In Focus: Ponatinib for Chronic Myeloid Leukemia

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Ponatinib is highly effective among patients with CML, but the optimal dose is still being determined. Current trials are evaluating an initial dose of 30 mg, with a reduction to 15 mg when a response
Ponatinib is highly effective among patients with CML, but the optimal dose is still being determined. Current trials are evaluating an initial dose of 30 mg, with a reduction to 15 mg when a response

The third-generation tyrosine kinase inhibitor (TKI), ponatinib, is approved by the US Food and Drug Administration (FDA) for the treatment of chronic myeloid leukemia (CML), though not without controversy.

Ponatinib was first granted accelerated approved in 2012.1 Yet in October 2013 the FDA requested that the manufacturer briefly suspend marketing and sales of the drug after initiating an investigation to evaluate the frequency of life-threatening thromboses and the narrowing of arteries and veins.2,3

In December 2013, the FDA allowed Ariad Pharmaceuticals, the drug's manufacturer, to resume marketing of ponatinib with new safety measures in place, as well as providing a risk evaluation and mitigation strategy (REMS). The agency also required postmarketing studies to optimize ponatinib's dosing.4

Despite the risks, ponatinib is highly effective and is currently the only approved TKI effective against the T315I mutation.

Indications

Since then, the FDA granted full approval to ponatinib for the treatment of adults with chronic-, accelerated-, or blast-phase CML or Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL), when no other TKIs are indicated. The indication was also expanded to include the treatment of adults with T315I-positive CML in chronic-, accelerated-, or blast-phase or T315I- and Ph chromosome–positive ALL.

Ponatinib is not recommended or indicated for patients with newly diagnosed, chronic-phase CML.

Dosing and Administration

Though 45 mg is indicated in the label as the starting dose for ponatinib, lower doses are associated with fewer adverse events (AEs).

“When we reduce the dose to 30 or 15 mg per day, the rate of adverse events decreased significantly. Therefore, in my practice, I use 30 mg per day as the starting dose and then reduce to 15 mg per day. That has significantly reduced the rate of vascular events,” Elias Jabbour, MD, of the MD Anderson Cancer Center in Houston, Texas told Cancer Therapy Advisor.

Dr Jabbour said that he reduces ponatinib to 15 mg when patients achieve a major response or a complete cytogenetic response (CCyR). “My advice is to use a lower dose as soon as possible,” he said.

A post-hoc analysis of pooled data from 3 clinical trials of ponatinib demonstrated that increasing dose intensity is associated with higher rates of AEs, particularly pancreatitis, rash, cardiac failure, cardiovascular events, arterial occlusive events, and, to a lesser extent, hypertension. For example, a 30-mg dose of ponatinib had a 10% probability of an arterial occlusion compared with about 15% with a 45-mg dose. Risk factors such as previous ischemic disease and diabetes were prognostic for arterial events.5

Dr Jabbour noted that “we need to optimize every risk factor for vascular event, and if we see any that we are not comfortable with, the patient should be referred to a specialist.”

Ariad also reduced the starting dose of ponatinib to 30 mg in its clinical trials, and further reduces the dose to 15 mg once patients experience a major molecular response.6

Mechanism of Action

Ponatinib is a third-generation TKI that binds with high potency to BCR-ABL1, including when the T135I mutation is present. There were also no single BCR-ABL1 mutations detected resulting in ponatinib resistance in the phase 2 PACE trial (ClinicalTrials.gov Identifier: NCT01207440).7

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