Friday, January 27, 2023
This article is intended for primary care clinicians, hematologists, oncologists, and other specialists who care for patients with leukemia who have taken ponatinib or for whom ponatinib is being considered.
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The US Food and Drug Administration (FDA) initially approved ponatinib 10 months ago as an antileukemia agent. Specific indications were for adults with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia. In addition, it was approved for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who could not tolerate or in whom imatinib or other agents were no longer helpful.
At the time of FDA approval, the label had a boxed warning regarding the risk for thrombotic events shown in clinical trials, with serious arterial thrombotic events in 8% of patients treated with ponatinib and venous thrombotic events in 3%.
At the request of the FDA, the leukemia drug ponatinib (Iclusig) has been temporarily pulled from the market because of safety concerns.
"We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks," said the FDA in a statement.
The drug manufacturer will suspend marketing and sales of ponatinib because of the risks for life-threatening blood clots and severe narrowing of blood vessels.
Ponatinib is indicated for adults with chronic-phase, accelerated-phase, or blast-phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia who do not tolerate or no longer benefit from other therapies, such as imatinib (Gleevec).
This action follows an FDA investigation into ponatinib, initiated this past October, that revealed "an increased frequency of blood clots and narrowing of blood vessels since the drug was approved in December 2012," according to an agency statement.
New data indicate that approximately 24% of patients in the phase 2 clinical trial (median treatment duration, 1.3 years) and approximately 48% of patients in the phase 1 clinical trial (median treatment duration, 2.7 years) experienced serious adverse vascular events. The events include fatal and life-threatening myocardial infarction; stroke; loss of blood flow to the extremities resulting in tissue death; and severe narrowing of blood vessels in the extremities, heart, and brain requiring urgent surgical procedures to restore blood flow.
In the phase 2 trial, heart failure, including fatalities, occurred in 8% of patients treated with the drug. Serious adverse reactions involving the eyes, which led to blindness or blurred vision, also occurred.
In some patients, fatal and serious adverse events have occurred as early as 2 weeks after starting ponatinib therapy.
Currently, the FDA cannot identify a dose level or exposure duration that is safe.
Patients taking ponatinib who are not responding should stop treatment and seek an alternative, according to the FDA.
For patients who are responding to ponatinib and whose healthcare professionals determine that the potential benefits outweigh the risks, the agency recommends that they continue to be treated under a single-patient Investigational New Drug (IND) application or under an expanded-access registry program while the FDA investigation continues.
More information on obtaining access to treatment under an IND can be found on the FDA Web site.
Clinicians should not start treating new patients with ponatinib unless no other treatments are available and all other available therapies have failed, according to the FDA.
When the FDA approved ponatinib in December 2012, it required the label to feature a boxed warning about the risk for blood clots. Clinical trials conducted before approval of the drug reported serious arterial blood clots in 8% of patients treated with the drug, and venous blood clots in 3%.
More information on the FDA safety change regarding ponatinib is available on the FDA Web site.
