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EASIX and cardiac adverse events after allogeneic hematopoietic cell transplantation

Abstract

This study investigates the interaction between endothelial activation, indirectly measured using EASIX, and the probability of presenting cardiac adverse events (CAE) during the first year after allo-HCT. The 437 consecutive adults undergoing PB allo-HCT from 2012 and 2021 were included. EASIX was retrospectively calculated before and during the first 6 months after allo-HCT and transformed to log2-base to conduct the statistical analysis. The median age was 53, 46 (10.5%) patients had previous history of cardiac disease, MAC allo-HCTs were performed in 186 (42.6%) patients, and PTCY was administered in 242 (55.5%). The 1-year incidence of CAE was 12.6% (n = 55). The most prevalent cardiac events were heart failure and arrhythmias, 32.7% and 23.6% respectively, and the day +100 mortality rate of these patients was 40.5%. During the first 6 months after allo-HCT, EASIX trends were significantly higher in patients who developed CAE. Regression analyses confirmed that higher log2-EASIX values were predictors for higher risk for CAE during the first year after allo-HCT. This analysis identifies a significant association between higher endothelial activation, indirectly measured using EASIX, and higher risk for cardiac toxicity diagnosed during the first year after allo-HCT and extends the applicability of EASIX for identifying patients at risk for CAE.

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Fig. 1: 2-year Post-transplant OS and NRM.
Fig. 2: EASIX trends.

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References

  1. Snowden JA, Sánchez-Ortega I, Corbacioglu S, Basak GW, Chabannon C, de la Camara R, et al. Indications for haematopoietic cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2022. Bone Marrow Transpl. 2022;57:1217–39.

    Article  Google Scholar 

  2. Kanate AS, Majhail N, DeFilipp Z, Dhakal B, Dholaria B, Hamilton B, et al. Updated indications for immune effector cell therapy: 2023 guidelines from the American Society for Transplantation and cellular therapy. Transpl Cell Ther. 2023;29:594–7.

    Article  Google Scholar 

  3. McDonald GB, Sandmaier BM, Mielcarek M, Sorror M, Pergam SA, Cheng GS, et al. Survival, nonrelapse mortality, and relapse-related mortality after allogeneic hematopoietic cell transplantation: comparing 2003–2007 versus 2013–2017 cohorts. Ann Intern Med. 2020;172:229–39.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Passweg JR, Baldomero H, Chabannon C, Basak GW, de la Cámara R, Corbacioglu S, et al. Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years. Bone Marrow Transpl. 2021;56:1651–64.

    Article  Google Scholar 

  5. Penack O, Peczynski C, Mohty M, Yakoub-Agha I, Styczynski J, Montoto S, et al. How much has allogeneic stem cell transplant-related mortality improved since the 1980s? A retrospective analysis from the EBMT. Blood Adv. 2020;4:6283–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yeh J, Whited L, Saliba RM, Rondon G, Banchs J, Shpall E, et al. Cardiac toxicity after matched allogeneic hematopoietic cell transplant in the posttransplant cyclophosphamide era. Blood Adv. 2021;5:5599–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Duléry R, Mohty R, Labopin M, Sestili S, Malard F, Brissot E, et al. Early cardiac toxicity associated with post-transplant cyclophosphamide in allogeneic stem cell transplantation. JACC CardioOncol. 2021;3:250–9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pérez-Valencia AI, Cascos E, Carbonell-Ordeig S, Charry P, Gómez-Hernando M, Rodríguez-Lobato LG, et al. Incidence, risk factors, and impact of early cardiac toxicity after allogeneic hematopoietic cell transplant. Blood Adv. 2023;7:2018–31.

    Article  PubMed  Google Scholar 

  9. Tichelli A, Passweg J, Wójcik D, Rovó A, Harousseau JL, Masszi T, et al. Late cardiovascular events after allogeneic hematopoietic stem cell transplantation: a retrospective multicenter study of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2008;93:1203–10.

    Article  PubMed  Google Scholar 

  10. Tichelli A, Bucher C, Rovó A, Stussi G, Stern M, Paulussen M, et al. Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation. Blood. 2007;110:3463–71.

    Article  CAS  PubMed  Google Scholar 

  11. Armenian SH, Horak D, Scott JM, Mills G, Siyahian A, Berano Teh J, et al. Cardiovascular function in long-term hematopoietic cell transplantation survivors. Biol Blood Marrow Transpl. 2017;23:700–5.

    Article  Google Scholar 

  12. Cooke KR, Jannin A, Ho V. The contribution of endothelial activation and injury to end-organ toxicity following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transpl. 2008;14:23–32.

    Article  Google Scholar 

  13. Palomo M, Diaz-Ricart M, Carreras E. Endothelial dysfunction in hematopoietic cell transplantation. Clin Hematol Int. 2019;1:45.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Ghimire S, Weber D, Mavin E, Wang XN, Dickinson AM, Holler E. Pathophysiology of GvHD and other HSCT-related major complications. Front Immunol. 2017;8:79.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Luft T, Dreger P, Radujkovic A. Endothelial cell dysfunction: a key determinant for the outcome of allogeneic stem cell transplantation. Bone Marrow Transpl Springe Nat. 2021;56:2326–35.

    Article  Google Scholar 

  16. Hildebrandt GC, Chao N. Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation. Br J Haematol. 2020;190:508–19.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bosch X, Rovira M, Sitges M, Domènech A, Ortiz-Pérez JT, De Caralt TM, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (prevention of left ventricular dysfunction with enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of malignant hEmopathies). J Am Coll Cardiol. 2013;61:2355–62.

    Article  CAS  PubMed  Google Scholar 

  18. Luft T, Benner A, Terzer T, Jodele S, Dandoy CE, Storb R, et al. EASIX and mortality after allogeneic stem cell transplantation. Bone Marrow Transpl. 2020;55:553–61. https://doi.org/10.1038/s41409-019-0703-1.

    Article  CAS  Google Scholar 

  19. Mariotti J, Magri F, Giordano L, De Philippis C, Sarina B, Mannina D, et al. EASIX predicts non-relapse mortality after haploidentical transplantation with post-transplant cyclophosphamide. Bone Marrow Transpl. 2022;58:247–56.

    Article  Google Scholar 

  20. Nawas MT, Sanchez-Escamilla M, Devlin SM, Maloy MA, Ruiz JD, Sauter CS, et al. Dynamic EASIX scores closely predict nonrelapse mortality after allogeneic hematopoietic cell transplantation. Blood Adv. 2022;6:5898–907.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Jiang S, Penack O, Terzer T, Schult D, Majer-Lauterbach J, Radujkovic A, et al. Predicting sinusoidal obstruction syndrome after allogeneic stem cell transplantation with the EASIX biomarker panel. Haematologica. 2020;106:446–53.

  22. Pedraza A, Salas MQ, Rodríguez-Lobato LG, Escribano-Serrat S, Suárez-Lledo M, Martínez-Cebrian N, et al. Easix score correlates with endothelial dysfunction biomarkers and predicts risk of acute graft-versus-host disease after allogeneic transplantation. Transpl Cell Ther. 2024;30:187.e1-187.e12

  23. Gent DG, Dobson R. The 2022 European Society of Cardiology cardio-oncology guidelines in focus. Eur Cardiol Rev. 2023;18(Apr):e16.

    Article  Google Scholar 

  24. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth universal definition of myocardial infarction. J Am Coll Cardiol. 2018;72:2231–64.

    Article  PubMed  Google Scholar 

  25. Ahmed N. Myocardial ischemia. In: Pathophysiology of ischemia reperfusion injury and use of fingolimod in cardioprotection [Internet]. Elsevier; 2019. 41–56. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780128180235000029.

  26. Adler Y, Charron P. The 2015 ESC Guidelines on the diagnosis and management of pericardial diseases. Eur Heart J. 2015;36:2873–4.

    Article  PubMed  Google Scholar 

  27. Mou SS, McCrory MC. Inflammatory heart disease: Pericardial effusion and tamponade, pericarditis, and myocarditis. In: Critical Heart Disease in Infants and Children. Elsevier; 2018. p. 351–364.e5.

  28. Ranganathan P, Pramesh C, Buyse M. Common pitfalls in statistical analysis: the perils of multiple testing. Perspect Clin Res. 2016;7:106.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    Article  CAS  Google Scholar 

  30. Medina-leyte DJ, Zepeda-garc O, Dom M. Endothelial dysfunction, inflammation and coronary artery disease: potential biomarkers and promising therapeutical approaches and new pharmacological and non-pharmacological promising th The endothelium is formed by a single layer of EC located about 1. Int J Mol Sci. 2021;22:1–28.

    Article  Google Scholar 

  31. Morbidelli L, Donnini S, Ziche M. Targeting endothelial cell metabolism for cardio-protection from the toxicity of antitumor agents. Cardio-Oncol. 2016;2:1–12. https://doi.org/10.1186/s40959-016-0010-6.

    Article  Google Scholar 

  32. Halcox JPJ, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002;106:653–8.

    Article  PubMed  Google Scholar 

  33. Zhao F, Satyanarayana G, Zhang Z, Zhao J, Ma XL, Wang Y. Endothelial autophagy in coronary microvascular dysfunction and cardiovascular disease. Cells. 2022;11:1–19.

    Article  Google Scholar 

  34. Zeiser R, Blazar BR. Pathophysiology of chronic graft-versus-host disease and therapeutic targets. N Engl J Med. 2017;377:2565–79.

    Article  CAS  PubMed  Google Scholar 

  35. Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 2007;7:803–15.

    Article  CAS  PubMed  Google Scholar 

  36. Mir E, Palomo M, Rovira M, Pereira A, Escolar G, Penack O, et al. Endothelial damage is aggravated in acute GvHD and could predict its development. Bone Marrow Transpl. 2017;52:1317–25. https://doi.org/10.1038/bmt.2017.121.

    Article  CAS  Google Scholar 

  37. Byrne P, Cullinan J, Smith A, Smith SM. Statins for the primary prevention of cardiovascular disease: an overview of systematic reviews. BMJ Open. 2019;9:e023085.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kalam K, Marwick TH. Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: a systematic review and meta-analysis. Eur J Cancer. 2013;49:2900–9. https://doi.org/10.1016/j.ejca.2013.04.030.

    Article  CAS  PubMed  Google Scholar 

  39. Oesterle A, Laufs U, Liao JK. Pleiotropic effects of statins on the cardiovascular system. Circulation Res Lippincott Williams Wilkins. 2017;120:229–43.

    CAS  Google Scholar 

  40. Pabst C, Schreck N, Benner A, Hegenbart U, Schönland S, Radujkovic A, et al. Statin-based endothelial prophylaxis and outcome after allogeneic stem cell transplantation. Eur J Clin Invest. 2023;53:e13883.

    Article  PubMed  Google Scholar 

  41. Park KH, Park WJ. Endothelial dysfunction: Clinical implications in cardiovascular disease and therapeutic approaches. J Korean Med Sci. 2015;30:1213–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank our patients and the nursing and support staff in the Hematopoietic Cell Transplant Program and the Cardiology Department at Hospital Clinic de Barcelona.

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Contributions

MQS designed the study. CTR collected the data. MQS and CTR analyzed and interpreted the results and wrote the paper. EC, EC and MDR provided a valuable support into the interpretation of the results and statement of the conclusions. LGRL, AP, MSL, PC, JM, MTS, JC, ML, LR, JE, AUI, FFA, CM, EC, MDR and MR provided valuable input into the study and reviewed and approved the manuscript.

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Correspondence to María Queralt Salas.

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Tolosa-Ridao, C., Cascos, E., Rodríguez-Lobato, L.G. et al. EASIX and cardiac adverse events after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02270-x

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