Unveiling the Cardiotoxicity Conundrum: Navigating the Seas of Tyrosine Kinase Inhibitor Therapies.
ReviewFree full text in Europe PMC
Abstract
Free full text
Unveiling the Cardiotoxicity Conundrum: Navigating the Seas of Tyrosine Kinase Inhibitor Therapies
Abstract
Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of various solid and hematologic malignancies by targeting dysregulated signaling pathways critical for malignant cell growth. However, these therapeutic benefits are often accompanied by cardiotoxicities, such as hypertension, left ventricular dysfunction, QT prolongation, and tachyarrhythmias, among others. These cardiotoxicities post a significant challenge in clinical management, often limiting the use of otherwise effective therapies. The underlying mechanism of TKI-induced cardiotoxicity appears to be multifaceted, involving several pathways including: direct cardiomyocyte damage, mitochondrial dysfunction, endothelial damage, and disruption of signaling pathways critical for cardiac function. The range and severity of cardiotoxicities vary significantly across different TKIs, necessitating a comprehensive understanding of each agent’s specific cardiovascular risk profile. Preventing and managing TKI-induced cardiotoxicity requires a comprehensive, multidisciplinary approach. Early identification of at-risk patients through baseline cardiovascular risk assessments and appropriate monitoring during therapy is crucial. Strategies to mitigate cardiotoxic effects include dose modification, the use of cardioprotective agents, and temporary discontinuation of therapy. Additionally, decision making via multidisciplinary teams ensures minimization of cardiovascular complications while also continuing effective cancer treatment. Historically, data have been limited regarding cardiotoxicity and most cancer therapies, which certainly includes TKIs. This review aims to synthesize the current body of knowledge on TKI-associated cardiotoxicities, while highlighting the importance of vigilance and proactive management to minimize cardiovascular complications.
Introduction
Receptor tyrosine kinases (RTKs) are cell surface receptors that function to transfer phosphate between substrates, specifically catalyzing the transfer of y-phosphate from ATP/GTP, and in doing so mediate cell-to-cell communication. Through this communication, they play a key role in many cellular functions including the regulation of cell cycle progression and cellular metabolism. 1 Under normal physiologic conditions, this activation of RTKs is closely regulated by protein tyrosine phosphates (PTPs), which function to positively and negatively modify RTK signaling. 2 RTKs have been implicated in inducing oncogenesis via two major mechanisms, over-expression resulting from gene amplification, and over-activation due to a gain of function mutations. 3 Due to this, tyrosine kinase inhibitors have emerged as a revolutionary option to target aberrant signaling pathways crucial for tumorigenesis for a wide variety of malignancies including chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), gastrointestinal stromal tumors, non-small cell lung cancer, melanoma, renal cell carcinoma, HER2-positive breast cancer, and Waldenstrom macroglobulinemia. 4
As effective as these medications are in inhibiting oncogenesis, inhibiting receptor tyrosine kinases can have unintended consequences and adverse effects. And although the incidence of these events can stabilize over time, there can be many consequences to long-term therapies. Among these consequences, cardiotoxicity associated with tyrosine kinase inhibitor therapies has become a growing concern.
The mechanisms driving TKI-induced cardiotoxicity are multifaceted, involving a delicate interplay between targeted inhibition of oncogenic kinases and unintended consequences on cardiac homeostasis. This happens through a variety of proposed mechanisms including the disruption of physiologic signaling cascades, mitochondrial dysfunction, disruption in pathways integral for cardiomyocyte survival, electrophysiological alterations, and endothelial dysfunction are among some of the understood mechanisms.5–8
The goal of this review is to synthesize the current body of knowledge of cardiotoxicity associated with tyrosine kinase inhibitors. In doing so we hope to provide a comprehensive overview of the landscape, shedding light on the challenges, and potential avenues for mitigating the cardiovascular risks associated with TKI treatment.
BCR-ABL Tyrosine Kinase Inhibitors
BCR-ABL is a chimeric protein with constitutive tyrosine kinase activity resulting from a gene fusion that drives chronic myeloid leukemia (CML). The inhibition of BCR-ABL tyrosine kinase using small molecule TKIs resulted in improved survival. However, associated adverse cardiovascular events are commonly reported. 9
Imatinib
The first of any tyrosine kinase inhibitors to be approved by the FDA was Imatinib, which was approved in 2001 as a first-generation BCR-ABL tyrosine kinase inhibitor, that additionally targets platelet-derived growth factor receptors (PDGFR) and the c-kit gene. Initially for the treatment of metastatic or unresectable malignant gastrointestinal stromal tumors. 10 Imatinib is thought to generally have the best adverse effect profile among BCR-ABL TKIs, especially from a cardiovascular toxicity perspective. 11
When examined under transmission electron micrograph, heart biopsies from those treated with Imatinib and developed severe clinical heart failure show significant cellular abnormalities of cultured cardiomyocytes. Mitochondrial abnormalities and abnormal accumulation of membranous whorls within the sarcoplasmic reticulum can be seen. Based on this Imatinib is thought to be cardiotoxic, at least in part, due to mitochondrial dysfunction resulting in myocyte contractile dysfunction. 12
In a 2013 retrospective cohort analysis done in 2390 patients with chronic phase chronic myeloid leukemia (CML-CP), imatinib was not found to increase the risk of peripheral arterial occlusive disease (POAD) compared to placebo. Interestingly, imatinib was found to have lower rates of POAD compared to placebo, suggesting a potential cardioprotective role. 13
This was not the only study that suggested imatinib may have certain cardioprotective results. Imatinib mesylate was used in patients being treated for pulmonary arterial hypertension (PAH) in the IMPRES trial in 2013 which demonstrated that those treated with imatinib compared to placebo had significant improvements in not only exercise capacity but also hemodynamics with a significant decrease in pulmonary vascular resistance. 14 The potential benefits of Imatinib in PAH would later be confirmed by showing improvements in RV function on transthoracic echocardiogram in these patients. 15
Nilotinib
Nilotinib is a second-generation BCR-ABL TKI approved for the treatment of CML, which is both more selective and also approximately 30 times more potent in inhibiting BCR-ABL. 16 Nilotinib was superior to imatinib as a first-line therapy for treating chronic myeloid leukemia in the ENESTnd study in 2010, with more patients achieving major and complete molecular responses at both 12 and 24 months. 17 While early data in 2013 suggested that nilotinib did not appear to be associated with the development of POAD, a 10-year update on the ENESTnd trial, found significantly higher rates of cardiovascular events, defined as ischemic heart disease, peripheral arterial occlusive disease, and cerebrovascular events, in those treated with nilotinib (16.5%-23.5%) compared to those treated with imatinib (3.6%).13,18
Dasatinib
Early studies showed significant amounts of edema related to dasatinib treatment with 30% of patients reporting any amount of fluid retention which was further categorized into 15% with superficial edema, 10% with peripheral edema, 4% with facial edema, and 17% with pleural effusions. 19 Additional studies would have similar findings including a 2006 randomized controlled trial that enrolled 84 patients with CML resistant to imatinib which demonstrated significant rates of peripheral edema (19.0%), pleural effusion (17.8%), and pericardial effusion (4.8%). 20
Initial reports of pulmonary hypertension in those treated with dasatinib were seen as early as 2012 in case series. 21 Continued evidence between the association of dasatinib and pulmonary hypertension would lead to the inclusion of dasatinib as a likely cause of pulmonary hypertension in the 2015 pulmonary hypertension guidelines by the European Society of Cardiology and the European Respiratory Society. 22
Many mechanisms have been proposed for dasatinib induced pulmonary hypertension. In murine models it was found that rats who were treated with dasatinib had a significantly stronger response to inducers of pulmonary hypertension, including monocrotaline (MCT) and chronic hypoxia (CHx), thought to be a result of dasatinib inducing damage to pulmonary endothelial cells. These results would also be replicated in cultured human pulmonary endothelial cells, as demonstrated by an increase in mitochondrial ROS production, a measure of oxidative stress, resulting in a dramatic increase in apoptotic cells in samples treated with dasatinib. None of these phenomena were noted with Imatinib, suggesting that these effects may not be specific to the BCR-ABL TKI class, but rather to dasatinib itself. 23 Ultimately, based on this growing body of evidence, the Sixth World Symposium on Pulmonary Hypertension would classify the association between PAH and dasatinib as “definite” in 2018. 24
Additionally, dasatinib association with pleural effusion was evaluation in two phase 3 trials, DASISION and CA180-034, which pooled a total of 2712 patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib. The annual risk of developing pleural effusions in the DASISION and CA180-034 trials was 6-9% and 5-15% respectively. At a minimum follow up of 5 years in DASISION the rates of pleural effusion were 28% and at a minimum follow up of 7 years the rates of pleural effusion in CA180-034 were 33%. Multivariate analysis between both trials reveals the most significant risk factor for developing pleural effusion in those treated with dasatinib was age. 25
The exact mechanism for the development of pleural effusion is not entirely known, but in vitro and in vivo observations found that dasatinib, through the increase of reactive oxygen species, causes multiple changes at the endothelial level. These changes include cell-cell junction abnormalities in the form of the loss of cadherin and zonula occludens-1, formation of actin stress fibers, and an increase in permeability to macromolecules. These changes are all thought to directly cause increased pulmonary endothelial permeability and thus lead to pleural effusion. 26
Bosutinib
A 2016 retrospective analysis of two open-label international studies included 570 patients with CML resistant to prior TKIs treated with bosutinib, found that in both studies the incidence of vascular and cardiac treatment-emergent adverse events in those treated with bosutinib (5%/8%) was not significantly higher than imatinib (4%/6%). 27
Ponatinib
The PACE trial, which included 270 patients with CML treated with ponatinib, it was found that of those treated with ponatinib, the rates of cerebrovascular events, cerebrovascular events, and peripheral vascular events were 7.1%, 3.6%, 4.9% respectively, of which 2.2%, 0.7%, and 1.6% respectively were deemed to be related to treatment at a median follow up of 15 months. 28 In a 5-year follow-up of this trial, it was found that a total of 31% of patients treated with ponatinib had arterial occlusive effects with 16% having cardiovascular, 13% cerebrovascular, and 14% with peripheral vascular events. Additionally, it would establish ischemic heart disease, hypertension, diabetes, hypercholesterolemia, age >65, male gender, obesity, and nonischemic heart disease as significant risk factors for the development of these arterial occlusive events. 29 Multivariate analysis of these results suggested that toxicity may be dose-dependent, with a 15 mg reduction in the daily dose leading to an approximate 33% reduction in all AOE. 30
PACE, a phase 2 clinical trial of ponatinib of varying doses in patients with chronic-phase chronic myeloid leukemia evaluated patients treated with doses of ponatinib of 45 mg, 30 mg, and 15 mg daily, found that arterial occlusive events on ponatinib were dose-dependent. 15 mg, 30 mg and 45 mg were found to have 3.2%, 5.3%, and 9.6% rates of arterial occlusive events at a median follow-up of 32 months. 31
Asciminib
Asciminib is a selective allosteric inhibitor of BCR-ABL1 tyrosine kinase approved in 2021 for treatment in those with T315I mutations. 32 It’s found to have an improved cardio-toxic profile compared to other in-class BRC-ABL TKIs with arterial ischemic events at 13%, cardiac failure at 2.2%, hypertension at 19%, and QTc prolongation at 7%. 33
A phase III trial which included 233 patients randomized to either asciminib or bosutinib for patients with refractory CML found higher rates of hypertension in those treated with asciminib at a median follow-up of 14.9 months, with 11.5% rates of all hypertension and grade 3 hypertension in 3.9%, compared to 5.8% and 2.8% respectively for bosutinib. Additionally, arterial-occlusive events were also higher in those treated with asciminib at 3.2% compared to 1.3% in those treated with bosutinib. 34
Vascular Endothelial Growth Factor (VEGF) Tyrosine Kinase Inhibitors
VEGF inhibitors act by inhibiting VEGF directly or by inhibiting tyrosine kinase receptors. In patients with cancer, this causes inhibition of VEGF-mediated tumor angiogenesis, leading to a decreased supply of oxygen and nutrients to tumor cells. 35
Concomitantly, this mechanism of action may lead to myocardial injury due to direct myocardial effect, as well as secondary toxicity via coronary or peripheral vascular damage. This damage leads to cardiac ischemia, hypertension, left ventricular systolic dysfunction, QTc prolongation, arrhythmias, and arterial and venous thromboembolism. 36
This correlated with a 2018 meta-analysis done on 71 randomized controlled trials which included patients treated with VEGF tyrosine kinase inhibitors which included 29,252 patients which found that VEGF tyrosine kinase inhibitors can have significant cardiovascular and thrombotic adverse effects including hypertension, cardiac ischemia, left ventricular systolic dysfunction, and QTc prolongation. 37
The most common adverse effect common to all VEGF TKIs is hypertension, which is thought to be due to the blocking of nitric oxide production by VEGF inhibition. The resulting decrease in nitric oxide leads to increased peripheral vascular resistance and arterial stiffness and thus hypertension. 38
Sunitinib
In 2007, a retrospective trial of patients with metastatic gastrointestinal stromal tumors on sunitinib was performed to evaluate the cardiovascular risk of Sunitinib therapy. In addition to this, sunitinib’s effects on cultured myocytes were evaluated under transmission electron microscopy. Significant evidence of cellular abnormality was seen, including mitochondrial swelling, membrane whorls, and cytochrome c release, suggestive of induced apoptosis of the cardiomyocytes. The retrospective trial included 75 patients, and it was found that a total of 11% of patients were found to have cardiotoxicity. 47% of patients developed hypertension, 28% had a decrease in LVEF of 10% or more, and 19% had an LVEF decrease of 15% or more. 39 While left ventricular systolic dysfunction can be seen in all VEGF TKI, however, the highest rates of this were seen in those who were treated with sunitinib (RR = 2.96; 95% CI: 1.93-4.53; P ≤ 0.001). 37
A 2008 meta-analysis of 13 clinical trials included a total of 4999 patients treated with sunitinib found those treated with sunitinib were found to have all-grade hypertension at 21.6%, and high-grade hypertension at 6.8, with a relative risk of 22.72 for high-grade hypertension. 33
Axitinib
In the AXIS trial, patients treated with axitinib compared to sorafenib had lower rates of all-grade hypertension with 29% with hypertension compared to 40% respectively. 40
Cabozantinib
In the initial prescribing information in 2012, hypertension occurred in 36% of patients treated with cabozantinib 60 mg daily, thromboembolism occurred in 7%. 41 These results pertaining to hypertension would be redemonstrated in 2016 in the METEOR trial, which was an open label randomized phase 3 trial which included 330 patients with advanced clear-cell renal cell carcinoma previously treated with an VEGFR tyrosine kinase inhibitor now being treated with cabozantinib 60 mg daily with a median duration of 7.6 months. The most common side effect in these patients was hypertension, with hypertension occurring in 37% of patients with 15% of patients with grade 3 or 4 hypertension. 42
A 2016 meta-analysis looking at phase II and III prospective trials evaluated a total of 1083 patients treated with cabozantinib across 8 prospective trials. Those treated with cabozantinib developed all grade hypertension 5.48 times more often than those treated with control and were 5.09 times more likely to develop high-grade hypertension. In addition to this the rates of high-grade hypertension were higher in those treated with cabozantinib compared to other FDA approved VEGFR-TKIs at the time including pazopanib, sunitinib, sorafenib and vandetanib. 43
In 2018 the CABOSUN trial again looked at patients with advanced renal cell carcinoma in those who were previously untreated and included 79 patients treated with cabozantinib 60 mg daily. In this study, the rates of hypertension were significantly higher than those previously seen in the METEOR trial, at a median treatment duration of 6.5 months and a median follow-up of 34.5 months, the incidence of all grade hypertension in those treated with cabozantinib was 81%, with 28% of the patients with grade 3 or 4 hypertension. 44
Lenvatinib
Lenvatinib is an FDA approved VEGF TKI which is FDA approved for the treatment of advanced renal cell carcinoma, advanced hepatocellular carcinoma, and radioactive iodine refractory differentiated thyroid cancer. 45
The most common, and oftentimes severe and treatment limiting adverse effect of lenvatinib is hypertension, with recent studies suggesting that the cause of this to be more complex than solely being a result of decreased peripheral vascular resistance in the setting of decrease NO as a result of VEGF inhibition. Through the use of reactive hyperemia-peripheral arterial tonometry, it was demonstrated that hypertension was caused in those treated with lenvatinib by inducing endothelial dysfunction. 46
A 2015 review found that in studies including patients treated with lenvatinib, cardiac dysfunction was seen in 7% of patients, and 2% of patients developing grade 3 or higher cardiac dysfunction with a >20% reduction in LVEF. 47
In the SELECT study, a 2018 multicenter, double-blind study which included 261 patients randomized to lenvatinib for the treatment of progressive radioiodine refractory differentiated thyroid cancer, of found that 73% of these patients treated with lenvatinib developed treatment emergent hypertension (TE-HTN), with the average onset of TE-HTN of 2.3 weeks after the initiation of the drug. 44% of patients on lenvatinib would experience grade 3 or higher hypertension, with 26% of patients requiring dose reductions or interruptions, and only 1% requiring complete drug withdrawal. Interestingly, univariate analysis found a statistically significant correlation between TE-HTN and progression free survival, suggesting that TE-HTN may have a role as a predictor of clinical efficacy. Additionally, in those treated with Lenvatinib, QT/QTc prolongation occurred in 9% of patients, with 2% found to have a QT >500 ms. Arterial thrombotic events occurred at 5%. 48
In 2020, the REFLECT trial, which included 168 patients with unresectable hepatocellular carcinoma treated with Lenvatinib, would show that 45% of patients treated with lenvatinib had all grade hypertension, with 24% of patients with grade 3 hypertension, with a median time to onset of new or worsening hypertension of 3.7 weeks. QTc interval increases of >60 ms was seen in 8%, and QTc intervals of >500 ms was seen in 2% of patients treated with lenvatinib. 2% of patients would develop arterial thrombotic events on lenvatinib in REFLECT. 49
Most recently in a 2021 retrospective analysis in patients with metastatic renal cell carcinoma included 55 patients treated with Lenvatinib. In these, 42% of patients developed any grade hypertension, with 13% of patients with grade 3 hypertension with the average time to onset of new or worsening hypertension was 5 weeks. QTc interval increases of >60 mg was seen in 11% of patients in Study 205 treated with lenvatinib. 2% of patients developed arterial thromboembolic events. 49
Pazopanib
A 2013 meta-analysis compared 13 trials with a combined 1651 patients in which patients received pazopanib, sorafenib, and sunitinib, and pazopanib was found to have significantly higher rates of hypertension than both Sorafenib and Sunitinib with relative risks of 1.99 for sorafenib, and 2.20 for sunitinib for developing all grade hypertension. Those treated with Pazopanib had incidences of all grade and high-grade hypertension at 35.9% and 6.5% respectively, with a relative risk of 4.97 for all grade hypertension and of 2.87 for high grade hypertension compared to control. The rates of developing high-grade hypertension would be similar across the three TKIs. 50
Sorafenib
In the previously mentioned 2018 meta-analysis on cardiotoxicity in VEGF TKIs, all were found to have a risk for cardiac ischemia, however, the highest risk was found to be in those treated with Sorafenib (RR = 2.01; 95% CI: 1.21-3.32; P = 0.007). 37 In a 2008 observational study with 74 patients with metastatic renal cell carcinoma treated either with sorafenib or sunitinib, in those treated with Sorafenib 33.8% were found to have cardiac adverse effects which were defined as an increase in cardiac enzymes, arrhythmia requiring treatment, LV dysfunction, or acute coronary syndrome. 51 In addition to this, it appears that those treated with sorafenib have a high risk for hypertension. A 2007 phase 3 randomized controlled trial of Sorafenib found that those treated with sorafenib for clear-cell renal-cell carcinoma, hypertension was seen in those treated with sorafenib at 17%. 52 A 2007 analysis of 4 phase 1 trials showed that sorafenib related hypertension seen in between 5-11% of patients. 53 In a phase II trial with a total of 54 patients treated with sorafenib for non-small cell lung cancer, 4% of patients would develop grade 3 hypertension, and one patient would suffer myocardial infarction. 54
Vandetanib
In a 2012 systematic review and meta-analysis on patients treated with Vandetanib which included phase II and III prospective trials included a total of 2188 patients. In this analysis, it was found that those treated with vandetanib for thyroid cancers were found to have QTc prolongation in 18.0% of patients with 12.0% of patients with high-grade QTc prolongation, with a Peto odds ratio of 7.22 times more likely to have any grade QTc prolongation compared to controls. In those treated for non-thyroid cancers, the rates for all QTc prolongation and high-grade prolongation were 16.4% and 3.7% respectively, with a Peto odds ratio of 5.7 for all grade QTc prolongation compared to control. 55
These findings were confirmed in the 2018 meta-analysis which showed that patients treated with VEGF TKI were at higher risk for QTc prolongation, specifically those treated with vandetanib were at the highest risk. (RR = 7.11; 95% CI: 3.66-13.81; P < 0.001). 37
Bruton’s Tyrosine Kinase Inhibitors
Bruton Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase (NRTK) that belongs to the Tec family of kinases (TFKs). BTK-A is expressed in all hematopoietic cells but is primarily found in B lymphocytes, assisting in cell maturation, differentiation, survival, and immunoglobulin synthesis through the B cell receptor (BCR) pathway. This tyrosine kinase plays a significant role in their malignant proliferation, survival, adhesion, and migration. 56
Toxicity of BTK inhibitors is mediated by both direct target inhibition of BTK and indirect target inhibition of other kinases that include interleukin-2–inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR). The toxicity profile of these TKIs is closely related to the pattern of kinase binding. 57 Recently, retrospective analyses of these agents showed increased ventricular arrhythmia incidence that appears to be a class effect. 58
One of the most common cardiac side effects of BKIs is hypertension, the exact indication unknown with several proposed mechanisms. One plausable mechanism is through the inhibition of cardiac PI3K-Akt signaling pathway, the inhibition of which is thought to cause hypertension through cellular remodelling and vascular tissue fibrosis. 59 Another postulated mechanism involved nitric oxide, as in vitro use of Ibrutinib has been seen to decrease nitric oxide production in dendtiric cells, with this downregulation resulting in endothelial dysfunction and thus hypertension. 60 This decrease in nitric oxide can be explained by additional in vitro studies which demonstrated that ibrutinib causes an anti-VEFG effect in a dose dependent fashion, with VEGF inhibition leading to the inhibition of endothelial nitric oxide synthetase. 61
Ibrutinib
Ibrutinib was a first-in-class irreversible BTK inhibitor that was first approved for the treatment of CLL in those with 17p13.1 chromosome deletion in 2013, 62 and more recently approved for a wide variety of conditions including small lymphocytic lymphoma (SLL), Waldenstrom macroglobulinemia, mantle cell lymphoma, marginal zone lymphoma, and chronic graft-vs-host disease. 63
Hypertension is one of the most common cardiovascular toxicities seen with Ibrutinib therapy, with a 2019 meta-analysis including 8 RTCs involving ibrutinib found a risk ratio of 2.85 (95% CI; 1.52-5.23) for ibrutinib. 64 A 2019 a trial including patients treated for lymphoid malignancies with ibrutinib included 562 patients, analyzed rates of new or worsening hypertension, in comparison to Framingham-heart predicted incidence of hypertension. At a median follow up of 30 months, 78.3% of patients on ibrutinib would develop either new, or worsening hypertension, with 37.6% of patients developing grade 3 or 4 hypertension, which included 17.7% of patients without a baseline history of hypertension. A majority of patients who would go on to suffer new or worsening hypertension would do so earlier in the course of treatment, as can be seen by 54.1% of patients with no history of hypertension reaching hypertension thresholds within 6 months of initiation of ibrutinib. 65
Another very common cardiovascular toxicities from Ibrutinib is atrial fibrillation, however the exact mechanism for this is not fully understood. A reduction in PI3K-Akt signaling was found to be suppressed in isolated rat myocardial cells treated with ibrutinib, thought to increase propensity for atrial fibrillation. Aberrant APs were seen in these treated myocardial cells, which resolved with the addition of PI3K. 66 The resulting electrophysiologic remodeling resulting in shortening of action potential and refractory period is thought to be the likely pathophysiological cause for the increase in atrial fibrillation. 67
A 2017 study that pooled data from 4 randomized controlled trials for a total of 1505 patients with CLL treated with ibrutinib found an atrial fibrillation incidence of 6.5% at an average of 16.6 month follow up. 68 In the RESONATE trial, which included 391 patients with relapsed or refractory CLL/SLL treated with ibrutinib, at a median follow-up of 9.4 months a total of 5% of patients developed atrial fibrillation, 3% of these being grade 3 or above. 69 An extended follow-up of patients in this RESONATE study was performed with a median follow-up of 19 months which revealed an Atrial fibrillation incidence of 7%. 70 In a follow-up randomized phase 3 trial RESONATE 2 which included 269 patients over the age of 65 years with CLL/SLL, those treated with ibrutinib were found to have a 6% prevalence of atrial fibrillation at a median follow-up at 17.4 months. 71 At a 5-year follow-up of the RESONATE-2 trial, it was found that 16% of patients had developed atrial fibrillation at any point, 72 with a later 8-year follow-up of the RESONATE-2, showed that prevalence rates of atrial fibrillation were 7% at 8 years and with 6% of patients having experienced grade 3 atrial fibrillation over this period. 73
Ibrutinib has also been found to be associated with ventricular fibrillation, however at a significantly lower rate than atrial fibrillation. In a 2018 retrospective study including 582 patients with lymphoid malignancies initiated with ibrutinib therapy, the estimated incidence rate of ventricular arrhythmias at a median follow up of 32 months was 617 per 100,000 person-years of ibrutinib exposure, with the median time to event of 16 months. Subset analysis of these events to exclude those with baseline coronary artery disease or heart failure with reduced ejection fraction would only slightly lower the incidence rate of ventricular arrhythmia to 596 per 100,000 person years of ibrutinib exposure. This, along with the fact that no electrocardiographic variables were associated with the development of ventricular arrhythmias, indicated that even when accounting for baseline cardiovascular disease the rates of ventricular arrhythmia remain elevated with long term ibrutinib use. 74 These findings would be similar to those of the HELIOS study, a randomized phase 3 study in 2016 looking at ibrutinib in addition to bendamustine and rituximab in those with CLL or SLL, of 287 patients receiving ibrutinib the rates of grade 3 or more ventricular arrhythmias, cardiac arrests and sudden cardiac deaths was 2%. 75 The mechanism of ventricular fibrillation in ibrutinib use is not thought to be caused by QT prolongation or early afterdepolarizations. 76
Acalabrutinib
Acalabrutinib is an irreversible Bruton tyrosine kinase, found to be more selective than ibrutinib, which is FDA-approved for the treatment of chronic lymphocytic leukemia, 77 which would be confirmed to be an effective treatment for CLL in A 2022 randomized controlled phase 3 trial ELEVATE-TN. Acalabrutinib is also thought to cause hypertension, but to a far lesser extent than ibrutinib, in ELEVATE-TN only 2% of patient’s in the acalabrutinib monotherapy group would develop grade 3 > hypertension. 78 In the ASCEND trial, a phase III randomized control trial including patients treated with acalabrutinib for relapsed or refractory CLL, only 3% of patients treated with Acalabrutinib would develop all grade hypertension. 79
The incidence of atrial fibrillation appears to be less than that of ibrutinib, however, when this occurs it can be associated with worse long-term survival. 58
Zanubrutinib
Approved by the FDA in 2019, zanubrutinib is a highly selective, irreversible second-generation BTK inhibitor, that was developed to ensure greater BTK specificity over TEC, with no interference of ITK activity, leading to fewer cardiac side effects than ibrutinib. 56
During early clinical development, it was noted that zanubrutinib when used as a monotherapy at a dose of either 160 mg twice a day or a single dose of 320 mg had complete and sustained BTK occupancy (level of drug binding to BTK) in samples of peripheral blood mononuclear cells, and the median BTK occupancy in lymph nodes was 100% with twice-daily doses and 94% with the once-daily dose. 80
In the APLINE trial, a phase 3 randomized control trial that included 652 patients with refractory chronic lymphocytic leukemia randomized to ibrutinib vs zanubrutinib, generally found a more favorable cardiotoxicity profile in zanubrutinib compared to ibrutinib at a median follow up of 29.6 months, with overall cardiac disorders developed in 21.3% of patients treated with Zanubrutinib compared to 29.6% in those treated with ibrutinib. Atrial fibrillation or Atrial flutter was seen in 5.2% of patients treated with zanubrutinib compared to ibrutinib. Hypertension developed more often in those treated with zanubrutinib compared to ibrutinib with 14.8% vs 11.1% respectively in each group. Zanubrutinib was discontinued due to these cardiac toxicities in only 0.3% of patients but was significantly higher in the ibrutinib group at 4.3%. 80
In the ASPEN study, a phase III randomized control trial, Zanubrutinib was compared to Ibrutinib for patients with symptomatic Waldenstrom Macroglubulinemia. The hazard ratio for hypertension in those treated with zanubrutinib compared to Ibrutinib was 0.59 (95% CI 0.29-1.20), with an indence of hypertension of 0.7 per 100 person-months for Zanubrutinib compared to 1.2 per 100 person-months for ibrutinib. 81
Pirtobrutinib
Pirtobrutinib is a highly selective third generation noncovalent BTK inhibitor which inhibits both BTK and C481-mutant BTK, which was designed to bypass the various mechanisms of resistance in the preexisting covalent BTK inhibitors. 82 In the BRUIN study, a recent phase 1-2 trial in which 277 patients with CLL or SLL who had previously been traded with at least one BTK inhibitor were treated with at least one dose of pirtobrutinib, low rates of cardiotoxicity was observed. Hypertension was seen in 14.2% and atrial fibrillation in 3.8% (with no grade 3 events of atrial fibrillation or atrial flutter) of patients treated with pirtobrutinib, with no drug related cases of ventricular arrhythmia or sudden cardiac death. 83
EGFR Tyrosine kinase Inhibitors
EGFR TKIs were found to be an effective therapeutic option for many cancers. A 2015 meta-analysis found that patients with upper gastrointestinal cancers treated with EGFR TKIs compared to standard therapy alone had improved disease control rate and progression-free survival, however they were also found to have higher rates of adverse effects, specifically cardiac events. 84
Gefitinib
Murine models with Gefitinib in rats show cardiotoxicity by several proposed mechanisms, the first being the downregulation of antihypertrophic gene markers such as α-MHC, in addition to the upregulation of pro-hypertrophic gene markers such as BNP and β-MHC. This combination leads to both increased cardiac hypertrophy and cardiomyocyte apoptosis due to oxidative stress in the setting of upregulation of apoptotic mediators p53 and caspase-3. 85
Erlotinib
Chronic erlotinib use was found to cause cardiac stress in animal models, thought to at least in part be mediated by increase in plasma substance P, and oxidative stress, which lead to decreased in left ventricular ejection fraction, % fractional shortening, and reduction in mitral valve E/A ratio suggestive of diastolic dysfunction. 86 The 2007 study which lead to the approval of Erlotinib compared it’s use with gemcitabine compared to gemcitabine alone found that those who were treated with erlotinib had myocardial ischemia/infarction in 2.3% of patients compared to 1.2% of patients who received gemcitabine alone. 87
A meta-analysis was performed on 7611 patients treated with the EGFR agents including monoclonal antibodies cetuximab and panitumumab, along with EGFR TKIs gefitinib, and erlotinib to evaluate the risk for thromboembolic events. Interestingly while both cetuximab and panitumumab were associated with significantly increased risks of thromboembolic events, the EGFR TKIsG gefitinib and erlotinib were not associated with a risk of developing venous thrombotic events. 88
Afatinib
Afatinib is a second-generation EGFR TKI, which is a non-reversible inhibitor of the ErbB family of receptors. This differs from the first-generation EGFR TKIs such as afatinib and gefitinib as it blocks all homodimers and heterodimers including EGFR (HER1/ErbB1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). 89
Pooled data analysis of phase II trials, which included 49 trials and 3865 patients treated with afatinib for EGFR mutation-positive non-small cell lung cancer found that risk-adjusted cardiac failure adverse events years (events/100 patients years) and rates of left ventricular dysfunction were not statistically different between afatinib and placebo. 90
Osimertinib
A retrospective single study which included 123 patients with EGFR-mutant advanced NSCLC treated with Osimertinib found that severe cardiac adverse events occurred in 4.9% of patients. These severe cardiac events included myocardial infarction, heart failure with reduced ejection fraction, and severe vascular heart disease, 83% of these patients had prior cardiac history. In addition to this, of 36 patients who were serially evaluated with echocardiogram, an average drop in LVEF of 6% was seen from 69.4% to 63.4%. 91
LV dysfunction and QT prolongation from Osimertinib were seen in the FLAURA trial, which was a double-blind phase 3 trial comparing Osimertinib to standard EGFR TKI, which was defined as gefitinib or erlotinib. This trial included 279 patients who received Osimertinib, and of these 10% of patients developed QT prolongation compared to 5% in the standard EGFR-TKI group. 8% of the patients who received osimertinib developed grade 1 or grade 2 QT prolongation, with 2% developing grade 3, and <1% developing grade 4 QT prolongation. Additionally, 3% of the patients in the osimertinib group would be found to have LVEF decrease, compared to just 1% of those treated with standard EGFR-TKI. 92
A later 2021 retrospective single center study including 183 patients treated with osimertinib for EGFR mutant NSCLC found that 8.7% of patients had an LVEF decrease by 10% or more, with 4.4% of patients satisfying criteria for CTRCD. Of those who reached criteria of osimertinib induced CTRCD, 75% would recover with either discontinuing of the medication, dose reduction, or treatment with alternative EGFR TKI. Across the board those treated with Osimertinib would have an average LVEF decrease of 3% from 69% to 66%. 93
Lapatinib
Lapatinib is an EGFR TKI which differs from the other TKIs in its class as it has both activity against EGFR and human epidermal growth factor receptor-2 (HER2). 94
Analysis of prospective data for those treated with lapatinib included 3689 patients, which found that a study defined cardiac events occurred in 1.6% of patients treated with lapatinib. The rate of symptomatic CHF was 0.2% of patients treated with lapatinib. It was found the mean time to onset of LVEF decrease was 13.0 weeks, with a mean nadir LVEF of 43%, with 88% of these patients demonstrating a partial or full recovery of LVEF. 95
ALK tyrosine kinase inhibitors
In 2007, the oncogene EML4-ALK was identified in patients with NSCLC, and it was suggested at this time that inhibition of the tyrosine kinase activity linked to EML4-ALK could have implications in the treatment of NSCLC. 96 Frequencies of EML4-ALK mutations in patients with NSCLC is seen in as many as 13% of all patients, and 33% among light/never smokers. 97 The most common adverse effects from ALK TKIs are typically nausea, diarrhea, vision disorders, and abnormal liver enzymes, however some important cardiotoxicities have been established including QTc prolongation, bradycardia, and hypercholesterolemia/hyperlipidemia, and hypertension. 98
Alectinib
An analysis of two studies which combined 225 patients treated with alectinib for NSCLC found no evidence of clinically significant QTc prolongation in those treated with alectinib. Those treated with alectinib were found to have an average HR of 11-13 beats slower, with only 5% experiencing symptomatic bradycardia and all the events limited to grade 1-2. 99
Ceritinib
Across trials in those treated with ceritinib, QTc prolongation was seen in as 1% of patients developed a QTc ≥ 500 ms, with an additional 3% of patients with an increase in their QTc ≥ 60 ms, with pharmacodynamic analysis showing that this increase in QTc was dose dependent. 100
Crizotinib
Data from clinical trials on crizotinib shows evidence of dose dependent QTc prolongation, with a mean QTcF change of 12.3 ms from baseline in those treated with crizotinib, with a total of 2.1% of patients developing a QTcF (Fridericia formula) of ≥ 500 ms, and 5.0% of patients with an increase in QTcF
≥ 60 ms compared to baseline.
101
Retrospective analysis of those in two trials treated with crizotinib found that on average those treated with crizotinib had a significant drop of 26.1 BPM in their average HR, with 69% of patients with at least one episode of sinus bradycardia (HR <60), and 31% experiencing profound bradycardia (HR <50).
102
Lorlatinib
Lorlatinib is a 3rd generation ALK TKI which is the most potent of the ALK TKIs, with the broadest activity against ALK mutations resistant to first and second-generation agents. 103 In the CROWN trial, a randomized controlled phase 3 trial that compared lorlatinib to crizotinib for ALK mutation-positive NSCLC found significantly higher rates of metabolic adverse effects in those treated with lorlatinib. In those treated with lorlatinib compared to crizotinib, the rates of hypercholesterolemia were 70% vs 4%, hypertriglyceridemia at 64% vs 6%, and increased weight at 38% compared to 13%. In addition to these high rates of hypertension (18% vs 2%) and peripheral edema (55% vs 39%) were also seen in those treated with lorlatinib compared to crizotinib. 104
Management of cardiotoxicity
The management of cardiotoxicity associated with tyrosine kinase inhibitors (TKIs) involves a multifaceted approach, including prevention, early detection, and treatment of cardiovascular complications. The first crucial step is reaching a consensus on the definition and categorization of cardiotoxicity resulting from TKI treatment, which is part of the broader category known as cancer therapy-related cardiac dysfunction (CTRCD).
Over the years, the definition of CTRCD has evolved significantly as our understanding of cardiotoxicity in the context of cancer treatment has advanced. In National Institute of Health’s (NIH) 5th version of the Common Terminology Criteria for Adverse Events (CTCAE), published in 2017, cardiac disorders including heart failure, myocarditis, and supraventricular tachycardias are graded in severity from grade 1 to grade 5. 105 The IC-OS 2021 consensus definition separates cancer therapy-related cardiac dysfunction (CTRCD) into two categories: asymptomatic and symptomatic. These categories are further graded to mild, moderate, severe and very severe, with a specific focus on commonly seen CRTCDs such as: cardiomyopathy and heart failure (HF), myocarditis, vascular toxicities, hypertension, cardiac arrhythmias, and corrected QT interval (QTc) prolongation. 106
The 2022 European Society of Cardiology (ESC) Cardio-Oncology guidelines, developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO), and the International Cardio-Oncology Society (IC-OS), provide consensus guidelines for baseline risk assessment, surveillance protocols, and prevention and management of cancer therapy-related cardiac dysfunction (CTRCD). 107
These guidelines emphasize the creation of individualized treatment plans based on the individual patient-specific risk factors to determine both the appropriate therapy and the necessary cardiac monitoring.108,109
Pretreatment assessment should encompass a thorough patient history, medication review, evaluation of cardiovascular risk factors (such as dyslipidemia, diabetes, prior cardiovascular disease, and family history of cardiovascular events), and a targeted cardiovascular examination. This examination should include an electrocardiogram (ECG), and in specific high cardiovascular risk patient’s the consideration for cardiac biomarkers and echocardiogram, along with routine monitoring of blood pressure. Risk stratification is essential to identify high-risk patients who may require closer monitoring and preventive measures to avoid the development of CTRCD.
Following pretreatment assessment, focus should shift to preventive strategies to mitigate the risk of cardiotoxicity. Focus should be made in encouraging patients to adopt healthy behaviors such as regular physical activity, balanced diet, smoking cessation, and weight management. Consideration for pharmacologic prophylaxis has been proposed and trials such as the SAFE trial suggest preventative treatments that offer cardioprotection such as ACE inhibitors, angiotensin II receptor blockers, beta blockers, or statins, all of which should be considered in high-risk patients. 110 Patients with significant cardiovascular risk factors, who are deemed to be high risk, should be referred to a Cardio-Oncologist to ensure optimal risk factor modification prior to initiating treatment. For those in resource limited areas, and without access to Cardio-Oncology services, a pragmatic approach can be had to minimizing risk for cardiotoxicity. Regardless of the setting, the approach to surveillance and monitoring for this should be considered a multidisciplinary one, and whether it be the Oncology or the Primary care providers, all can aid in limiting Cardiotoxicity in the ways mentioned above: obtaining a thorough patient history, performing regular blood pressure measurements, and encouraging lifestyle modifications Table 1.
Table 1.
Summary of TKIs and Common Studies Endpoints and Results.
| TKI investigated | Reference | Publication year | Study type | Number of patients | Common Endpoints | Results |
|---|---|---|---|---|---|---|
| Imatinib | Kerkela, R., et al 12 | 2006 | Case series | 10 | Transmission electron micrographs of heart biopsies | Biopsies showed mitochondrial abnormalities and abnormal accumulation of membrane whorls in vacuoles. This signifies endoplasmic reticulum stress response |
| Imatinib | Perik, PJ, et al 111 | 2008 | Prospective trial | 55 | NT-proBNP and cTnT | Elevated in NT-proBNP and cTnT were not seen in a majority of patients except those with preexisting cardiac disease |
| Sunitinib | Chu, Tammy F et al 39 | 2007 | Retrospective analysis | 75 | LVEF, BP, cardiac death, myocardial infarction, and CHF. | A total of 11% of patients were found to have cardiotoxicity. 47% of patients developed hypertension, 28% had a decrease in LVEF of 10% of more, and 19% had LVEF decrease of 15% or more |
| Nilotinib, and imatinib | Giles, F. J., et al 13 | 2013 | Retrospective analysis | 2390 | Incidence of peripheral arterial occlusive disease (PAOD) | Nilotinib was found to have no impact on PAOD rates, while imatinib decreased rates. Nilotinib with higher rates of PAOD compared to imatinib |
| Imatinib and dasatinib | Kantarjian, Hagop, et al 19 | 2007 | Randomized controlled trial | 150 | Evidence of fluid retention including superficial edema, peripheral edema, face edema, or pleural effusion | Patients treated with dasatinib with 5% with superficial edema, 10% with peripheral edema, 4% with face edema, and 17% with pleural effusions, compared to 86%, 41%, 20% and 0% respectively for those on imatinib |
| Imatinib and dasatinib | Talpaz, Moshe, et al 20 | 2006 | Randomized controlled trial | 84 | Evidence of peripheral edema, pleural effusion, and pericardial effusion | Those treated with dasatinib found to have peripheral edema (19.0%), pleural effusion (17.8%), and pericardial effusion (4.8%) |
| Ibrutinib | Brown, Jennifer R., et al 68 | 2017 | Pooled analysis of 4 RTCs | 1505 | Incidence of atrial fibrillation at follow up | AF incidence was 6.5% [95% confidence interval (CI): 4.8, 8.5] |
| Ibrutinib | Byrd, John C., et al 69 | 2014 | Randomized controlled trial | 391 | Incidence of atrial fibrillation at follow-up | 5% of patients developed atrial fibrillation, 3% of these being grade 3 or above, at median follow up of 9.4 months |
| Ibrutinib | Brown, J. R., et al 70 | 2018 | Randomized controlled trial | 195 | Incidence of atrial fibrillation at follow-up | Atrial fibrillation incidence of 7% at a median follow-up of 19 months |
| Ibrutinib | Burger JA, et al 71 | 2015 | Randomized controlled trial | 269 | Incidence of atrial fibrillation at follow-up | 6% prevalence of atrial fibrillation at a median follow-up of 17.4 months |
| Ibrutinib | Barr, Paul M., et al 73 | 2022 | Randomized controlled trial | 60 | Incidence of atrial fibrillation at follow-up | Prevalence of atrial fibrillation was 7% at 8 years, with 6% of patients having experienced grade 3 atrial fibrillation over this period |
| Nilotinib vs imatinib | Kantarjian, Hagop M., et al 18 | 2021 | Randomized controlled trial | 836 | Cumulative incidence of cardiovascular events including ischemic heart disease, peripheral arterial occlusive disease, and cerebrovascular disease | Those receiving nilotinib 300 mg BID and 400 mg BID respectively had 16.5% and 23.5% rates of CVE, compared to 3.6% in those receiving imatinib |
| Bosutinib vs imatinib | Cortes, Jorge E et al 27 | 2016 | Retrospective analysis | 570 | Incidence of vascular/cardiac events | Cardiovascular events in those treated with bosutinib at follow-up of >48 months(5%/8%) was not significantly higher than imatinib (4%/6%) |
| Ponatinib | Cortes, Jorge E., et al 28 | 2013 | Randomized controlled trial | 270 | Incidence of cardiovascular, cerebrovascular and peripheral vascular events | Rates of cerebrovascular events, cerebrovascular events, and peripheral vascular events were 7.1%, 3.6%, 4.9% respectively |
| Ponatinib | Cortes, Jorge E., et al 29 | 2018 | Randomized controlled trial | 270 | Incidence of cardiovascular, cerebrovascular and peripheral vascular events | 16% of patients had cardiovascular events, 13% had cerebrovascular events, and 14% with peripheral vascular events |
| Ponatinib | Dorer DJ, knickerbocker RK, baccarani M, et al 30 | 2016 | Multivate analysis | 270 | Incidence of arterial occlusive events with dose reduction | 15 mg reduction in the daily dose of ponatinib leads to an approximate 33% reduction in all AOE |
| Axitinib, lenvatinib, nintedanib, pazopanib, regorafenib, sorafenib and sunitinib | Totzeck, Matthias, et al 37 | 2018 | Meta-analysis | 29,252 | Incidence of cardiac ischemia, LV dysfunction, QTc prolongation, arterial hypertension | Cardiac ischemia risk in all VEGF TKI, highest in sorafenib with RR 2.01. Left ventricular systolic dysfunction in all VEGF TKI, the highest rates of this were seen in those who were treated with sunitinib RR = 2.96. QTc prolongation seen in all VEGF TKI, highest in those treated with vandetanib were at the highest risk. RR = 7.11 |
| Lapatinib | Perez, Edith A., et al 95 | 2008 | Meta-analysis | 3689 | Cardiac events defined as symptomatic or asymptomatic | Cardiac events occurred in 1.6% of patients treated with lapatinib. The rates of symptomatic CHF was 0.2% of patients treated with lapatinib |
| Ponatinib | Cortes, Jorge, et al 31 | 2021 | Randomized, open-label phase 2 clinical trial | 283 | Incidence of arterial occlusive events | Arterial occlusive events on ponatinib were dose-dependent. 15 mg, 30 mg and 45 mg were found to have 3.2%, 5.3%, and 9.6% rates of arterial occlusive events at a median follow-up of 32 months |
| Sunitinib | Zhu, Xiaolei, et al 33 | 2009 | Meta-analysis | 4999 | Incidence of all-grade and high-grade hypertension | Those treated with sunitinib were found to have all-grade hypertension at 21.6%, and high-grade hypertension at 6.8, with a relative risk of 22.72 for high-grade hypertension |
| Axitinib vs sorafenib | Rini BI et al 40 | 2011 | Randomised phase 3 trial | 723 | Incidence of all-grade hypertension | Axitinib, compared to sorafenib had lower rates of all-grade hypertension with 29% with hypertension compared to 40% respectively |
| Asciminib vs bosutinib | United States prescribing information 112 | 2021 | Prescribing data | 356 | Incidence of arterial ischemic events, cardiac failure, hypertension and QTc prolongation | Arterial ischemic events at 13%, cardiac failure at 2.2%, hypertension at 19%, and QTc prolongation at 7% |
| Sorafenib | Strumberg D, et al 53 | 2007 | Review article | 173 | Incidence of all-grade hypertension | A 2007 analysis of 4 phase 1 trials showed that sorafenib related hypertension seen in between 5-11% of patients |
| Sorafenib | Escudier B. et al 52 | 2007 | Phase 3, randomized controlled trial | 903 | Incidence of all-grade hypertension | Hypertension was seen in those treated with sorafenib at 17% |
| Sorafenib and Sunutinib | Schmidinger M, et al 51 | 2008 | Observational, single-center study | 86 | Cardiac adverse effects: Increase in cardiac enzymes, arrhythmia requiring treatment, LV dysfunction, or acute coronary syndrome | Of those treated with sorafenib or sunutinib, 33.8% were found to have cardiac adverse effects |
| Vandetanib | Zang, Jiajie, et al 55 | 2012 | Systematic review and meta-analysis | 2188 | Incidence of all-grade and high-grade QTc prolongation | Those treated with vandetanib for thyroid cancers were found to have QTc prolongation in 18.0% of patients with 12.0% of patients with high-grade QTc prolongation, with a peto odds ratio of 7.22 compared to controls. In those treated for non-thyroid cancers, QTc prolongation and high-grade prolongation were 16.4% and 3.7% respectively, with a peto odds ratio of 5.7 compared to control |
| Asciminib vs bosutinib | Rea, Delphine, et al 34 | 2021 | Phase 3, open-label, randomized study | 233 | Incidence of hypertension and arterial-occlusive events | Hypertension in asciminib, with 11.5% rates of all hypertension and grade 3 hypertension in 3.9%, compared to 5.8% and 2.8% respectively for bosutinib. Arterial-occlusive events higher in those treated with asciminib at 3.2% compared to 1.3% in those treated with bosutinib |
| Pazopanib, sarafenib, and sunitinib | Qi, Wei-Xiang, et al 50 | 2013 | Meta-analysis | 1615 | Incidence of all-grade and high-grade hypertension | Relative risks for sorafenib, sunitinib and the development of hypertension 1.99 and 2.20 respectively. Pazopanib with incidences of all grade and high-grade hypertension at 35.9% and 6.5% respectively, with a relative risk of 4.97 for all grade hypertension and of 2.87 for high grade hypertension |
| Erlotinib | Senderowicz, Adrian M., et al 87 | 2007 | Randomized, double-blind, placebo-controlled, multi-institutional phase III study | 569 | Incidence of myocardial ischemia | Those who were treated with erlotinib had myocardial ischemia/infarction in 2.3% of patients compared to 1.2% of patients who received gemcitabine alone |
| Crizotinib | United States prescribing information 101 | 2017 | Prescribing data | 1719 | QTcF prolongation and changed in QTcF from baseline | Mean QTcF change of 12.3 ms from baseline in those treated with crizotinib, with a total of 2.1% of patients developing a QTcF of ≥ 500 ms, and 5.0% of patients with an increase in QFcF |
| Alectinib | Morcos, peter N., et al 99 | 2017 | Analysis of two single-arm trials | 225 | QTc prolongation, average heart rate, symptomatic bradycardic events | No evidence of clinically significant QTc prolongation. Those treated with alectinib were found to have an average HR of 11-13 beats slower, with only 5% experiencing symptomatic bradycardia and all the events limited to grade 1-2 |
| Ceritinib | United States prescribing information 100 | 2017 | Prescribing data | 919 | Incidence of QTc prolongation | QTc prolongation was seen in as 1% of patients developed a QTc ≥ 500 ms, with an additional 3% of patients with an increase in their QTc ≥ 60 ms, with pharmacodynamic analysis showing that this increase in QTc was dose dependent |
| Crizotinib | Ou, Sai‐Hong Ignatius, et al 102 | 2013 | Retrospective analysis | 42 | Heart rate, episodes of bradycardia and severe bradycardia | Those treated with crizotinib had a drop of 26.1 BPM in their average HR, with 69% of patients with at least one episode of sinus bradycardia (HR <60), and 31% experiencing profound bradycardia (HR <50) |
| Lorlatinib vs crizotinib | Shaw, Alice T et al 104 | 2020 | Randomized, phase 3 trial | 296 | Incidence of hypercholesterolemia, hypertriglyceridemia, weight, hypertension, and peripheral edema | In those treated with lorlatinib compared to crizotinib, the rates of hypercholesterolemia were 70% vs 4%, hypertriglyceridemia of 64% vs 6%, and weight gain in 38% compared to 13%. Higher rates of hypertension (18% vs 2%) and peripheral edema (55% vs 39%) with lorlatinib compared to crizotinib |
| Osimertinib | Kunimasa K, kamada R, Oka T, et al 91 | 2020 | Retrospective single-center cohort study | 123 | Incidence of severe cardiac AE including acute myocardial infarction, heart failure with reduced EF, valvular heart disease, and serial LVEF monitoring | Severe cardiac adverse events occurred in 4.9% of patients, of which 83% of these patients had prior cardiac history. In addition to this, of 36 patients who were serially evaluated with echocardiogram, an average drop in LVEF of 6% was seen from 69.4% to 63.4% |
| Osimertinib vs gefitinib and erlotinib | Soria, Jean-charles, et al 92 | 2018 | Double-blind, phase 3 trial | 556 | QT prolongation and LVEF decrease | Those receiving osimertinib, 10% of patients developed QT prolongation, 8% developed grade 1 or grade 2 QT prolongation, with 2% developing grade 3, and <1% developing grade 4 QT prolongation. 3% of the patients in the osimertinib group with decrease in LVEF. |
| Osimertinib | Kunimasa K, Oka T, Hara S, et al 93 | 2021 | Retrospective single center study | 183 | Decrease in LVEF, satisfaction of criteria for CTRCD | 8.7% of patients had an LVEF decrease by 10% or more. 4.4% of patients satisfying criteria for CTRCD, of which 75% would recover with either discontinuing of the medication, dose reduction, or treatment with alternative EGFR TKI. Those treated with osimertinib would have an average LVEF decrease of 3% from 69% to 66% |
| Zanubrutinib vs ibrutinib | Brown, Jennifer R., et al 80 | 2023 | Multinational, phase 3, head-to-head trial | 652 | Incidence of atrial fibrillation/flutter, hypertension, incidence of medication discontinuation due to cardiotoxicity | Cardiac disorders developed in 21.3% of patients treated with zanubrutinib compared to 29.6% in those treated with ibrutinib. Atrial fibrillation or atrial flutter was seen in 5.2% of patients with zanubrutinib compared to 13.3% in ibrutinib. Hypertension developed more often in those treated with zanubrutinib compared to ibrutinib with 14.8% vs 11.1% respectively. Zanubrutinib was discontinued due to these cardiac toxicities in only 0.3% of patients ibrutinib discontinued in 4.3% |
| Cabozantinib | U.S. Food and drug Administration 41 | 2012 | Prescriber data | 409 | Incidence of hypertension and thromboembolism | Hypertension occurred in 36% of patients treated with cabozantinib 60 mg daily, thromboembolism occurred in 7% |
| Cabozantinib | Choueiri, T.K, et al 42 | 2016 | Open label randomized phase 3 trial | 330 | Incidence of all-grade hypertension and high-grade hypertension | Hypertension occurring in 37% of patients with 15% of patients with grade 3 or 4 hypertension |
| Cabozantinib | Choueiri, Toni K et al 44 | 2018 | Randomised phase 2 trial | 157 | Incidence of all-grade hypertension and high-grade hypertension | Incidence of all grade hypertension in those treated with cabozantinib was 81%, with 28% of the patients with grade 3 or 4 hypertension |
| Cabozantinib | Zhang, X, et al 43 | 2016 | Systematic review and meta-analysis | 1083 | Incidence of all-grade hypertension and high-grade hypertension | Those treated with cabozantinib developed all grade hypertension 5.48 times more often than those treated with control and were 5.09 times more likely to develop high-grade hypertension |
| Dasatinib | Hughes, Timothy P et al 25 | 2019 | Multivariate analyses of dasatinib clinical trial data | 2712 | Incidence of pleural effusion | The annual risk of developing pleural effusions in the DASISION and CA180-034 trials was 6-9% and 5-15% respectively. At a follow up of 5 years in DASISION the rates of pleural effusion were 28%, and 33% at 7 years in CA180-034 were 33% |
| Ibrutinib | Guha, Avirup, et al 74 | 2018 | Retrospective study | 582 | Incidence of ventricular arrhythmias with events per 100,000 person-years of ibrutinib exposure | Incidence rate of ventricular arrhythmias at a median follow up of 32 months was 617 per 100,000 person-years of ibrutinib exposure, with the median time to event of 16 months Subset analysis of these events to exclude those with baseline coronary artery disease or heart failure with reduced ejection shows incidence rate of ventricular arrhythmia of 596 per 100,000 person years of ibrutinib exposure |
| Ibrutinib | Chanan-Khan, Asher, et al 75 | 2016 | Randomised, double-blind, phase 3 study | 578 | Rates of ventricular arrythmias, cardiac arrests, and sudden cardiac deaths | 287 patients receiving ibrutinib the rates of grade 3 or more ventricular arrhythmias, cardiac arrests and sudden cardiac deaths was 2% |
| Lenvatinib | Wirth, Lori J., et al 48 | 2018 | Multicenter, double blind study | 261 | Incidence of treatment emergent hypertension (TE-HTN), rates of QT/QTc prolongation, and rates of arterial thrombotic events | 73% of patients treated with lenvatinib developed TE-HTN, with the average onset of 2.3 weeks. 44% of patients on lenvatinib would experience grade 3 or higher hypertension. QT/QTc prolongation occurred in 9% of patients, with 2% found to have a QT >500 ms. Arterial thrombotic events occurred at 5% |
| Lenvatinib | Yamashita, Tatsuya et al 49 | 2020 | Phase 3 randomzied controlled trial | 168 | Incidence of hypertension, median time to onset of hypertension, QTc prolongation, and rates of arterial thrombotic events | 45% of patients treated with lenvatinib had all grade hypertension, with 24% of patients with grade 3 hypertension, with a median time to onset of new or worsening hypertension of 3.7 weeks. QTc interval increases of >60 ms was seen in 8%, and QTc intervals of >500 ms was seen in 2% of patients treated with lenvatinib. 2% of patients would develop arterial thrombotic events |
| Lenvatinib | Lee, chung-Han et al 113 | 2021 | Retrospective analysis | 55 | Incidence of hypertension, median time to onset of hypertension, QTc prolongation, and rates of arterial thrombotic event | 42% of patients developed any grade hypertension, with 13% of patients with grade 3 hypertension with the average time to onset of new or worsening hypertension was 5 weeks. QTc interval increases of >60 mg was seen in 11% of patients in study 205 treated with lenvatinib. 2% of patients developed arterial thromboembolic events |
| Lenvatinib | Shah, R.R. et al 15 | 2015 | Review article | 3737 | Incidence of cardiac dysfunction | Cardiac dysfunction was seen in 7% of patients, and 2% of patients developing grade 3 or higher cardiac dysfunction with a >20% reduction in LVEF |
Collaborating with regional healthcare facilities for periodic specialist consultations and leveraging telemedicine for remote expert advice can also be beneficial. Ensuring patients adhere to these preventive measures and maintaining open communication with any available specialists, even remotely, can help manage the risk of cardiotoxicity effectively in these settings.
Ongoing monitoring during treatment is crucial for early detection and management of cardiotoxicity. Many modalities are available to assist with early detection, including ECGs, echocardiograms, and cardiac biomarker assessment, all of which can all be performed to detect early signs of cardiotoxicity, with the 2022 ESC Cardio-Oncology guidelines providing guidance for surveillance protocol based on the patient’s baseline risk factors. 107
When cardiotoxicity is detected, a timely intervention is essential. Interventions will depend on the severity of the cardiotoxicity, but may include dose adjustments, initiation of cardioprotective medications, or even medication discontinuation. Decisions regarding dose adjustment or discontinuation should be made based on the severity of toxicity, and close collaboration between oncologists, cardiologists, and other healthcare providers is key to optimizing treatment plans and managing side effects, allowing patients to continue their therapy with minimal interruptions.
Long-term follow-up is important to ensure sustained cardiovascular health post-TKI therapy. Routine monitoring of cardiovascular status even after completion of TKI therapy helps detect late-onset cardiotoxic effects and address any long-term cardiovascular conditions resulting from TKI therapy.
In a subset of patient population, tailored management should be employed based specific clinical scenarios. For example, in patients with multiple CV risk factors, the physician should favor more selective drugs such as acalabrutinib or Zanubrutinib over Ibrutinib. In patients with history of ventricular arrhythmia, family history of sudden cardiac death, severe uncontrolled hypertension, or severe/uncontrolled congestive heart failure, BTK inhibitors are not recommended, however ultimately these decisions should be made with close collaboration of a multidisciplinary team.
In summary, managing cardiotoxicity in patients undergoing tyrosine kinase inhibitor (TKI) therapy requires a comprehensive and proactive approach, particularly in resource-limited settings. By integrating thorough pretreatment assessments, preventive strategies, vigilant monitoring, and timely interventions, healthcare providers can significantly mitigate the risk of cardiotoxicity. Accurate risk stratification is critical, ensuring high-risk patients receive appropriate surveillance while avoiding unnecessary withholding of treatment in lower-risk patients. Emphasizing lifestyle modifications and utilizing available diagnostic tools, even in constrained environments, can help maintain cardiovascular health and optimize treatment outcomes. Collaboration among multidisciplinary teams and leveraging remote consultations further enhance patient care. Ultimately, a well-structured, individualized management plan is essential to ensure the safety and efficacy of TKI therapy, thereby improving overall patient outcomes.
Limitations
Despite the growing nature of research in the field of Cardio-Oncology, especially when it comes to Cardiotoxicity in the setting of tyrosine kinase inhibitors (TKIs), several significant limitations to this review must be acknowledged.
First, due to the nature of clinical trials on tyrosine kinase inhibitors (TKIs), patients with prior cardiovascular risks are often excluded. This causes a disparity between trial populations and real-world patients who often do present with complex cardiovascular histories. Due to this, it is likely that many trials do not accurately represent the real-world incidence of cardiotoxicity, potentially significant underestimating the risks certain patients may face. And not only are these patients often excluded from trials, historically very few clinical trials mandate appropriate routine cardiovascular monitoring, consequently leading to underreporting of clinically significant adverse events. One such example is the association between ibrutinib and ventricular tachycardia. While there is a clear association between ibrutinib and ventricular tachycardia, ventricular tachycardia (VT) that survive and reach medical attention represent only a subset of the true incidence, which excludes both those with asymptomatic events, and those who suffered sudden cardiac death.
In a similar vein, there is a paucity of analyses that consider patients’ baseline CV risks, including histories significant to oncology patients such as: anthracycline use or prior radiation therapy. As research in Cardio-Oncology grows, more is understood about how factors such as these can be significant contributors to cardiovascular complications, but at the time these tend to be insufficiently addressed in current research.
These limitations underscore the need for more inclusive and rigorous trial designs that better reflect real-world patient populations and incorporate comprehensive CV monitoring. Addressing these gaps is essential to provide a more accurate assessment of the cardiotoxic risks associated with TKI therapy, ultimately improving patient care and outcomes.
Conclusions
Tyrosine kinase inhibitors have tremendously improved the survival of patients with many malignancies. The adverse cardiac profile associated with such drugs ranges from mild requiring no intervention to severe and life-threatening necessitating treatment interruption and cardiac intervention. Establishing a strong cardio-oncology culture that encourages interdisciplinary collaboration can be essential in managing cardiotoxicities and minimizing cancer-therapy interruption.
Footnotes
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethical Statement
Ethical Approval
No IRB exemption was required as this manuscript is a review article with no patient information. Informed consent was not applicable.
References
Articles from Cancer Control : Journal of the Moffitt Cancer Center are provided here courtesy of SAGE Publications
Citations & impact
This article has not been cited yet.
Impact metrics
Alternative metrics
Discover the attention surrounding your research
https://www.altmetric.com/details/168572753
Similar Articles
To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.
Intracellular Signaling Pathways Mediating Tyrosine Kinase Inhibitor Cardiotoxicity.
Heart Fail Clin, 18(3):425-442, 01 Jun 2022
Cited by: 5 articles | PMID: 35718417 | PMCID: PMC10391230
Review Free full text in Europe PMC
Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors.
J Pharmacokinet Pharmacodyn, 45(3):401-418, 14 Feb 2018
Cited by: 7 articles | PMID: 29446053
The Role of p90 Ribosomal S6 Kinase (RSK) in Tyrosine Kinase Inhibitor (TKI)-Induced Cardiotoxicity.
J Cardiovasc Transl Res, 17(2):334-344, 19 Sep 2023
Cited by: 0 articles | PMID: 37725271
Review
Cardiotoxicity of Biological Therapies in Cancer Patients: An In-depth Review.
Curr Cardiol Rev, 19(3):e310522205428, 01 Jan 2023
Cited by: 5 articles | PMID: 35642110 | PMCID: PMC10280990
Review
Free full text in Europe PMC