The role of ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

The introduction of tyrosine kinase inhibitors has improved outcomes in Philadelphia chromosome-positive acute lymphoblastic leukemia, yet relapse due to the development of resistance mutations remains a major obstacle. Ponatinib is a novel tyrosine kinase inhibitor designed to overcome single-resistance mutations in the ABL kinase. Three clinical trials confirmed the efficacy of ponatinib in the relapsed and front-line setting in Philadelphia positive acute lymphoblastic leukemia, even in the presence of the T315I mutation, which confers resistance to other tyrosine kinase inhibitors. The rate of relapse appears to be very low when used in combination with chemotherapy, suggesting a role for ponatinib in newly diagnosed patients. A major concern with the use of ponatinib is the associated high risk of life-threatening vascular thrombotic events. Potential strategies to reduce this risk include minimizing the use of ponatinib in patients with significant baseline cardiovascular risk, careful surveillance and treatment of cardiovascular risk-factors and dose reduction of ponatinib.

Keywords:

• acute lymphoblastic leukemia
• adverse events
• Philadelphia chromosome
• ponatinib
• resistance mutations

Financial & competing interests disclosure

H Kantarjian has received research grants from ARIAD, Novartis, Bristol-Myers Squibb and Pfizer. E Jabbour has received research grants from ARIAD and has received consultancy fees from ARIAD, Bristol-Myers Squibb, Pfizer and TEVA. J Cortes has received research grants from ARIAD, Novartis, Bristol-Myers Squibb and Pfizer. F Ravandi has received research grants from Novartis and Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• The Philadelphia chromosome is found in approximately 20% of adult cases of ALL and has historically been associated with a poor prognosis.

• The incorporation of TKIs that inhibit the BCR-ABL fusion protein has improved response rates as well as survival in Ph-positive ALL.

• Relapse appears to occur in at least 25% of patients using first- and second-generation TKIs and is frequently associated with the development of resistance mutations.

• Ponatinib is a novel TKI that is active against all single resistance mutations, including the T315I mutant, which confers resistance to other commercially available TKIs.

• Phase I and II clinical trials demonstrated the efficacy of ponatinib in Ph-positive ALL in the relapsed and front-line setting.

• A Phase II clinical trial incorporating ponatinib with the hyper-CVAD regimen reported a low rate of relapse (2.5%) after a median follow-up of 20 months, although 8% of patients experienced a vascular thrombotic event resulting in death.

• The risk of vascular thrombotic events in patients using ponatinib is high and the incidence has ranged between 8 and 37% in the published clinical trials.

• Potential strategies to reduce thrombotic risk include patient selection, careful surveillance and treatment of CV risk factors and reducing the dose of ponatinib.