By: Sherine Jaison, PharmD Candidate c/o 2015
The leukemia chemotherapy drug ponatinib (Iclusig) has just been taken off the market. The drug was under investigation by the Food and Drug Administration (FDA) following several reports of serious and life threatening blood clots and narrowing of the blood vessels.1 Ponatinib is a BCR-ABL tyrosine kinase inhibitor that was approved in December 2012 for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) in patients who are resistant or intolerant to prior tyrosine kinase inhibitor therapy.2 Philadelphia chromosome is an abnormality in which a part of chromosome 9 is transferred to chromosome 22. Patients who are positive for this chromosome often have chronic myelogeous leukemia or chronic lymphocytic leukemia.3 Ponatinib was granted accelerated approval by the FDA based on the results from the Phase II PACE trial. In the trial, Ponatinib, used at a dose of 45 mg daily, was seen to have substantial antileukemic activity in patients with CML or Ph+ ALL. The study enrolled patients who were resistant or tolerant to dasatinib or nilotinib, or those who harbored a T313I mutation.4
Even though the medication showed significant toxicity during the experimental trials, it was approved because of its clinical advantage. However, the medication warranted a black box warning because of high rates of arterial thrombosis and hepatotoxicity. During the post-marketing follow up, the rates of serious arterial thrombosis substantially increased. Approximately 24% of the patients in the Phase II clinical trial and about 48% of the patients in the Phase I trial experienced serious vascular events such as fatal and life threatening heart attack, stroke and loss of peripheral blood flow, which resulted in tissue death. There were also cases of severe narrowing of blood vessels in the extremities, heart, and brain, which required urgent surgical procedures to restore blood flow.1 In some instances, patients experienced these side effects as early as two weeks into the treatment. Since both these clinical trials did not include control groups, it is not possible to pinpoint ponatinib as the sole factor for the adverse effects.1 However, the increasing rates of serious adverse vascular events suggest that these are directly correlated to the drug. In addition, 67% percent of the patients developed hypertension in Phase II clinical trials. Patients also experienced very serious side effects such as blindness or blurred vision when treated with ponatinib.1
Earlier in October, Phase III EPIC trial, in which ponatinib was used in patients who were untreated for chronic myeloid leukemia, was discontinued because of high occurrence of thrombotic events.1 As of right now, healthcare providers may continue patients on ponatinib only for those who are responding to the drug and for whom the benefits outweigh the risk of treatment. 5
These significant side effects have prompted the FDA to ask the manufacturers to suspend marketing and sales of ponatinib, which has been in the market for less than a year.1 The FDA will continue to evaluate the drug to understand its risks and to assess if the drug may provide benefits in any other patient populations.1 The drug manufacturer, Ariad Pharmaceuticals, has agreed to FDA’s request to suspend marketing and sales of ponatinib while the investigation goes on.
- Iclusig: Ponatinib. Food and Drug Administration Website. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm373072.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Updated October 31, 2013. Accessed November 2,2013.
- Inman S. Late-stage ponatinib study discontinued. OncLive Website. October 18, 2013. http://www.onclive.com/web-exclusives/Frontline-Late-Stage-Ponatinib-Study-Discontinued. Accessed November 2, 2013.
- Philadelphia chromosome. National cancer institute at the institutes of health. http://www.cancer.gov/dictionary?cdrid=44179. Accessed November 2, 2013.
- Inman I. Safety concerns halt ponatinib development. OncLive Website. October 9, 2013. http://www.onclive.com/web-exclusives/Safety-Concerns-Halt-Ponatinib-Development. Accessed November 1, 2013.
- FDA Drug Safety communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales. Food and Drug Administration Website. http://www.fda.gov/Drugs/DrugSafety/ucm373040.htm.Updated November 12,2013. Accessed November 18,2013
- Mechcatie E. Sales of leukemia drug suspended because of treatment-associated vascular events. Internal Medicine News: News and Views that matter to physicians. October 31, 2013. http://www.internalmedicinenews.com/index.php?id=2049&type=98&tx_ttnews%5Btt_news%5D=222161&cHash=da03e20e36. Accessed November 1, 2013.