Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors

Ross, David M.; Arthur, Chris; Burbury, Kate; Ko, Brian; Mills, Anthony K.; Shortt, Jake; Kostner, Karam

doi:10.1111/imj.13716

Cited by 24 publications

(21 citation statements)

References 31 publications

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“…Notably, the diagnosis was suggested only by echocardiogram in 5 of the 9 patients with this finding; catheterization was only performed (and confirmed the diagnosis) in 4 patients. The overall frequencies of vascular 5,[11][12][13][14][15][16][17][18]37 and cardiac [19][20][21][22][23][24][25][26] AEs varied across various clinical trials depending on the study design, type of TKI, treatment durations, AE definitions, and eligibility criteria. Contrary to some reports, 38 we observed that dasatinib was associated with a higher risk of AT-AE relative to imatinib, with a risk that appears similar to that with nilotinib.…”

Section: Discussionmentioning

confidence: 99%

Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

Jain¹,

Kantarjian²,

Boddu³

et al. 2019

Blood Advances

104

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Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P < .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P < .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.

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Section: Discussionmentioning

confidence: 99%

Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

Jain¹,

Kantarjian²,

Boddu³

et al. 2019

Blood Advances

104

View full text Add to dashboard Cite

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“…Numerous studies have sought to define risk factors for VAE development during nilotinib treatment, with a key commonality being the high incidence of at least 1 preexisting cardiovascular risk factor in patients who experience VAEs. 9 Strategies to predict the overall likelihood of VAEs have been proposed 1,17,18 and have formed the basis of recommendations for pre-TKI risk assessment and the avoidance of nilotinib where possible in those at higher risk. 2,9 In addition, regular monitoring for risk factors throughout treatment is recommended, with some authors suggesting a role for angiologic testing such as ankle-brachial index assessment 2,19 and computed tomography coronary calcium scores.…”

Section: Months After First Vaementioning

confidence: 99%

“…9 Strategies to predict the overall likelihood of VAEs have been proposed 1,17,18 and have formed the basis of recommendations for pre-TKI risk assessment and the avoidance of nilotinib where possible in those at higher risk. 2,9 In addition, regular monitoring for risk factors throughout treatment is recommended, with some authors suggesting a role for angiologic testing such as ankle-brachial index assessment 2,19 and computed tomography coronary calcium scores. 9 In line with previous findings, we demonstrated that VAEs were more common in older patients 20 and in those with preexisting cardiovascular risk factors.…”

Section: Months After First Vaementioning

confidence: 99%

“…2,9 In addition, regular monitoring for risk factors throughout treatment is recommended, with some authors suggesting a role for angiologic testing such as ankle-brachial index assessment 2,19 and computed tomography coronary calcium scores. 9 In line with previous findings, we demonstrated that VAEs were more common in older patients 20 and in those with preexisting cardiovascular risk factors. 17,18 However, unlike early studies where risk factors were assessed together, 1,17 our study specifically identified smoking history and dyslipidemia as independent risk factors for VAEs, with dyslipidemia remaining significant on multivariate analysis.…”

Section: Months After First Vaementioning

confidence: 99%

“…6,7 The incidence of nilotinib-associated VAEs ranges from 0.5% to 35% of patients in published literature. 2,[8][9][10][11] Factors contributing to the variability include inconsistent duration of follow-up, lack of a standardized definition of vascular events, 8 and exclusion of patients with a history of impaired cardiac function in some randomized controlled trials. 3,10 Despite the increasing understanding of the incidence and predisposing risk factors for nilotinib-associated AEs, there is a paucity of data to assist clinicians in their management.…”

Section: Introductionmentioning

confidence: 99%

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The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia

et al. 2019

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Key Points• In contrast to other AEs, there is a high risk of recurrent vascular AEs with continuing nilotinib therapy for CML.Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinibassociated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%).VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years.Multivariate analysis identified age (P 5 .022) and dyslipidemia (P 5 .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P 5 .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.Nilotinib has a unique adverse effect (AE) profile, including both hematological and nonhematological AEs. 2 Five-year follow-up of phase 3 data documented grade 3 to 4 AEs of any kind in 61% and 72% of

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Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study

et al. 2021

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Background. Tyrosine kinase inhibitors (TKIs) have shown long-term survival benefits in chronic myeloid leukemia (CML) patients. Nevertheless, significant concern has been raised regarding long-term TKI-associated vascular adverse events (VAEs). The objective of this retrospective cohort study was to investigate the incidence of VAEs in Taiwanese CML patients treated with different TKIs (imatinib, nilotinib, and dasatinib) as well as potential risk factors. Methods. We conducted a retrospective cohort study using the Taiwan Cancer Registry Database (TCRD) and National Health Insurance Research Database (NHIRD). Adult patients diagnosed with CML from 2008 to 2016 were identified and categorized into three groups according to their first-line TKI treatment (imatinib, nilotinib, and dasatinib). Propensity score matching was performed to control for potential confounders. Cox regressions were used to estimate the hazard ratio (HR) of VAEs in different TKI groups. Results. In total, 1,111 CML patients were included in our study. We found that the risk of VAEs in nilotinib users was significantly higher than that in imatinib users, with a hazard ratio (HR) of 3.13 (95% confidence interval (CI) 1.30-7.51), while dasatinib users also showed a nonsignificant trend for developing VAEs, with an HR of 1.71 (95% CI 0.71-4.26). In multivariable logistic regression analysis, only nilotinib usage, older age and history of cerebrovascular diseases were identified as significant risk factors. The annual incidence rate of VAEs was highest within the first year after the initiation of TKIs. Conclusion. These findings can support clinicians in making treatment decisions and monitoring VAEs in CML patients in Taiwan. The Oncologist 2021;9999:• • Implications for Practice: Our study found that CML patients treated with nilotinib and dasatinib may exposed to higher risk of developing vascular adverse events compared to those who treated with imatinib. Thus, we suggest that CML patients who are older or have a history of cerebrovascular diseases should be under close monitoring of VAEs, particularly within the first year after the initiation of TKIs.

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Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors

Cited by 24 publications

References 31 publications

Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia

Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study

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