Little more than a decade ago, the approval of imatinib confirmed the therapeutic value of BCR-ABL inhibition for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) and other Ph+ leukemias. However, resistance to imatinib or the two additional tyrosine kinase inhibitors (TKIs) approved for newly diagnosed patients—dasatinib and nilotinib —undermines these gains in patient care.1

About 20% of individuals who are resistant to TKIs exhibit the T315I “gatekeeper” mutation, which confers a high degree of resistance by blocking the ATP-binding site.2 Ponatinib (Iclusig®) is a TKI structurally designed to outsmart this common mutation. In a phase 1 dose-finding study, ponatinib demonstrated activity in patients carrying the T315I mutation along with other mutations in patients with TKI-refractory or -resistant CML. Among patients carrying the T315I mutation, 67% achieved major molecular response (MMR), a treatment milestone with positive implications for long-term prognosis, and among patients resistant to all three TKIs, 24% achieved MMR.1,2

In a phase 2 trial—Ponatinib Ph ALL and CML Evaluation (PACE)—patients resistant to or intolerant of dasatinib or nilotinib or who carry the T315I mutation were treated with ponatinib 45 mg once daily.3 Overall, 46% of patients with CML-CP achieved complete cytogenetic response, and 34% achieved MMR. Among patients carrying the T315I mutation, 56% achieved MMR.3

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Based on the (at the time, unpublished) results of PACE, ponatinib received accelerated approval from the US Food and Drug Administration (FDA) for second- or third-line treatment of CML-CP and other Ph+ leukemias, with a boxed warning about the risk for vascular occlusion.4 The final results of this trial were published in the New England Journal of Medicine on November 7, 2013,3 just 1 week after the FDA suspended marketing of ponatinib.5,6

New data reviewed by the FDA indicated that 24% of patients in the phase 2 trial and 48% in the phase 1 trial had experienced serious adverse vascular events related to thrombosis and extreme narrowing of blood vessels throughout the body.5 Clinical trial and postmarketing data showed a broad range of serious thrombotic events related to ponatinib use, including fatal myocardial infarction, worsening coronary artery disease, strokes, narrowing of large cerebral arteries and peripheral blood vessels in the extremities, as well as events requiring surgical intervention to restore blood flow.6 Serious events occurred in all types of patients, including young adults and individuals without cardiovascular risk factors.5 The phase 3 Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study (NCT01650805) has been halted after a review of safety data.7

In short, a promising therapy for patients with TKI-resistant/refractory CML has now been sidelined by serious concerns over arterial and venous thrombotic events. The ponatinib story underscores some of the risks associated with accelerated approval and the ever-present possibility that serious adverse events not evident during clinical trials will emerge with long-term use.


  1. Cortes J, Goldman JM, Hughes T. Current issues in chronic myeloid leukemia: monitoring, resistance, and functional cure. J Natl Compr Canc Netw. 2012;10(suppl 3):S1-S13.
  2. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075-2088.
  3. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783-1796.
  4. US Food and Drug Administration. Approved drugs: ponatinib. Accessed November 20, 2013.
  5. National Cancer Institute. Ponatinib hydrochloride withdrawn from US markets. Accessed November 20, 2013.
  6. US Food and Drug Administration. Iclusig (ponatinib): Drug Safety Communication—increased reports of serious blood clots in arteries and veins. Accessed November 20, 2013.
  7. Ponatinib in newly diagnosed chronic myeloid leukemia. Accessed November 20, 2013.