The frequency of cardiovascular events caused by second-generation tyrosine kinase inhibitors may depend on the treatment intensity in patients with chronic myeloid leukemia

The frequency of cardiovascular events caused by second-generation tyrosine kinase inhibitors may depend on the treatment intensity in patients with chronic myeloid leukemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The frequency of cardiovascular events caused by second-generation tyrosine kinase inhibitors may depend on the treatment intensity in patients with chronic myeloid leukemia Taro Takahashi, Ken-ichi Ohashi, Tetsuro Ochi, Kentaro Nasu, Hiroshi Nakamura, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4734401/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Second-generation tyrosine kinase inhibitors (2GTKIs) have not improved overall survival compared to imatinib due to an increase in cardiovascular events (CVEs) and deaths unrelated to chronic myeloid leukemia (CML). We retrospectively analyzed the incidence of CVEs among CML patients treated with TKIs at our institution and analyzed the risk factors for CVEs. Method and results: Fifty-nine newly diagnosed CML patients were included. Imatinib, nilotinib, dasatinib, bostinib, and ponatinib were given to 29, 34, 21, 3, and 4 patients, respectively. The cumulative incidence of CVEs was 16.1% at 5 years and 32.4% at 10 years. According to the univariate analysis, a history of vascular events (p=0.046) and the presence of any risk factor for atherosclerotic disease (p=0.046) were significant, and nilotinib (p=0.053) tended to increase the risk of CVEs. According to the multivariate analysis, nilotinib (p<0.001) and a history of vascular events (p=0.04) were significant risk factors for CVEs, but dasatinib tended to decrease the risk of CVEs (p=0.17, hazard ratio (HR)=0.26, 95% CI 0.04-1.76). The only significant difference between nilotinib and dasatinib was the dose intensity of each TKI (1.0 vs 0.5, p=0.001). Conclusion: In addition to existing interventions targeting atherosclerotic factors, response-adapted dose adjustments may be necessary to reduce CVEs. chronic myeloid leukemia second-generation tyrosine kinase inhibitors cardiovascular events dose intensity Figures Figure 1 Figure 2 Introduction After the development of the first-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib, the survival of chronic myeloid leukemia (CML) patients has approached that of the general population.[ 1 – 3 ] Although an increasing number of patients with CML have achieved deep molecular response with second-generation TKIs (2GTKIs), which are required for TKI cessation, only 40–45% of patients are eligible for treatment-free remission (TFR), and their rate of successful TFR is approximately 50%.[ 4 – 8 , 13 – 17 ] This means that the majority of patients with CML will require long-term TKI therapy. On the other hand, it has become a concern that long-term treatment with 2GTKIs leads to an increase in cardiovascular events (CVEs). [ 5 , 9 , 10 ] The long-term follow-up of the ENESTnd trial revealed an increase in non-CML-related deaths, including those related to CVEs, while CML-related deaths decreased in patients treated with nilotinib compared to those treated with imatinib, resulting in no improvement in overall survival (OS), especially among elderly individuals. [ 11 ] This is also true in clinical trials of other 2GTKIs comparing them with imatinib as a first-line setting.[ 4 , 6 ] Therefore, there is an urgent need to elucidate the appropriate use of 2GTKIs to exert their potent effects while reducing adverse effects and, consequently, to improve the prognosis of CML patients. In this study, we retrospectively analyzed the incidence and risk factors for CVEs among CML patients treated with TKIs at our institution and discussed the appropriate use of 2GTKIs to improve the prognosis of CML patients. Patients and methods This study was approved by the institutional review board of Osaki Citizen Hospital. We retrospectively reviewed the medical records of 62 consecutive patients with newly diagnosed CML in the chronic phase (CML-CP) who were referred to our hospital between January 2009 and January 2022. Three patients were excluded because they had discontinued treatment for nonmedical reasons for more than a month. The following patient pretreatment characteristics were extracted: age, sex, comorbidities (hypertension, diabetes, dyslipidemia), current smoking status, history of cardiovascular disease, cerebrovascular disease, arteriosclerosis obliterans, TKI received, duration of each TKI therapy, long-term dose intensity of each TKI, and presence of cardiovascular events (CVEs) after TKI treatment. CVEs were defined as ischemic heart disease, ischemic cerebrovascular events, and peripheral artery disease. We analyzed the risk factors for CVEs and the incidence of CVEs for each TKI treatment group. This study was performed in accordance with the Declaration of Helsinki. The study was approved by the Institutional Review Board of Osaki Citizen Hospital. Written informed consent was obtained from all individuals included in this study. Statistical methods: Patient characteristics were compared using Fisher's exact test for categorical variables and the Mann‒Whitney U test or Kruskal‒Wallis test for continuous variables. The probability of OS and survival free from accelerated phase/blast crisis (AP/BC) was estimated using the Kaplan‒Meier method, and the log-rank test was used for comparison. The probability of CVEs was estimated using cumulative incidence curves, taking into account competing risks, and Gray's test was used for comparison. For CVEs, death was considered a competing risk. In the multivariate analysis, we used the Fine and Gray proportional hazards model for the cumulative incidence of CVEs to estimate hazard ratios (HRs) with 95% confidence intervals. All P values are two-sided, with the type 1 error rate fixed at 0.05. Statistical analyses were performed using EZR version 1.52 (Saitama Medical Centre, Jichi Medical University, Saitama, Japan).[ 12 ] Results Fifty-nine patients were included in this analysis. The clinical characteristics of the patients are summarized in Table 1. The median age at diagnosis was 61 years (range, 18–86). Forty-three patients were male, and 16 were female. Imatinib was given to 29 patients, nilotinib to 34 patients, dasatinib to 21 patients, bosutinib to 3 patients, and ponatinib to 4 patients. Some patients received multiple TKIs due to an insufficient response or intolerance. As first-line therapy, imatinib was given to 18 patients, nilotinib to 26, dasatinib to 13, and bosutinib to 1. The frequency of each risk factor for atherosclerotic disease, including hypertension, diabetes, dyslipidemia, and current smoking status, was not significantly different between the two TKI groups (Table 1). The 10-year overall survival (OS) was 85.1% for the entire cohort, 100% for patients under 60 years, and 73.4% for those 60 years or older (p = 0.0045). The 10-year AP/BC-free survival rate was 97.3%. The cumulative incidence of CVEs was 16.1% at 5 years and 32.4% at 10 years. According to the univariate analysis, a history of vascular events (p = 0.046) and the presence of any risk factor for atherosclerotic disease, including hypertension, diabetes, dyslipidemia, and current smoking (p = 0.046), were significant risk factors for CVEs. Nilotinib (p = 0.053) tended to increase the risk of CVEs. Unexpectedly, dasatinib was associated with a trend toward a lower risk of CVEs (p = 0.149) (Table 2, Fig. 1 A). According to the multivariate analysis, nilotinib (p < 0.001) and a history of vascular events (p = 0.04) were significant risk factors for CVEs. Dasatinib was associated with a lower risk for CVEs, although the difference was not statistically significant (p = 0.17, HR = 0.26, 95% CI 0.04–1.76) (Table 3). Patients were classified as high risk if they had any risk factors for atherosclerotic disease, such as hypertension, diabetes, dyslipidemia, or current smoking, or if they started 2GTKIs at 60 years or older, while the others were classified as standard risk. Nilotinib did not cause any CVEs in standard-risk patients, and it caused CVEs only in high-risk patients (Fig. 1 B), while dasatinib did not increase CVEs even in these high-risk patients (Fig. 1 C). This finding is not consistent with previous reports indicating that 2GTKIs, including dasatinib, increase the incidence of CVEs. Thus, we examined the causes of this discrepancy in the results. There were no significant differences in baseline atherosclerotic risk factors (p = 0.35-1.0) or the duration of each TKI therapy between the nilotinib and dasatinib groups (median 702 days vs 688 days, p = 0.4) (Table 4, Fig. 2 A). The only significant difference was the dose intensity of each TKI, which was analyzed only for patients who had taken each TKI for more than 1 year. The median dose of nilotinib was 1.0 (interquartile range; IQR, 0.25-1.0), while that of dasatinib was 0.5 (IQR, 0.20-0.775) (p = 0.001) (Fig. 2 B). Similar levels of molecular response were achieved with each dose of TKI (Table 4). Discussion Compared to imatinib, 2GTKIs result in faster and deeper molecular responses in more patients, making more patients eligible for TFR. [ 7 ] However, in reality, most patients require long-term TKI treatment. However, long-term use of 2GTKIs has not improved OS, particularly in elderly patients, due to an increase in non-CML-related events, including CVEs, compared to imatinib.[ 4 – 6 , 9 – 11 ] This highlights the importance of managing side effects, including CVEs, in the treatment of 2GTKIs. Our results showed that the CVE rate was 16.1% at 5 years and 32.4% at 10 years, which were comparable to the rates observed in the ENESTnd trial. [ 5 , 11 ] According to the 5-year analysis of the ENESTnd trial, despite strong recommendations for therapeutic intervention to prevent atherosclerosis, CVEs continued to increase without reaching a plateau even at 10 years. [ 11 ] At our hospital, we made efforts to detect arteriosclerotic diseases early through routine electrocardiograms, ankle-brachial index measurements, and carotid artery echocardiography, in addition to aggressive therapeutic interventions for hypertension, diabetes, and hyperlipidemia, as well as smoking cessation counseling, but CVEs still occurred at a high frequency. These findings indicate that existing therapeutic interventions targeting atherosclerotic factors alone are insufficient to prevent CVEs. In this multivariate analysis of our patients, we found that nilotinib was a significant risk factor for CVEs, whereas dasatinib, contrary to previous reports, showed a trend of not increasing but decreasing CVEs. [ 4 , 9 , 10 ] Comparing nilotinib and dasatinib, neither the atherosclerotic risk factors for the patients nor the duration of each TKI showed significant differences. However, the only significant difference was the long-term dose intensity of each TKI. In our analysis, dasatinib did not cause CVEs even in high-risk patients whose dose was reduced to 60% of the standard dose. This would mean that dasatinib had various adverse events (AEs) that led to a reduction in its dose, resulting in a decrease in CVEs, while nilotinib had so few AEs that no dose reduction was necessary, resulting in CVEs being the first adverse event. Additionally, the molecular response of dasatinib was similar to that of nilotinib at the 100% standard dose. These findings suggest that reducing the dose of TKIs after achieving an adequate molecular response may be effective in preventing CVEs while maintaining a response. The DESTINY trial aimed to reduce TKIs to half the standard dose after achieving a response better than a major molecular response (MMR) before treatment discontinuation. [ 18 ] This trial showed that most patients maintained MMR to half-dose TKIs. Using a mathematical model, Fassoni et al. demonstrated that dose de-escalation to half the standard dose does not compromise the long-term efficacy of treatment for most patients who have already achieved sustained remission.[ 19 ] The OPTIC trial showed that reducing the dose of ponatinib after achieving a complete cytogenetic response reduced the incidence of CVEs compared to the PACE trial, where response-based dose modification was not performed. [ 20 , 21 ] These reports suggest that in the majority of patients with excellent responses to TKIs, overtreatment is being performed and that dose reduction after adequate molecular response is feasible. It has been shown that 2GTKIs are essential for reducing CML-related mortality in Sokal high-risk patients.[ 11 , 22 ] Therefore, elucidating the long-term safe and effective administration of 2GTKIs in such high-risk patients is an urgent issue. If 2GTKIs can be administered long enough for the TFR without causing CVEs through dose reduction, more patients may be eligible for the TFR. It has been shown that a lower dose of TKI may not affect the TFR. Claudiani et al. demonstrated that 91.9% of patients who received a lower than standard dose of TKI due to adverse events after achieving MMR maintained their MMR, and the two-year treatment-free remission rate in patients who eventually discontinued the lower dose of TKI was 74.1%.[ 23 ] The weakness of our analysis is that it was retrospective, and it is difficult to evaluate whether the therapeutic intervention for arteriosclerosis was appropriate. However, the latter point also applies to the ENESTnd trial. Another weakness is that the risk of CVEs associated with nilotinib and dasatinib may not necessarily be the same. Although there has been no direct comparison, the results from clinical trials suggest that nilotinib may carry a greater risk of CVEs than dasatinib. 4,5 However, meta-analyses of CVEs with TKIs have shown that the risk increases with both 2GTKIs. [ 9 , 10 ] In our analysis, it is important to note that while nilotinib increased the incidence of CVEs in high-risk patients, dasatinib did not cause such adverse events in that population. Conclusion Our results suggest that dose reduction of 2GTKIs could reduce CVEs without compromising adequate response, although this needs to be prospectively examined. If this method proves to be effective, it could be one of the solutions that maximizes the benefits of 2GTKIs while reducing side effects and, as a result, leads to an improvement in the OS of CML patients. Declarations Ethical Approval The study was performed in accordance with the Declaration of Helsinki. The study was approved by the Institutional Review Board of Osaki Citizen Hospital(R4-17;20220930-17). Consent to participate and consent to publish Written informed consent was obtained from all individuals included in this study. Funding This study did not receive any funding from any organization. Competing Interests The authors declare no competing interests. Data Availability All relevant summary data are provided in the manuscript text, and tables. Further inquiries can be directed to the corresponding author upon reasonable request. Author Contribution T.T. analyzed the data and wrote the manuscript. T.T., O.K., O.T., K.N., and N.H. treated the patients and collected medical records. H.H. supervised the study and approved the manuscript. All authors read and approved the final manuscript. Acknowledgement The authors would like to thank all medical and nurse personnel of the Osaki Citizen Hospital for dedicated work. 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Tables Tables 1 to 3 are available in the Supplementary Files section. Table 4 are not available with this version. Additional Declarations No competing interests reported. Supplementary Files table1.docx table2.docx table3.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4734401","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":332244340,"identity":"ff1f15e2-2ab9-4a0f-9a5a-cd05d24d7334","order_by":0,"name":"Taro Takahashi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYPCCBAZ+MFVAhFoeiI4EBskGEG1AihaDAyAGMVrs2c8+fMz7I81u8/nViR8eGDDI84sdIGALT7qxMU9CTvK2G283SwAdZjhzdgIhh6WxSfMkVCSb3Ti7AaQlweA2IS38zyBajGec3fyDOC0SYFty7Az4e7cRacuNZ8yGc9LSEiRu8G6zSDCQIOwX9v40xgdvbJLt+fvPbr75o8JGnl+agBYYSGyQAKuUIE45CNgz8B8gXvUoGAWjYBSMLAAAFdo/E2vRukoAAAAASUVORK5CYII=","orcid":"","institution":"Osaki Citizen Hospital","correspondingAuthor":true,"prefix":"","firstName":"Taro","middleName":"","lastName":"Takahashi","suffix":""},{"id":332244343,"identity":"a85ffe8d-f7a7-4e4e-822a-a00cdfd691d9","order_by":1,"name":"Ken-ichi Ohashi","email":"","orcid":"","institution":"Osaki Citizen Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ken-ichi","middleName":"","lastName":"Ohashi","suffix":""},{"id":332244346,"identity":"6e58982e-e0d5-4ea9-ac2a-43b778f2e51b","order_by":2,"name":"Tetsuro Ochi","email":"","orcid":"","institution":"Osaki Citizen Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tetsuro","middleName":"","lastName":"Ochi","suffix":""},{"id":332244347,"identity":"6a80f20a-3ea9-4f00-80f5-165119decd89","order_by":3,"name":"Kentaro Nasu","email":"","orcid":"","institution":"Osaki Citizen Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kentaro","middleName":"","lastName":"Nasu","suffix":""},{"id":332244348,"identity":"e1862097-f72d-42ea-8dd8-3420549cd415","order_by":4,"name":"Hiroshi Nakamura","email":"","orcid":"","institution":"Osaki Citizen Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Nakamura","suffix":""},{"id":332244349,"identity":"b393494c-ac32-46d1-a592-e80d3c4ff54e","order_by":5,"name":"Hideo Harigae","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Hideo","middleName":"","lastName":"Harigae","suffix":""}],"badges":[],"createdAt":"2024-07-13 08:57:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4734401/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4734401/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62733030,"identity":"308290e3-7b96-45c3-bbd7-daf1c4213590","added_by":"auto","created_at":"2024-08-18 23:51:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":82799,"visible":true,"origin":"","legend":"\u003cp\u003eA: Cumulative incidence of CVEs according to TKI(imatinib,nilotinib,and dasatinib).\u003c/p\u003e\n\u003cp\u003eBosutinib and ponatinib were not shown because they included few patients.\u003c/p\u003e\n\u003cp\u003eB: Cumulative incidence of CVEs in high-risk vs standard-risk patients treated with nilotinib.\u003c/p\u003e\n\u003cp\u003ePatients were classified as high-risk if they had any risk factors for atherosclerotic disease, such as hypertension, diabetes, dyslipidaemia, or current smoking, or if they started 2GTKIs at 60 years or older. Others were classified as standard risk.\u003c/p\u003e\n\u003cp\u003eC: Cumulative incidence of CVEs in high-risk patients treated with nilotinib vs dasatinib.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4734401/v1/76cfe79e99fdc3eabc2fe216.png"},{"id":62732308,"identity":"42b2a15c-2479-444d-910e-671c71d6821d","added_by":"auto","created_at":"2024-08-18 23:43:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":37161,"visible":true,"origin":"","legend":"\u003cp\u003eA: Comparison of the duration of administration between dasatinib(median 688[IQR,150-1781] days) and nilotinib(median 702[IQR,282-2839] days).\u003c/p\u003e\n\u003cp\u003eB: Comparison of the dose intensity between dasatinib(median 0.5[IQR,0.20-0.775]) and nilotinib(median 1.0 [IQR,0.25-1.0]).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4734401/v1/d1bec5236e354527c0de8751.png"},{"id":65483776,"identity":"4b8450da-a337-453c-abae-e0da8135b9aa","added_by":"auto","created_at":"2024-09-28 06:46:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":393743,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4734401/v1/61d55447-828f-419b-a60e-ce99f9df2ef7.pdf"},{"id":62733032,"identity":"2aa82988-0cea-48c6-a5c7-0ecbe01502cc","added_by":"auto","created_at":"2024-08-18 23:51:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":54487,"visible":true,"origin":"","legend":"","description":"","filename":"table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4734401/v1/532fd425595b7ddadfba3ba7.docx"},{"id":62732312,"identity":"e7db4aef-d67f-4c0f-8028-9d21afd2576a","added_by":"auto","created_at":"2024-08-18 23:43:48","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":39300,"visible":true,"origin":"","legend":"","description":"","filename":"table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-4734401/v1/c6099b8ab8c5a302a97e8ce7.docx"},{"id":62732310,"identity":"f54defe2-7f89-4de7-aa7a-0a924d08746b","added_by":"auto","created_at":"2024-08-18 23:43:48","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":25960,"visible":true,"origin":"","legend":"","description":"","filename":"table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4734401/v1/22c74462f13a976b979eac04.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The frequency of cardiovascular events caused by second-generation tyrosine kinase inhibitors may depend on the treatment intensity in patients with chronic myeloid leukemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAfter the development of the first-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib, the survival of chronic myeloid leukemia (CML) patients has approached that of the general population.[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Although an increasing number of patients with CML have achieved deep molecular response with second-generation TKIs (2GTKIs), which are required for TKI cessation, only 40–45% of patients are eligible for treatment-free remission (TFR), and their rate of successful TFR is approximately 50%.[\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e–\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] This means that the majority of patients with CML will require long-term TKI therapy. On the other hand, it has become a concern that long-term treatment with 2GTKIs leads to an increase in cardiovascular events (CVEs). [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] The long-term follow-up of the ENESTnd trial revealed an increase in non-CML-related deaths, including those related to CVEs, while CML-related deaths decreased in patients treated with nilotinib compared to those treated with imatinib, resulting in no improvement in overall survival (OS), especially among elderly individuals. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] This is also true in clinical trials of other 2GTKIs comparing them with imatinib as a first-line setting.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] Therefore, there is an urgent need to elucidate the appropriate use of 2GTKIs to exert their potent effects while reducing adverse effects and, consequently, to improve the prognosis of CML patients. In this study, we retrospectively analyzed the incidence and risk factors for CVEs among CML patients treated with TKIs at our institution and discussed the appropriate use of 2GTKIs to improve the prognosis of CML patients.\u003c/p\u003e "},{"header":"Patients and methods","content":"\u003cp\u003e This study was approved by the institutional review board of Osaki Citizen Hospital. We retrospectively reviewed the medical records of 62 consecutive patients with newly diagnosed CML in the chronic phase (CML-CP) who were referred to our hospital between January 2009 and January 2022. Three patients were excluded because they had discontinued treatment for nonmedical reasons for more than a month. The following patient pretreatment characteristics were extracted: age, sex, comorbidities (hypertension, diabetes, dyslipidemia), current smoking status, history of cardiovascular disease, cerebrovascular disease, arteriosclerosis obliterans, TKI received, duration of each TKI therapy, long-term dose intensity of each TKI, and presence of cardiovascular events (CVEs) after TKI treatment. CVEs were defined as ischemic heart disease, ischemic cerebrovascular events, and peripheral artery disease. We analyzed the risk factors for CVEs and the incidence of CVEs for each TKI treatment group.\u003c/p\u003e\u003cp\u003e This study was performed in accordance with the Declaration of Helsinki. The study was approved by the Institutional Review Board of Osaki Citizen Hospital. Written informed consent was obtained from all individuals included in this study.\u003c/p\u003e\u003cp\u003eStatistical methods:\u003c/p\u003e\u003cp\u003ePatient characteristics were compared using Fisher's exact test for categorical variables and the Mann‒Whitney U test or Kruskal‒Wallis test for continuous variables. The probability of OS and survival free from accelerated phase/blast crisis (AP/BC) was estimated using the Kaplan‒Meier method, and the log-rank test was used for comparison. The probability of CVEs was estimated using cumulative incidence curves, taking into account competing risks, and Gray's test was used for comparison. For CVEs, death was considered a competing risk.\u003c/p\u003e\u003cp\u003eIn the multivariate analysis, we used the Fine and Gray proportional hazards model for the cumulative incidence of CVEs to estimate hazard ratios (HRs) with 95% confidence intervals. All P values are two-sided, with the type 1 error rate fixed at 0.05. Statistical analyses were performed using EZR version 1.52 (Saitama Medical Centre, Jichi Medical University, Saitama, Japan).[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFifty-nine patients were included in this analysis. The clinical characteristics of the patients are summarized in Table\u0026nbsp;1. The median age at diagnosis was 61 years (range, 18–86). Forty-three patients were male, and 16 were female. Imatinib was given to 29 patients, nilotinib to 34 patients, dasatinib to 21 patients, bosutinib to 3 patients, and ponatinib to 4 patients. Some patients received multiple TKIs due to an insufficient response or intolerance. As first-line therapy, imatinib was given to 18 patients, nilotinib to 26, dasatinib to 13, and bosutinib to 1. The frequency of each risk factor for atherosclerotic disease, including hypertension, diabetes, dyslipidemia, and current smoking status, was not significantly different between the two TKI groups (Table\u0026nbsp;1). The 10-year overall survival (OS) was 85.1% for the entire cohort, 100% for patients under 60 years, and 73.4% for those 60 years or older (p = 0.0045). The 10-year AP/BC-free survival rate was 97.3%. The cumulative incidence of CVEs was 16.1% at 5 years and 32.4% at 10 years. According to the univariate analysis, a history of vascular events (p = 0.046) and the presence of any risk factor for atherosclerotic disease, including hypertension, diabetes, dyslipidemia, and current smoking (p = 0.046), were significant risk factors for CVEs. Nilotinib (p = 0.053) tended to increase the risk of CVEs. Unexpectedly, dasatinib was associated with a trend toward a lower risk of CVEs (p = 0.149) (Table\u0026nbsp;2, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). According to the multivariate analysis, nilotinib (p \u0026lt; 0.001) and a history of vascular events (p = 0.04) were significant risk factors for CVEs. Dasatinib was associated with a lower risk for CVEs, although the difference was not statistically significant (p = 0.17, HR = 0.26, 95% CI 0.04–1.76) (Table\u0026nbsp;3). Patients were classified as high risk if they had any risk factors for atherosclerotic disease, such as hypertension, diabetes, dyslipidemia, or current smoking, or if they started 2GTKIs at 60 years or older, while the others were classified as standard risk. Nilotinib did not cause any CVEs in standard-risk patients, and it caused CVEs only in high-risk patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eB), while dasatinib did not increase CVEs even in these high-risk patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). This finding is not consistent with previous reports indicating that 2GTKIs, including dasatinib, increase the incidence of CVEs. Thus, we examined the causes of this discrepancy in the results. There were no significant differences in baseline atherosclerotic risk factors (p = 0.35-1.0) or the duration of each TKI therapy between the nilotinib and dasatinib groups (median 702 days vs 688 days, p = 0.4) (Table\u0026nbsp;4, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The only significant difference was the dose intensity of each TKI, which was analyzed only for patients who had taken each TKI for more than 1 year. The median dose of nilotinib was 1.0 (interquartile range; IQR, 0.25-1.0), while that of dasatinib was 0.5 (IQR, 0.20-0.775) (p = 0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Similar levels of molecular response were achieved with each dose of TKI (Table\u0026nbsp;4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCompared to imatinib, 2GTKIs result in faster and deeper molecular responses in more patients, making more patients eligible for TFR. [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] However, in reality, most patients require long-term TKI treatment. However, long-term use of 2GTKIs has not improved OS, particularly in elderly patients, due to an increase in non-CML-related events, including CVEs, compared to imatinib.[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] This highlights the importance of managing side effects, including CVEs, in the treatment of 2GTKIs.\u003c/p\u003e \u003cp\u003eOur results showed that the CVE rate was 16.1% at 5 years and 32.4% at 10 years, which were comparable to the rates observed in the ENESTnd trial. [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] According to the 5-year analysis of the ENESTnd trial, despite strong recommendations for therapeutic intervention to prevent atherosclerosis, CVEs continued to increase without reaching a plateau even at 10 years. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] At our hospital, we made efforts to detect arteriosclerotic diseases early through routine electrocardiograms, ankle-brachial index measurements, and carotid artery echocardiography, in addition to aggressive therapeutic interventions for hypertension, diabetes, and hyperlipidemia, as well as smoking cessation counseling, but CVEs still occurred at a high frequency. These findings indicate that existing therapeutic interventions targeting atherosclerotic factors alone are insufficient to prevent CVEs.\u003c/p\u003e \u003cp\u003eIn this multivariate analysis of our patients, we found that nilotinib was a significant risk factor for CVEs, whereas dasatinib, contrary to previous reports, showed a trend of not increasing but decreasing CVEs. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Comparing nilotinib and dasatinib, neither the atherosclerotic risk factors for the patients nor the duration of each TKI showed significant differences. However, the only significant difference was the long-term dose intensity of each TKI. In our analysis, dasatinib did not cause CVEs even in high-risk patients whose dose was reduced to 60% of the standard dose. This would mean that dasatinib had various adverse events (AEs) that led to a reduction in its dose, resulting in a decrease in CVEs, while nilotinib had so few AEs that no dose reduction was necessary, resulting in CVEs being the first adverse event. Additionally, the molecular response of dasatinib was similar to that of nilotinib at the 100% standard dose. These findings suggest that reducing the dose of TKIs after achieving an adequate molecular response may be effective in preventing CVEs while maintaining a response. The DESTINY trial aimed to reduce TKIs to half the standard dose after achieving a response better than a major molecular response (MMR) before treatment discontinuation. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] This trial showed that most patients maintained MMR to half-dose TKIs. Using a mathematical model, Fassoni et al. demonstrated that dose de-escalation to half the standard dose does not compromise the long-term efficacy of treatment for most patients who have already achieved sustained remission.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] The OPTIC trial showed that reducing the dose of ponatinib after achieving a complete cytogenetic response reduced the incidence of CVEs compared to the PACE trial, where response-based dose modification was not performed. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] These reports suggest that in the majority of patients with excellent responses to TKIs, overtreatment is being performed and that dose reduction after adequate molecular response is feasible.\u003c/p\u003e \u003cp\u003eIt has been shown that 2GTKIs are essential for reducing CML-related mortality in Sokal high-risk patients.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Therefore, elucidating the long-term safe and effective administration of 2GTKIs in such high-risk patients is an urgent issue. If 2GTKIs can be administered long enough for the TFR without causing CVEs through dose reduction, more patients may be eligible for the TFR. It has been shown that a lower dose of TKI may not affect the TFR. Claudiani et al. demonstrated that 91.9% of patients who received a lower than standard dose of TKI due to adverse events after achieving MMR maintained their MMR, and the two-year treatment-free remission rate in patients who eventually discontinued the lower dose of TKI was 74.1%.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe weakness of our analysis is that it was retrospective, and it is difficult to evaluate whether the therapeutic intervention for arteriosclerosis was appropriate. However, the latter point also applies to the ENESTnd trial. Another weakness is that the risk of CVEs associated with nilotinib and dasatinib may not necessarily be the same. Although there has been no direct comparison, the results from clinical trials suggest that nilotinib may carry a greater risk of CVEs than dasatinib. 4,5 However, meta-analyses of CVEs with TKIs have shown that the risk increases with both 2GTKIs. [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] In our analysis, it is important to note that while nilotinib increased the incidence of CVEs in high-risk patients, dasatinib did not cause such adverse events in that population.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur results suggest that dose reduction of 2GTKIs could reduce CVEs without compromising adequate response, although this needs to be prospectively examined. If this method proves to be effective, it could be one of the solutions that maximizes the benefits of 2GTKIs while reducing side effects and, as a result, leads to an improvement in the OS of CML patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical Approval\u003c/p\u003e\n\u003cp\u003eThe study was performed in accordance with the Declaration of Helsinki. The study was approved by the Institutional Review Board of Osaki Citizen Hospital(R4-17;20220930-17).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate and consent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all individuals included in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any funding from any organization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll relevant summary data are provided in the manuscript text, and tables. Further inquiries can be directed to the corresponding author upon reasonable request.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.T. analyzed the data and wrote the manuscript. T.T., O.K., O.T., K.N., and N.H. treated the patients and collected medical records. H.H. supervised the study and approved the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank all medical and nurse personnel of the Osaki Citizen Hospital for dedicated work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDruker BJ, Talpaz M, Resta DJ,Peng B, Buchdunger E, Ford JM,et al.Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031-1037.\u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994\u0026ndash;1004.\u003c/li\u003e\n\u003cli\u003eHannah Bower, Magnus Bj\u0026uml;orkholm, Paul W. Dickman, Martin H\u0026uml;oglund, Paul C. Lambert, and Therese M.-L. Andersson. Life Expectancy of Patients With Chronic Myeloid Leukemia Approaches the Life Expectancy of the General Population. J Clin Oncol. 2016;34:2851-2857.\u003c/li\u003e\n\u003cli\u003eCortes JE, Saglio G, Kantarjian HM,Baccarani M, Mayer J,Boqu\u0026acute;e C, et al. Final 5-year study results of DASISION: The dasatinib versus imatinib study in treatment-na\u0026uml;ıve chronic myeloid leukemia patients trial. J Clin Oncol. 2016 ;34:2333-2340.\u003c/li\u003e\n\u003cli\u003eHochhaus A, Saglio G, Hughes TP, Larson RA, Kim D-W, Issaragrisil S, et al: Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016; 30: 1044-1054.\u003c/li\u003e\n\u003cli\u003eBr\u0026uuml;mmendorf TH, Cortes JE, Milojkovic D, Gambacorti-Passerini C, Clark RE, Le Coutre P,et al. Bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia: final results from the BFORE trial. Leukemia. 2022;36:1825\u0026ndash;1833.\u003c/li\u003e\n\u003cli\u003eHochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley J. F., Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 2020; 34:966\u0026ndash;984.\u003c/li\u003e\n\u003cli\u003eCortes J, Rea D, Lipton JH. Treatment-free remission with first- and second-generation tyrosine kinase inhibitors.Am J Hematol. 2019;94:346\u0026ndash;357.\u003c/li\u003e\n\u003cli\u003eVener C,Banzi R, Ambrogi F, Ferrero A, Saglio G, Pravettoni G, et al. First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis. Blood Advances 2020;4(12):2723-2735.\u003c/li\u003e\n\u003cli\u003eDouxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogn\u0026eacute; JM, et al. Association Between BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia and Cardiovascular Events, Major Molecular Response, and Overall Survival A Systematic Review and Meta-analysis. JAMA Oncol. 2016;2(5):625-632.\u003c/li\u003e\n\u003cli\u003eKantarjian HM, Hughes TP, Larson R.A, Kim DW, Issaragrisil S, Le Coutre P, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35(2):440\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eKanda Y. Investigation of the freely available easy-to-use software \u0026lsquo;EZR\u0026rsquo; for medical statistics. Bone Marrow Transplant. 2013; 48:452-458.\u003c/li\u003e\n\u003cli\u003eHochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, G\u0026oacute;mez Casares MT, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENEST freedom study. Leukemia. 2017; 31, 1525\u0026ndash;1531.\u003c/li\u003e\n\u003cli\u003eDAsatinib DIscontinuation for 1st-line treatment with CML-CP with 1 year CMR (1st DADI). Kimura S, Imagawa J, Murai K, Hino M, Kitawaki T, Okada M, et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial. 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Lancet Oncol. 2018;19(6):747-757.\u003c/li\u003e\n\u003cli\u003eClark RE, Polydoros F, Apperley JF, Milojkovic D, Pocock C, Smith G,et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol. 2017;4: e310\u0026ndash;16.\u003c/li\u003e\n\u003cli\u003eFassoni AC, Baldow C, Roeder I,and Glauche I. Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: a simulation study based on phase III trial data. Haematologica. 2018;103(11):1825-1834.\u003c/li\u003e\n\u003cli\u003eCortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C,et al. Ponatinib efficacy and safety in Philadelphia chromosome\u0026ndash;positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393-404\u003c/li\u003e\n\u003cli\u003eCortes J, Apperley J, Lomaia E, Moiraghi B, Sutton MU, Pavlovsky C,et al. Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial. Blood. 2021;138(21):2042-50.\u003c/li\u003e\n\u003cli\u003eKizaki M, Takahashi N, Iriyama N, Okamoto S, Ono T, Usui N,et al. Efficacy and safety of tyrosine kinase inhibitors for newly diagnosed chronic-phase chronic myeloid leukemia over a 5-year period: results from the Japanese registry obtained by the New TARGET system. \u0026middot;Int J Hematol. 2019;109:426\u0026ndash;439.\u003c/li\u003e\n\u003cli\u003eClaudiani S, Apperley JF, Szydlo R, Khan A, Nesr G, Hayden C, et al. TKI dose reduction can effectively maintain major molecular remission in patients with chronic myeloid leukaemia. Br J Haematol. 2021;193:346\u0026ndash;355.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e\n\u003cp\u003eTable 4 are not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"chronic myeloid leukemia, second-generation tyrosine kinase inhibitors, cardiovascular events, dose intensity","lastPublishedDoi":"10.21203/rs.3.rs-4734401/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4734401/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSecond-generation tyrosine kinase inhibitors (2GTKIs) have not improved overall survival compared to imatinib due to an increase in cardiovascular events (CVEs) and deaths unrelated to chronic myeloid leukemia (CML). We retrospectively analyzed the incidence of CVEs among CML patients treated with TKIs at our institution and analyzed the risk factors for CVEs.\u003c/p\u003e\n\u003cp\u003eMethod and results:\u003c/p\u003e\n\u003cp\u003eFifty-nine newly diagnosed CML patients were included. Imatinib, nilotinib, dasatinib, bostinib, and ponatinib were given to 29, 34, 21, 3, and 4 patients, respectively. The cumulative incidence of CVEs was 16.1% at 5 years and 32.4% at 10 years. According to the univariate analysis, a history of vascular events (p=0.046) and the presence of any risk factor for atherosclerotic disease (p=0.046) were significant, and nilotinib (p=0.053) tended to increase the risk of CVEs. According to the multivariate analysis, nilotinib (p\u0026lt;0.001) and a history of vascular events (p=0.04) were significant risk factors for CVEs, but dasatinib tended to decrease the risk of CVEs (p=0.17, hazard ratio (HR)=0.26, 95% CI 0.04-1.76). The only significant difference between nilotinib and dasatinib was the dose intensity of each TKI (1.0 vs 0.5, p=0.001).\u003c/p\u003e\n\u003cp\u003eConclusion: In addition to existing interventions targeting atherosclerotic factors, response-adapted dose adjustments may be necessary to reduce CVEs.\u003c/p\u003e","manuscriptTitle":"The frequency of cardiovascular events caused by second-generation tyrosine kinase inhibitors may depend on the treatment intensity in patients with chronic myeloid leukemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-18 23:43:43","doi":"10.21203/rs.3.rs-4734401/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"03bc404c-b5fe-44e7-989e-be3f3926215a","owner":[],"postedDate":"August 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-28T06:38:34+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-18 23:43:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4734401","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4734401","identity":"rs-4734401","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}