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Ponatinib: Another new treatment for CML
It is remarkable that, in the past year, the FDA approved three new agents to treat patients with chronic myeloid leukemia.
Bosutinib (Bosulif, Pfizer) is an orally administered tyrosine kinase inhibitor that has activity in disease caused by many BCR-ABL mutations, but not the T315I or V299L mutations. Omacetaxine (Synribo, Teva Pharmaceuticals), which is administered subcutaneously, works by inhibiting protein synthesis but is not a BCR-ABL TKI.
The most recent approval was for ponatinib (Iclusig, Ariad), which has activity against all tested BCR-ABL mutations, including the highly resistant T315I mutation.
Lisa K. Lohr
Although the development of TKIs has revolutionized the treatment of CML, up to 25% of patients have disease that develops resistance to or is inherently resistant to TKIs. The T315I mutation confers resistance to all TKIs, up until now.
Pharmacology
Ponatinib, formerly known as AP24534, is an orally administered multitargeted TKI. Besides ABL, it also inhibits various VEGFR, PDGFR and SRC families of kinases, as well as the KIT, RET and FLT3 kinases. It has activity against all of the tested ABL mutants, as well as the T315I mutation.
Ponatinib is approved for the treatment of adult patients with any phase of CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant or intolerant to prior TKI therapy.
Pharmacokinetics
The absolute oral bioavailability of ponatinib is not known, but it is not affected by food intake. The solubility — and presumably the bioavailability — is reduced in higher gastric pHs.
Ponatinib is highly protein bound and has an extremely large apparent volume of distribution. It is largely metabolized in the liver, mostly by CYP3A4, as well as CYP2C8, CYP2D6 and CYP3A5.
The mean half-life was about 24 hours (range, 12 to 66 hours). It has not been studied in patients with hepatic or renal impairment. Ponatinib has not been studied in pediatric patients. As a group, patients aged older than 65 years who have been enrolled in studies experienced higher rates of adverse effects.
It is likely that there will be drug interactions between ponatinib and medications that are strong CYP3A4 inducers and inhibitors, as well with medications that raise gastric pH.
Dosing
The initial dose of ponatinib in most patients is 45 mg orally once daily. It can be taken with or without food.
The appropriate starting dose in patients concomitantly treated with medications that are strong CYP3A4 inhibitors is 30 mg orally daily. Dose modifications are recommended for neutropenia, thrombocytopenia, hepatotoxicity, pancreatitis and high lipase levels, which develop after starting ponatinib.
Ponatinib is provided as 15 mg and 45 mg oral tablets.
Adverse effects
Ponatinib is fairly well tolerated. The proportion of patients in one study who discontinued ponatinib due to side effects ranged from 9% to 15%. However, a fairly high rate of patients (74%) required dose delays or reductions due to side effects.
Source: Lisa K. Lohr, PharmD, BCPS, BCOP
Potential adverse effects are shown in Table 1. In a QT assessment, ponatinib showed no large changes in the QTc interval.
Clinical trials
In a phase 1 trial published in The New England Journal of Medicine, Cortes and colleagues studied ponatinib in an escalating dose fashion in a group of 81 patients with resistant CML and Ph+ALL.
Doses ranged from 2 mg to 60 mg daily. Dose-limiting side effects included increased lipase/amylase levels and pancreatitis. Other common adverse effects were rash, myelosuppression, fatigue and nausea.
On the basis of these findings, the dose of 45 mg orally daily was recommended for further development. Although this was a dose-ranging study and not all patients were treated with the subsequently recommended dose, researchers noted a high rate of clinical efficacy. In particular, there was a high rate of hematologic and cytogenetic responses, even in patients with the T315I mutation and those with Ph+ALL.
Cortes and colleagues also studied the activity of ponatinib in a recently completed phase 2 trial. The researchers, who presented their findings at the ASCO Annual Meeting last year, studied a group of 449 patients with resistant or intolerant CML (chronic, accelerated or blast phase) or Ph+ALL.
All patients were treated with ponatinib 45 mg orally daily. This was a highly pretreated population, with 94% resistant/intolerant to two or more prior TKIs, and 59% resistant/intolerant to three or more previous TKIs. Twenty-nine percent had the T315I mutation. Efficacy, as measured by predefined outcomes, is shown in Table 2.
About 10% of patients in this study discontinued ponatinib due to adverse effects, the most common of which were thrombocytopenia, rash and dry skin.
Conclusion
In summary, ponatinib is a multitargeted TKI that shows significant activity in patients with CML and Ph+ALL who are intolerant or resistant to prior TKI treatment, including those with the T315I mutation.
References:
Cortes JE. N Engl J Med. 2012;367:2075-2088.
Cortes JE. Abstract #6503. Presented at: ASCO Annual Meeting; June 1-5, 2012; Chicago.
For more information:
Lisa K. Lohr, PharmD, BCPS, BCOP, is a clinical pharmacy specialist and oncology medication therapy management provider at the University of Minnesota Physicians Cancer Care at Fairview in Minneapolis. She also is a HemOnc Today Editorial Board member. She may be reached at the University of Minnesota Physicians Cancer Care at Fairview, 424 Harvard St. SE (MMC 114), Minneapolis, MN 55455.
Disclosure: Lohr reports no relevant financial disclosures.