What are the side effects of Ponatinib (Iclusig)?

From the Guidelines

Ponatinib is associated with significant side effects, including cardiovascular problems, blood-related disorders, and other adverse events, which necessitate careful monitoring and prompt reporting of unusual symptoms to healthcare providers. The side effects of ponatinib can be severe and impact the patient's quality of life, morbidity, and mortality. According to the study published in 2020 1, ponatinib can cause serious arterial occlusive events, venous thromboembolic events, cardiovascular, cerebrovascular, and peripheral arterial occlusive events.

Some of the common side effects of ponatinib include:

• Low platelet counts (thrombocytopenia), with 31.8% of patients experiencing grade 3/4 toxicity 1
• Low white blood cell counts (neutropenia), with 17.8% of patients experiencing grade 3/4 toxicity 1
• Anemia, with 5.9% of patients experiencing grade 3/4 toxicity 1
• Cardiovascular problems, such as heart attack, stroke, and blood clots
• Liver problems, high blood pressure, and pancreatitis
• Skin rashes, dry skin, abdominal pain, constipation, headache, fatigue, fever, and joint pain

The study published in 2020 1 highlights the importance of careful monitoring and management of patients taking ponatinib, particularly those with a history of cardiovascular disease or other risk factors. Healthcare providers should closely monitor patients for signs of cardiovascular problems, blood-related disorders, and other adverse events, and adjust treatment accordingly to minimize the risk of serious side effects.

From the FDA Drug Label

Most common adverse reactions (occurring in >20% of patients) are: ICLUSIG as a single agent: rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. ICLUSIG in combination with chemotherapy: hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias The most common Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase, and increased alanine aminotransferase.

The side effects of ponatinib include:

• Common adverse reactions: rash, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention, pyrexia, nausea, pancreatitis, hemorrhage, anemia, and hepatic dysfunction
• Grade 3 or 4 laboratory abnormalities: decreased platelet count, decreased neutrophil count, decreased white blood cell count, decreased lymphocyte count, decreased hemoglobin, increased lipase, and increased alanine aminotransferase
• Cardiovascular events: blood clots, heart attack, stroke, and heart failure
• Other side effects: reversible posterior leukoencephalopathy syndrome, tumor lysis syndrome, impaired wound healing, and gastrointestinal perforation 2, 2, 2

From the Research

Side Effects of Ponatinib

The side effects of ponatinib are a significant concern in its clinical use. Some of the common side effects include:

• Cardiovascular adverse events (CAEs) such as arrhythmia, hypertension, and myocardial infarction 3
• Thrombocytopenia, which occurs in a dose-dependent fashion 3
• Pancreatitis, rash, and cardiac failure, which have strong associations with dose intensity 4
• Arterial occlusive events, venous thromboembolic events, and increased lipase 4
• Neutropenia, hypertension, increased alanine aminotransferase, and increased aspartate aminotransferase 4
• Hypertriglyceridemia and arthralgia 4

Cardiovascular Toxicity

Ponatinib's significant cardiovascular toxicity poses a challenge to its clinical use 5, 6. The drug's cardiotoxicity is mediated by a few kinases, some of which were previously unassociated with cardiovascular disease 6. Strategies to minimize its toxicity and side effects are being developed, including the engineering of safer analogs of ponatinib that retain potency against T315I BCR-ABL kinase activity and suppress T315I mutant CML tumor growth 6.

Dose-Dependent Side Effects

The dose intensity of ponatinib has a significant impact on the risk of certain adverse events 4. Multivariate analyses have identified significant associations between dose intensity and most events, including pancreatitis, rash, and cardiac failure 4. Time-to-event analyses have also shown significant associations between dose intensity and risk of arterial occlusive events and each subcategory 4.

Management of Side Effects

Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits and minimize its side effects 3. Cardio-oncology referral has also been shown to be associated with a decrease in cardiovascular adverse events 3.