What is the role of ponatinib in the treatment of chronic myelogenous leukemia (CML)?

Updated: May 23, 2021
  • Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, FACP  more...
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The third-generation TKI ponatinib (Iclusig) was approved by the FDA in December 2012 for use in patients with CML that had relapsed or become refractory to other therapies. Many of these patients will have developed a T315I mutation, which confers resistance to imatinib and other tyrosine kinase inhibitors. [53, 54, 55]

In the phase 2 PACE (Ponatinib PH+ ALL [acute lymphoblastic leukemia] and CML Evaluation) trial, the drug successfully treated patients with chronic-phase CML (major cytogenetic response in 55% of cases, including 70% of patients with the T315I mutation, within 12 months), with accelerated-phase CML (major hematologic response in 57% of cases within 6 months), or with blast-phase CML/Ph1-positive ALL (major hematologic response in 34% of cases within 6 months). [53, 54, 55]

In October 2013, at the FDA’s request, ponatinib was temporarily removed from the market because of safety concerns. The FDA cited an increased risk for life-threatening blood clots and severe narrowing of blood vessels. [56] In December 2013, the FDA allowed resumption of marketing, since the benefits of response to ponatinib far outweigh the risk of complications from the drug. However, the FDA required the addition of a black box warning regarding arterial and venous thrombosis and occlusions, which have occurred in at least 27% of patients in early trials, typically within 2 weeks of starting ponatinib. In addition, the FDA limited the indications for use of ponatinib to the following [57] :

  • Adult patients with T315I -positive CML in chronic, accelerated, or blast phase (or T315I-positive, Ph1-positive ALL)

  • Adult patients with chronic, accelerated, or blast phase CML for whom no other TKI therapy is indicated

The FDA has also revised the dosing recommendations to state that the optimal dose of ponatinib has not been identified. The recommended starting dose remains 45 mg once daily, but additional information is included regarding dose decreases and discontinuations.

The author agrees that the FDA acted appropriately in limiting the use of ponatinib but making it available from the market while experts determine the optimal dose and dosing schedule for lessening toxicity from ponatinib without compromising its efficacy. This is a process that many other agents have had to undergo, following FDA approval. The T315I mutation for which ponatinib is effective is very rare, affecting only a small minority of CML patients. Nevertheless, for some of those patients, ponatinib has proved lifesaving.      

A German expert consensus panel has published recommendations on management of cardiovascular risk in patients receiving ponatinib. [58]      

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