This patient had no history of HTN and no other major CV risk factors. Ensuring his CPAP is working adequately to control his sleep apnea and discussing lifestyle habits including diet and exercise would be reasonable. His laboratory test values were unremarkable; since starting cancer therapy, his BP had been persistently elevated in the office and at home. Most likely, this elevation was an adverse effect of ponatinib, a BCR-ABL TKI. The development of HTN is thought to occur via off-target kinase inhibition and represents an important CV complication of several TKIs.^1,2 If not appropriately managed, it can contribute to endothelial damage, glomerular impairment, myocardial infarction (MI), cerebrovascular accidents, peripheral artery disease, and heart failure (HF).²

In clinical trials, HTN developed within weeks to months of initiating ponatinib. Approximately 45% of patients experience adverse CV events and 9% encounter thrombotic complications, with HTN being the most common (33%).³ The proposed mechanism involves inhibition of the vascular endothelial growth factor (VEGF) pathway, leading to endothelial dysfunction, vasoconstriction, and elevated BP. Additional factors such as dysregulation of the renin-angiotensin-aldosterone system, nitric oxide pathway, endothelin-1 signaling, capillary rarefaction, and oxidative stress have also been implicated.⁴

To prevent CV complications such as MI and stroke, HTN management should not be delayed. Initiation of antihypertensive therapy is recommended when BP is consistently >130/80 mm Hg or when diastolic BP increases >20 mm Hg from baseline.⁵ Cancer therapies should be managed by oncologists with input from cardiology, cardio-oncology, or onconephrology to guide adjustments or cessation if necessary. Notably, antihypertensive treatment does not appear to diminish the efficacy of TKIs in cancer therapy. Regular monitoring of BP is essential.

Per the National Cancer Institute (NCI), indications for reducing or discontinuing oncologic therapy include persistent systolic BP >160 mm Hg, diastolic BP >100 mm Hg, hypertensive crisis, or refractory HTN unresponsive to antihypertensive interventions.⁵ Once BP is adequately controlled, oncologic treatment may be resumed.

A basic diagnostic workup should include a CBC, CMP, urinalysis, and possibly a spot urine total protein-to-creatinine ratio.² Worsening kidney function, proteinuria, hemolytic anemia, or thrombocytopenia may indicate thrombotic microangiopathy, a potential adverse effect warranting referral to a nephrologist for diagnostic biopsy.⁶

Dihydropyridine calcium channel blockers and renin-angiotensin system (RAS) inhibitors, particularly in the presence of proteinuria, are generally more effective for BP management in this population.² Beta adrenergic antagonists can be added, especially if HF is present. Although specific BP targets for this population have not been systematically evaluated, the NCI and American Heart Association (AHA) HTN guidelines recommend a target of <130/80 mm Hg.⁵

Whereas data from in vitro studies suggest nifedipine may increase VEGF levels, this does not reduce its antineoplastic effect. Nondihydropyridine calcium channel blockers should be avoided, as they inhibit cytochrome P450 family 3 subfamily A member 4 (CYP3A4), potentially increasing VEGF inhibitor drug levels.⁷ Diuretics can be considered as second-line or third-line agents for resistant HTN after initiating a dihydropyridine calcium channel blocker and/or RAS inhibitor. Monitoring should continue for patients if they taper or stop the TKI because of concerns for hypotension and the possibility of discontinuing antihypertensive medications.⁵

References

1. Jain P, Kantarjian H, Boddu PC, et al. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs. Blood Adv 2019;3:851-61.
2. Sayegh N, Yirerong J, Agarwal N, et al. Cardiovascular toxicities associated with tyrosine kinase inhibitors. Curr Cardiol Rep 2023;25:269-80.
3. García-Gutiérrez V, Hernández-Boluda JC. Tyrosine kinase inhibitors available for chronic myeloid leukemia: efficacy and safety. Front Oncol 2019;9:603.
4. Santoro M, Mancuso S, Accurso V, Di Lisi D, Novo G, Siragusa S. Cardiovascular issues in tyrosine kinase inhibitors treatments for chronic myeloid leukemia: a review. Front Physiol 2021;12:[ePub ahead of print].
5. Cohen JB, Brown NJ, Brown SA, et al.; American Heart Association Council on Hypertension; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on the Kidney in Cardiovascular Disease. Cancer therapy-related hypertension: a scientific statement from the American Heart Association. Hypertension 2023;80:e46-e57.
6. Shyam Sunder S, Sharma UC, Pokharel S. Adverse effects of tyrosine kinase inhibitors in cancer therapy: pathophysiology, mechanisms and clinical management. Signal Transduct Target Ther 2023;8:262.
7. Camarda ND, Lu Q, Meola DM, et al. Identifying mitigating strategies for endothelial cell dysfunction and hypertension in response to VEGF receptor inhibitors. Clin Sci 2024;138:1131-50.