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Arterial occlusive events (AOE) are rare adverse event in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitor such as ponatinib. We treated a 47-year-old woman with chronic myeloid leukemia. She was failed to achieve optimal molecular response in prior two lines tyrosine kinase inhibitors treatment (dasatinib and bosutinib) for first 30 months. Finally, she was treated with ponatinib and achieve complete molecular remission in 28 months. However, she was suffered from AOE, in bilateral stenosis of the middle cerebral arteries. The patient's responsible vascular lesions of AOE were atypical site rather than usually affected lesions in common arteriosclerosis., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia., Methods: We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events., Results: Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia., Conclusions: This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis., (© The Author(s) 2024. Published by Oxford University Press.)

Ponatinib (Iclusig®, Takeda/Incyte) is a third-generation highly-potent-pan-inhibitor of tyrosine kinases, active in all single resistance ABL kinase mutations including the T315l mutation. It is approved to treat of chronic myeloid leukemia (CML) in every phase of disease-resistant or intolerant to second-generation tyrosine kinase inhibitors (2GTKIs) and for whom imatinib is not clinically appropriate as well as for patients with T315I mutation. The drug is also indicated for Ph+ acute lymphoblastic leukemia (ALL). The approved starting dose for ponatinib is 45 mg once daily. Available data revealed ponatinib dose-dependent increased risk of cardiovascular toxicity. There is still no consensus about the optimal, initial dose of ponatinib and its management during therapy. It is crucial to start treatment with the risk-adjusted dose and assess the benefit-risk profile of ponatinib dosing. Evaluation of dosing modification should be considered during treatment, mainly if toxicity occurs. Our study summarizes current knowledge and recommendations about the choice of starting dose of ponatinib and management of ponatinib dosing during the treatment. [ABSTRACT FROM AUTHOR]

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML) in the chronic phase. However, only 50-60% of patients stay on the same TKI for 5 years, and the long-term progression-free survival rate is significantly reduced if an early molecular response is not achieved. Possible mechanisms of therapeutic resistance against BCR::ABL1 dependent clones include point mutations in the ABL1 kinase domain, BCR::ABL1 splicing variants, BCR::ABL1 overexpression, and altered pharmacokinetics by the ABC transporter. Ponatinib, the most potent inhibitor among TKIs, and the STAMP inhibitor asciminib are important drugs for overcoming BCR::ABL1-dependent resistance.

Introduction: Chronic myeloid leukemia is now a highly treatable leukemia due to the availability of multiple tyrosine kinase inhibitors (TKIs) inhibiting the BCR-ABL1 oncogene. Some patients with CML can display resistance or intolerance to multiple TKIs, oftentimes due to the presence of mutations in BCR-ABL1, such as T315I, which limits effective treatment options. Ponatinib is a third-generation, rationally-designed TKI with clinically meaningful activity in this difficult-to-treat population. Ponatinib is associated with an increased risk of arterial occlusive events (AOEs) which has required a reexamination of its dosing in order to limit the risk of these events., Areas Covered: This review will provide an overview of the mechanism of action of ponatinib and the safety and efficacy data from clinical trials in chronic myeloid leukemia., Expert Opinion: Ponatinib is a potent pan-BCR-ABL1 TKI with substantial activity in patients with more resistant or advanced CML. Its efficacy needs to be balanced with the increased risk of vascular events, which seems to be at least partially diminished by the implementation of mitigation strategies aimed at modifying cardiovascular risk factors and adaptive dosing of the drug.