PonatinibIclusig

Ponatinib, marketed as Iclusig, is an oral multikinase inhibitor used in the treatment of certain Philadelphia chromosome–positive leukemias. It inhibits the activity of BCR-ABL1 and a broad range of other kinases, including VEGFR, FGFR, PDGFR, KIT, and RET, which can suppress the growth of leukemic cells driven by these signaling pathways. Ponatinib is particularly notable for its activity against BCR-ABL mutations such as T315I, which confer resistance to many other tyrosine kinase inhibitors.

Indications and use: Ponatinib is approved for adults with chronic myeloid leukemia (CML) in chronic, accelerated, or blast phase, and for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL), including cases with the BCR-ABL T315I mutation or those resistant to or intolerant of prior TKI therapy. In some regions, pediatric use may be indicated for specific CML or ALL cases under careful monitoring. Treatment decisions typically weigh the potential benefits against the risk of serious adverse effects.

Mechanism of action: By binding to the ATP-binding site of BCR-ABL1 and other kinases, ponatinib blocks signaling pathways that promote leukemic cell proliferation and survival, leading to reduced leukemic burden in responsive patients.

Administration and dosing: Ponatinib is given orally once daily. Dosing commonly starts around 45 mg once daily for resistant or intolerant disease, with dose reductions to 30 mg or 15 mg daily based on tolerance, response, and safety considerations. Dosing may be adjusted for hepatic impairment and in the context of concomitant medications, especially those affecting CYP3A4 activity.

Safety and adverse effects: Major safety concerns include arterial and venous thromboembolic events, hepatotoxicity, pancreatitis, hypertension, and wound healing impairment. Because of these risks, patients require baseline cardiovascular assessment and ongoing monitoring of liver function, lipids, and blood pressure. Ponatinib is often subject to risk-management programs (REMS) in many regions.

Regulatory status: Since its approval for CML and ALL with limited prior TKI options, ponatinib remains an option for patients with resistant or intolerant disease, with use guided by a careful assessment of benefits and risks.