RESUMEN
Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high-very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1-4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection.
Asunto(s)
Enfermedades Cardiovasculares , Leucemia Mielógena Crónica BCR-ABL Positiva , Piridazinas , Adulto , Humanos , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Leucemia Mielógena Crónica BCR-ABL Positiva/inducido químicamente , Imidazoles/efectos adversos , Pirimidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12 months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200 mg/dL and LDL > 70 mg/dL 3 months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P = 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P < 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P = 0.008; HR = 3.5; 95% CI = 1.4-8.7 and P < 0.001; HR = 4.4; 95% CI = 2-9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins.Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.
Asunto(s)
Antineoplásicos/uso terapéutico , Arteriopatías Oclusivas/sangre , Dislipidemias/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Lipoproteínas LDL/sangre , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Arteriopatías Oclusivas/etiología , Colesterol/sangre , Dislipidemias/complicaciones , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenAsunto(s)
Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Pirimidinas/administración & dosificación , ARN Mensajero , ARN Neoplásico , Translocación Genética , Adulto , Anciano , Anciano de 80 o más Años , Cromosomas Humanos Par 22/genética , Cromosomas Humanos Par 22/metabolismo , Cromosomas Humanos Par 9/genética , Cromosomas Humanos Par 9/metabolismo , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/sangre , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , ARN Mensajero/sangre , ARN Mensajero/genética , ARN Neoplásico/sangre , ARN Neoplásico/genética , Tasa de SupervivenciaRESUMEN
Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.
Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Hipertensión/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Trombosis/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Incidencia , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/epidemiología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/clasificación , Sistema Renina-Angiotensina/efectos de los fármacos , Factores de Riesgo , Análisis de Supervivencia , Trombosis/prevención & controlAsunto(s)
Antineoplásicos/uso terapéutico , Arteriopatías Oclusivas/sangre , Colesterol/sangre , Imidazoles/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Lipoproteínas LDL/sangre , Piridazinas/uso terapéutico , Triglicéridos/sangre , Adulto , Anciano , Anciano de 80 o más Años , Arteriopatías Oclusivas/etiología , Arteriopatías Oclusivas/prevención & control , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Factores Protectores , Adulto JovenRESUMEN
BACKGROUND: Limited information is available regarding the rate of long-term cardiovascular (CV) mortality in chronic myeloid leukaemia (CML) patients treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs) in the real-life practice. METHODS: We identified 656 consecutive CML patients treated with nilotinib, dasatinib, bosutinib and ponatinib. RESULTS: The 15-year CV-mortality free survival was 93⯱â¯2.8%. Age ≥65 years (pâ¯=â¯0.005) and a positive history of CV disease (pâ¯=â¯0.04) were significantly associated with a lower CV-mortality free survival. CV disease accounted for 16.5% and 5% of potential years of life lost (PYLL) in male and female patients, respectively. The standard mortality ratio (SMR) following ischemic heart disease (IHD) was 3.9 in males and 3.8 in female patients, meaning an excess of IHD deaths observed, in comparison with the population of control. CONCLUSION: Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered.
Asunto(s)
Compuestos de Anilina , Cardiotoxicidad , Enfermedades Cardiovasculares , Dasatinib , Imidazoles , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nitrilos , Piridazinas , Pirimidinas , Quinolinas , Anciano , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Cardiotoxicidad/etiología , Cardiotoxicidad/mortalidad , Cardiotoxicidad/prevención & control , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Femenino , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Italia/epidemiología , Esperanza de Vida , Efectos Adversos a Largo Plazo/inducido químicamente , Efectos Adversos a Largo Plazo/mortalidad , Masculino , Mortalidad , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/administración & dosificación , Piridazinas/efectos adversos , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Ajuste de Riesgo/métodosRESUMEN
There is little information about cardiovascular adverse event (CV-AE) incidence in chronic myeloid leukemia (CML) patients treated with bosutinib in the real-life practice. We identified 54 consecutive CML patients treated with bosutinib, stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 40-month cumulative incidence of CV-AEs was 25.2 ± 8.1%. Patients with the SCORE of high-very high showed a significantly higher incidence of CV-AEs (55 ± 12.9% vs 9 ± 9.5%; p = 0.002). Overall, 9 CV-AEs were reported, with 2 deaths attributed to CV-AE. In conclusion, the SCORE assessment before starting treatment is helpful in identifying CV-AE high-risk patients during bosutinib treatment.
Asunto(s)
Compuestos de Anilina/efectos adversos , Antineoplásicos/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Infarto del Miocardio/inducido químicamente , Nitrilos/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Quinolinas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Angina de Pecho/inducido químicamente , Angina de Pecho/diagnóstico , Angina de Pecho/fisiopatología , Compuestos de Anilina/administración & dosificación , Antineoplásicos/administración & dosificación , Isquemia Encefálica/inducido químicamente , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/fisiopatología , Dasatinib/administración & dosificación , Dasatinib/efectos adversos , Susceptibilidad a Enfermedades , Esquema de Medicación , Femenino , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/enzimología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/fisiopatología , Nitrilos/administración & dosificación , Enfermedades Vasculares Periféricas/inducido químicamente , Enfermedades Vasculares Periféricas/diagnóstico , Enfermedades Vasculares Periféricas/fisiopatología , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Quinolinas/administración & dosificación , Estudios RetrospectivosRESUMEN
Arterial occlusive events (AOEs) represent emerging complications in chronic myeloid leukemia (CML) patients treated with ponatinib. We identified 85 consecutive CML adult patients who were treated with ponatinib in 17 Italian centers. Patients were stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 60-month cumulative incidence rate of AOEs excluding hypertension was 25.7%. Hypertension was reported in 14.1% of patients. The median time of exposure to ponatinib was 28 months (range, 3-69 months). Patients with a high to very high SCORE risk showed a significantly higher incidence rate of AOEs (74.3% vs 15.2%, P < 0.001). Patients aged ≥60 years showed a significantly higher incidence rate of AOEs (51.5% vs 16.9%, P = 0.008). In multivariate analysis, no association was found between AOEs and positive history of CV disease, age, dose of ponatinib, previous exposure to nilotinib, and comorbidities. Only the SCORE risk was confirmed as a significant predictive factor (P = 0.01; HR = 10.9; 95% C.I. = 1.7-67.8). Patients aged ≥60 years who were treated with aspirin had a lower incidence rate of AOEs (33.3% vs 61.8%). Among the 14 reported AOEs, 78.6% of them showed grade 3 to 4 toxicity. This real-life study confirmed the increased incidence of AOEs in CML patients treated with ponatinib, with high to very high SCORE risk. We suggest that patients aged ≥60 years who were treated with ponatinib should undergo prophylaxis with 100 mg/day of aspirin. Our findings emphasize personalized prevention strategies based on CV risk factors.