Cardiovascular toxicity in patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors in the real-life practice: Identification of risk factors and the role of prophylaxis.
Giovanni Caocci,Olga Mulas,Mario Annunziata,Luigiana Luciano,Massimiliano Bonifacio,Ester Orlandi,Patrizia Pregno,Sara Galimberti,Antonella Russo Rossi,Elisabetta Abruzzese,Alessandra Iurlo,Bruno Martino,Nicola Sgherza,Gianni Binotto,Fausto Castagnetti,Antonella Gozzini,Claudio Fozza,Monica Bocchia,Anna Sicuranza,Fabio Stagno,Fabio Efficace,Emilio Usala,Fiorenza De Gregorio,Luigi Scaffidi,Chiara Elena,Francesca Pirillo,Claudia Baratè,Malgorzata Monika Trawinska,Daniele Cattaneo,Claudia Labate,Gabriele Gugliotta,Matteo Molica,Giorgina Specchia,Giorgio La Nasa,Robin Foà,Massimo Breccia +35 more
TLDR
A large real-life cohort of Italian patients with CML treated with a 2TKIs as firstor subsequent-line of treatment was analyzed to evaluate the incidence of CV AEs and the association with the SCORE assessment and other baseline risk factors and the role of primary prophylaxis in preventing CV atherothrombotic events.Abstract:
To the Editor: Long-term treatment with the second-generation tyrosine kinase inhibitors (2TKIs) nilotinib and dasatinib may result in cardiovascular (CV) complications. Accumulating evidence suggests that the combination of a median age at the time of chronic myeloid leukemia (CML) diagnosis of greater than 60 years, when CV adverse events (AEs) are common, and the CV toxicity of 2TKIs represents per se a potential predisposing factor, which requires preventive strategies and CV surveillance in patients with CML. Previous studies have suggested the usefulness of the systematic coronary risk evaluation (SCORE) assessment at disease baseline, a 10-year risk estimation of fatal CV disease based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels, to identify patients who are at heightened risk of CV AEs during nilotinib treatment. A preventive strategy with primary prophylaxis based on aspirin remains under discussion. We therefore analyzed a large real-life cohort of Italian patients with CML treated with a 2TKIs as firstor subsequent-line of treatment. The primary objective was to evaluate the incidence of CV AEs and the association with the SCORE assessment and other baseline risk factors. The secondary objectives were to evaluate the role of primary prophylaxis in preventing CV atherothrombotic events. We identified consecutive adult patients with CML who initiated nilotinib or dasatinib as firstor subsequent-line treatment, between January 2012 and December 2015 in 20 Italian centers. Patients were stratified into low-moderate (SCORE 5%) or high-very high (SCORE >5%) CV risk. Additional risk factors were the presence of diabetes, body mass index>24.5 kg/m, mild or severe renal insufficiency, and dyslipidemia. Patients were also evaluated for comorbidities and a positive anamnesis of CV diseases, including angina, myocardial infarction, stroke, heart failure, arterial hypertension, cardiomyopathy, heart arrhythmia, valvular heart disease, aortic aneurysms, ischemic cerebrovascular events, peripheral artery disease, thromboembolic disease, and venous thrombosis. The presence of antithrombotic prophylaxis before initiating CML treatment was also recorded. The probability of the cumulative incidence of CV and atherothrombotic AEs was estimated after initiating treatment with 2TKIs. The cumulative incidence of deep molecular response (MR) was evaluated from the initiation of 2TKIs treatment. Multivariate analyses were performed using the Cox proportional hazards regression model. A total of 506 patients with CML were retrospectively recruited. The patients’ characteristics are shown in Supporting Information Table S1. The mean age at diagnosis was 52 years (range 18–87) and 57% were men. Sokal score was intermediate-high in 55% of patients. The mean follow-up time since CML diagnosis was 5.4 years (range 0.2–23). Overall, 286 patients were treated with nilotinib and 220 with dasatinib. 2TKIs were administered as first-, second-, and third-line treatment in 61%, 32%, and 7% of cases, respectively. The reasons for switching treatments in 196 patients were inefficacy in 63.8%, intolerance in 29.6%, and protocol requirements in 6.6%. The majority of patients (93%) were classified as at low-intermediate risk (SCORE 5%) and 7% as at high-very high risk (SCORE>5%). A positive history for CV diseases was noted in 181 (35.8%) patients. The 60-month CV AE cumulative incidence registered in the total cohort of patients was 21.762.8%. Patients treated with nilotinib and dasatinib showed CV AE incidence of 24.763.9% and 16.463.7%, respectively (P5 .25; NS) (Supporting Information Figure S1). Patients treated with 2TKIs administered as firstor second-line of treatment and as subsequent-line treatment showed a CV AE incidence of 12.963.5% and 22.964.4%, respectively (P5 .004). Patients with high-very high SCORE showed significantly high incidence of CV AEs (46.6616.6% vs. 2062.8%; P< .001). The mean time between the initiation of 2TKI treatment and the occurrence of CV AEs was 35.5 (range 1–69) months. Overall, 68 CV AEs were registered, with 2 event-related deaths; 40% of CV AEs were graded as 3/4 of common toxicity criteria. Supporting Information Table S2 reports the CV AEs and their management in the reallife. We did not find any association between TKI dose and CV AE incidence. The frequency of peripheral arterial disease (PAOD or atheromasic carotid disease) was significantly high in patients undergoing nilotinib treatment. Two patients died due to myocardial infarction during treatment. Overall, in 44% of cases 2TKI treatment did not require dose modification; 16% of patients reduced the dose andread more
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Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life practice are predicted by the Systematic Coronary Risk Evaluation (SCORE) chart.
Giovanni Caocci,Olga Mulas,Elisabetta Abruzzese,Luigiana Luciano,Alessandra Iurlo,Immacolata Attolico,Fausto Castagnetti,Sara Galimberti,Nicola Sgherza,Massimiliano Bonifacio,Mario Annunziata,Antonella Gozzini,Ester Orlandi,Fabio Stagno,Gianni Binotto,Patrizia Pregno,Claudio Fozza,Malgorzata Monika Trawinska,Fiorenza De Gregorio,Daniele Cattaneo,Francesco Albano,Gabriele Gugliotta,Claudia Baratè,Luigi Scaffidi,Chiara Elena,Francesca Pirillo,Emilia Scalzulli,Giorgio La Nasa,Robin Foà,Massimo Breccia +29 more
TL;DR: 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, and patients' AOEs were identified.
Journal ArticleDOI
The CoV-2 outbreak: how hematologists could help to fight Covid-19.
Sara Galimberti,Chiara Baldini,Claudia Baratè,Federica Ricci,Serena Balducci,Susanna Grassi,Francesco Ferro,Gabriele Buda,Edoardo Benedetti,Rita Fazzi,Laura Baglietto,Ersilia Lucenteforte,Antonello Di Paolo,Mario Petrini +13 more
TL;DR: Pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19 are discussed and a possible combined treatment algorithm for CO VID-19 is proposed.
Journal ArticleDOI
Recurrent arterial occlusive events in patients with chronic myeloid leukemia treated with second- and third-generation tyrosine kinase inhibitors and role of secondary prevention
Giovanni Caocci,Olga Mulas,Massimiliano Bonifacio,Elisabetta Abruzzese,Sara Galimberti,Ester Orlandi,Alessandra Iurlo,Mario Annunziata,Luigiana Luciano,Fausto Castagnetti,Antonella Gozzini,Fabio Stagno,Gianni Binotto,Patrizia Pregno,Francesco Albano,Bruno Martino,Claudio Fozza,Luigi Scaffidi,Malgorzata Monika Trawinska,Claudia Baratè,Chiara Elena,Daniele Cattaneo,Emilia Scalzulli,Giorgio La Nasa,Robin Foà,Massimo Breccia +25 more
TL;DR: CML patients with a previous history of AOE treated with 2ndG/3rdG TKI represent a particular patient population with a higher probability of experiencing a recurrent AOE; individualized treatment is needed to optimize secondary prevention.
Journal ArticleDOI
Long-term mortality rate for cardiovascular disease in 656 chronic myeloid leukaemia patients treated with second- and third-generation tyrosine kinase inhibitors
Giovanni Caocci,Olga Mulas,Mario Annunziata,Luigiana Luciano,Elisabetta Abruzzese,Massimiliano Bonifacio,Ester Orlandi,Francesco Albano,Sara Galimberti,Alessandra Iurlo,Patrizia Pregno,Nicola Sgherza,Bruno Martino,Gianni Binotto,Fausto Castagnetti,Antonella Gozzini,Monica Bocchia,Claudio Fozza,Fabio Stagno,Maria Pina Simula,Fiorenza De Gregorio,Malgorzata Monika Trawinska,Luigi Scaffidi,Chiara Elena,Imma Attolico,Claudia Baratè,Daniele Cattaneo,Francesca Pirillo,Gabriele Gugliotta,Anna Sicuranza,Matteo Molica,Giorgio La Nasa,Robin Foà,Massimo Breccia +33 more
TL;DR: Prevention strategies based on CV risk factors, in particular in those patients with a previous history of CV disease, should be considered.
Journal ArticleDOI
Kill Two Birds with One Stone: A Multifunctional Dual‐Targeting Protein Drug to Overcome Imatinib Resistance in Philadelphia Chromosome‐Positive Leukemia
Bohan Ma,Hui Feng,Chao Feng,Yi Liu,Hailing Zhang,Jin-Cheng Wang,Wenjuan Wang,Pengcheng He,Fan Niu +8 more
TL;DR: A dual‐targeted proteolysis‐targeting chimera (PROTAC) protein drug is designed by engrafting an MDM2/p53 inhibition peptide sequence onto the Bcr/Abl tetramerization domain, which has the potential to overcome drug resistance mutations in the kinase domain.
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Management of Sickle Cell Disease: Summary of the 2014 Evidence-Based Report by Expert Panel Members
Barbara P. Yawn,George R. Buchanan,Araba Afenyi-Annan,Samir K. Ballas,Kathryn L. Hassell,Andra H. James,Lanetta B. Jordan,Sophie Lanzkron,Richard Lottenberg,William J. Savage,Paula Tanabe,Russell E. Ware,M. Hassan Murad,Jonathan C. Goldsmith,Jonathan C. Goldsmith,Eduardo Ortiz,Robinson Fulwood,Ann Horton,Joylene John-Sowah +18 more
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