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Cardiac Toxicity of High-Dose Cyclophosphamide in Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation

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Abstract

High-dose cyclophosphamide is a well-known mobilization regimen in patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation. Highly differing rates of cardiac complications associated with high-dose cyclophosphamide have been reported. To date, no systematic clinical study has investigated high-dose cyclophosphamide mobilization regimens in multiple myeloma patients and evaluated its cardiotoxicity. We administered high-dose cyclophosphamide (4 g/m2) to 23 consecutive multiple myeloma patients and followed the patients for 15 days by serially measuring the cardiotoxicity biomarkers troponin I (TnI), brain natriuretic peptide (BNP), and endothelin 1 (ET-1). Systolic and diastolic left ventricular function was assessed by complete echocardiography before and at 6 to 8 weeks after the therapy. Patients younger than 55 years showed significant differences between basal TnI levels and TnI concentrations determined at 15 days after high-dose cyclophosphamide treatment (P = .028). Significant differences between basal BNP concentrations and BNP levels measured at 8 hours after high-dose cyclophosphamide treatment were found in the entire group of patients as well as in 2 subgroups, patients younger than 55 years and those older than 55 years (P < .0001, P < .001, and P = .001, respectively). ET-1 results for the entire group of patients showed a significant difference between baseline ET-1 values and ET-1 values determined 8 hours after high-dose cyclophosphamide administration (P = .004). Echocardiographic measurements revealed a barely nonsignificant decrease in cardiac output after high-dose cyclophosphamide infusion compared with pretreatment values (P = .06), a result in accord with echocardiographically detected increases in mild functional mitral regurgitation (P = .025). TnI levels at 15 days after the completion of treatment correlated with left ventricular diastolic dysfunction, as indicated by the s/d index (r = 0.61; P = .04). In conclusion, the significant neurohumoral activation of heart failure occurring after high-dose cyclophosphamide treatment is manifested by an increase in BNP and ET-1 levels, yet without concomitant cardiomyocyte necrosis. BNP levels and to a lesser extent ET-1 levels are much more sensitive indicators of myocardial injury than functional tests, such as echocardiography, whereas diastolic functional parameters are more sensitive predictors of early cyclophosphamide-induced cardiotoxicity. Mild functional mitral regurgitation may develop in patients given high-dose cyclophosphamide therapy. cr 2007 The Japanese Society of Hematology

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References

  1. Attal M, Harousseau J-L, Stoppa A-M, et al, for The Intergroupe FranÇais du Myélome. A prospective, randomized trial of autolo-gous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91–97.

    Article  PubMed  CAS  Google Scholar 

  2. Child JA, Gareth JM, Davies FE, et al.High dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875–1883.

    Article  PubMed  CAS  Google Scholar 

  3. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997;89:789–793.

    PubMed  CAS  Google Scholar 

  4. Attal M, Harousseau J-L, Facon T, et al, for the InterGroupe Francophone du Myélome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003;349:2495–2502.

    Article  PubMed  CAS  Google Scholar 

  5. Kupari M, Volin L, Soukas A, Hekali P, Ruutu T. Cardiac involvement in bone marrow transplantation: serial changes in left ventricular size, mass and performance. J Intern Med. 1990;227:259–266.

    Article  PubMed  CAS  Google Scholar 

  6. Bearman SI, Appelbaum FR, Buckner CD, et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol. 1998;6:1562–1568.

    Article  Google Scholar 

  7. Auner HW, Tinchon C, Brezinschek RI, et al. Monitoring of cardiac function by serum cardiac troponin T levels, ventricular repolarisation indices, and echocardiography after conditioning with fractionated total body irradiation and high-dose cyclophos-phamide. Eur J Haematol. 2002;69:1–6.

    Article  PubMed  CAS  Google Scholar 

  8. Mori T, Yanagi N, Moruyama T, et al. Left ventricular diastolic dysfunction induced by cyclophosphamide in blood stem cell transplantation. Jpn Heart J. 2002;43:249–261.

    Article  PubMed  Google Scholar 

  9. Buja LM, Ferrans VJ, Graw RG Jr. Cardiac pathologic findings in patients treated with bone marrow transplantation. Human Pathol. 1976;7:17–45.

    Article  CAS  Google Scholar 

  10. Gottdiener JS, Appelbaum FR, Ferrans VJ, Deisseroth A, Ziegler J. Cardiotoxicity associated with high-dose cyclophosphamide therapy. Arch Intern Med. 1981;141:758–763.

    Article  PubMed  CAS  Google Scholar 

  11. Antman EM. Decision making with cardiac troponin tests. N Engl J Med. 2002;346:2079–2082.

    Article  PubMed  Google Scholar 

  12. Mark DB, Felker M. B-type natriuretic peptide: a biomarker for all seasons. N Engl J Med. 2004;350:718–720.

    Article  PubMed  CAS  Google Scholar 

  13. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004;350:655–663.

    Article  PubMed  CAS  Google Scholar 

  14. Nousianen T, Vanninen E, Jantunen E, et al. Natriuretic peptides during the development of doxorubicin-induced left ventricular diastolic dysfunction. J Intern Med. 2002;251:228–234.

    Article  Google Scholar 

  15. Seino Y, Ogawa A, Yamashita T, et al. Application of NT-proBNP and BNP measurements in cardiac care: a more discerning marker for the detection and evaluation of heart failure. Eur J Heart Fail. 2004;6:295–300.

    Article  PubMed  CAS  Google Scholar 

  16. Levin ER. Endothelins. N Engl J Med. 1995;333:356–361.

    Article  PubMed  CAS  Google Scholar 

  17. Nakamura S, Naruse M, Naruse K, Demura H, Uemura H. Immunocytochemical localization of endothelin in cultured bovine endothelial cells. Histochemistry. 1990;94:475–477.

    Article  PubMed  CAS  Google Scholar 

  18. Wei CM, Lerman A, Rodeheffer RJ, et al. Endothelin in human congestive heart failure. Circulation. 1994;89:1580–1586.

    Article  CAS  PubMed  Google Scholar 

  19. Giannuzzi P, Temporelli PL, Bossimi E, et al. Independent and incremental prognostic value of Doppler-derived mitral deceleration time of early filling in both symptomatic and asymptomatic patients with left ventricular dysfunction. J Am Coll Cardiol. 1996;28:383–390.

    Article  CAS  PubMed  Google Scholar 

  20. Benvenuto GM, Ometto R, Fontanelli A, et al. Chemotherapy- related cardiotoxicity: new diagnostic and preventive strategies. Ital Heart J. 2003;10:655–667.

    Google Scholar 

  21. Suzuki J, Yanagisawa A, Shigeyama T, et al. Early detection ofanthracycline-induced cardiotoxicity by radionuclide angiocardiography. Angiology. 1999;50:37–45.

    Article  PubMed  CAS  Google Scholar 

  22. Morandi P, Ruffini PA, Benvenuto GM, La Vecchia L, Mezzena G, Raimondi R. Serum cardiac troponin I levels and ECG/Echo monitoring in breast cancer patients undergoing high-dose (7 g/m2) cyclophosphamide. Bone Marrow Transplant. 2001;28:277–282.

    Article  PubMed  CAS  Google Scholar 

  23. Venge P, Johnston N, Lagerquist B, Wallentin L, Lindahl B, and the FRISC-II Study Group. Clinical and analytical performance of the Liaison cardiac troponin I assay in unstable coronary artery disease and the impact of age on the definition of reference limits: a FRISC-II Substudy. Clin Chem. 2003;49:880–886.

    Article  PubMed  CAS  Google Scholar 

  24. Sagnella GA. Measurement and significance of circulating natriuretic peptides in cardiovascular disease. Clin Sci (Lond). 1998;95:519–529.

    Article  CAS  Google Scholar 

  25. Okishima N, Hajiwara Y, Seito T, Yano M, Kido H. Specific sandwich-type enzyme immunoassays for smooth muscle constricting novel 31-amino acid endothelins. Biochem Biophys Res Commun. 1999;256:1–5.

    Article  PubMed  CAS  Google Scholar 

  26. Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am J Cardiol. 1976;37:7–11.

    Article  PubMed  CAS  Google Scholar 

  27. Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler echocardiographic determination of stroke volume and cardiac output: clinical validation of two new methods using the apical window. Circulation. 1984;70:425–431.

    Article  PubMed  CAS  Google Scholar 

  28. Appleton CP, Firstenberg MS, Garcia MJ, Thomas JD. The echo-Doppler evaluation of left ventricular diastolic function: a current prospective. Cardiol Clin. 2000;18:513–546.

    Article  PubMed  CAS  Google Scholar 

  29. Goldberg MA, Antin JH, Guinan EC, Rappeport JM. Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor. Blood. 1986;68:1114–1118.

    PubMed  CAS  Google Scholar 

  30. Sparano JA, Brown DL, Wolff AC. Predicting cancer therapy-induced cardiotoxicity: the role of troponins and other markers. Drug Saf. 2002;25:301–311.

    Article  PubMed  CAS  Google Scholar 

  31. Morjana NA. Degradation of human cardiac troponin I after myocardial infarction. Biotechnol Appl Biochem. 1998;28:105–111.

    PubMed  CAS  Google Scholar 

  32. Klootwijk P, Hamm C. Acute coronary syndromes: diagnosis. Lancet. 1999;353(suppl 2):SII10-SII15.

    Article  Google Scholar 

  33. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109:2749–2754.

    Article  PubMed  CAS  Google Scholar 

  34. Valli N, Gobinet A, Bordenave L. Review of 10 years of the clinical use of brain natriuretic peptide in cardiology. J Lab Clin Med. 1999;134:437–444.

    Article  PubMed  CAS  Google Scholar 

  35. Cowburn PJ, Cleland JGF. Endothelin antagonists for chronic heart failure: do they have a role? Eur Heart J. 2001;22:1772–1784.

    Article  PubMed  CAS  Google Scholar 

  36. Luescher TF, Barton M. Endothelins and endothelin receptors antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation. 2000;102:2434–2440.

    Article  Google Scholar 

  37. Benvenuto GM, La Vecchia L, Morandi P, Ruffini PA, Mezzena G. Assessment of cardiotoxicity of high dose cyclophosphamide with electrocardiographic, echocardiographic, and troponin I monitoring in patients with breast tumors [in Italian]. Ital Heart J Suppl. 2000;1:1457–1463.

    PubMed  CAS  Google Scholar 

  38. Lahtinen R, Kuikka J, Nousiainen T, Uusitupa M, Lansimies E. Cardiotoxicity of epirubicin and doxorubicin: a double blind randomised study. Eur J Haematol. 1991;46:301–305.

    Article  PubMed  CAS  Google Scholar 

  39. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000;22:263–302.

    Article  PubMed  CAS  Google Scholar 

  40. Ryberg M, Nielsen D, Skovsgaard T, Hansen J, Jensen BV. Epiru- bicin cardiotoxicity: an analysis of 469 patients with metastatic breast cancer. J Clin Oncol. 1998;16:3502–3508.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology, University Clinical Center Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia

    Samo Zver & Peter Cernelc

  2. Institute of Oncology, Ljubljana, Slovenia

    Vesna Zadnik

  3. Department of Cardiology, University Clinical Center Ljubljana, Ljubljana, Slovenia

    Matjaz Bunc & Mirta Kozelj

  4. Institute of Physiology, Ljubljana, Slovenia

    Polona Rogel

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  1. Samo Zver
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  2. Vesna Zadnik
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  3. Matjaz Bunc
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  4. Polona Rogel
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Correspondence to Samo Zver.

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Zver, S., Zadnik, V., Bunc, M. et al. Cardiac Toxicity of High-Dose Cyclophosphamide in Patients with Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation. Int J Hematol 85, 408–414 (2007). https://doi.org/10.1532/IJH97.E0620

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  • DOI: https://doi.org/10.1532/IJH97.E0620

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