deininger, Michael W N

AU - Talpaz, Moshe

PY - 2012/11/29

Y1 - 2012/11/29

N2 - BACKGROUND:Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. METHODS:In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). RESULTS:Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. CONCLUSIONS:Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)

AB - BACKGROUND:Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. METHODS:In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). RESULTS:Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. CONCLUSIONS:Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.)

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